The public health significance of HIV-1 subtypes : AIDS (original) (raw)
Introduction
Since the first descriptions of HIV/AIDS, HIV-1 has emerged as the most significant pathogen worldwide, with approaching 60 million infections to the end of 2000. Over 18 million deaths from AIDS have occurred, and HIV/AIDS is now classed among the top five causes of global mortality [1]. As with other infectious pathogens that exhibit a high degree of genetic variation, such as influenza, the extensive genetic variability of HIV-1 poses significant challenges for disease control and epidemiological surveillance [2].
The genetic heterogeneity of HIV-1 isolates is one of the major characteristics of the virus and the epidemic. This diversity, generated by the processes of mutation and recombination [3], has led to the development of a subtype nomenclature for the classification of isolates [4]. The major (M) group of HIV-1, responsible for the majority of infections in the epidemic, contains several recognized non-recombinant subtypes and sub-subtypes, and at least 10 circulating recombinant forms (CRFs) [4]. These subtypes show uneven regional distribution, and past attempts have been made to use them to describe the global molecular epidemiology of HIV-1 [5,6]. In this context, undertaking systematic sampling and monitoring of populations is important to determine the value of these studies. We review here the public health and clinical significance of HIV-1 genetic variability, and the methods and rationale for public health surveillance of subtypes.
Diversity of subtypes
Epidemiological and genetic evidence suggest that the two main types of HIV (HIV-1 and HIV-2) are zoonoses (human infections originating from animals), acquired via several independent transmission events from the chimpanzee (Pan troglodytes) and sooty mangabey (Cercocebus atys), respectively [7,8]. While HIV-1 appears to have been present in humans since around the 1930s [9], modern sociodemographic changes together with chance introductions into vulnerable populations have created optimal conditions for its rapid spread [10].
HIV-1 genetic variability is generated by the lack of proof-reading ability of the reverse transcriptase (RT) [11], the rapid turnover of HIV-1 _in vivo_[12], host selective immune pressures [13], and recombination events during replication [3]. This variability has allowed HIV-1 to be classified into the M group of sequences as well as outlier (O), and non-M, non-O (N) groups [14-16]. Recently, guidelines for the definition of subtypes and CRFs have been proposed that take into account the genetic diversity and evolution of the epidemic [17]. A new subtype or CRF may be defined by the existence of at least three fully characterized genomes, obtained from epidemiologically unlinked individuals. Phylogenetic analyses should group these sequences approximately equidistantly from all other subtypes. At the time of writing, group M consists of nine 'full-length' subtypes, designated A-D, F-H, J and K [4,14]. Further analysis of complete genome sequences from viruses initially described as belonging to subtype E (now classified CRF_01AE) and subtype I has revealed these viruses to be recombinant strains, and not distinct subtypes as initially proposed [18,19]. More detailed phylogenetic analysis has also led to the re-classification of some subtype groupings. For example, subtype F was originally classified into three sub-subtypes (F1, F2 and F3) based on gag and env phylogenetic comparisons [20]. However, subsequent full-length genome analysis has led to the re-classification of sub-subtype F3 as subtype K [21]. Groups O and N currently represent only a small number of characterized strains, although env and gag sequence analysis of group O isolates has demonstrated that they belong to four distinct phylogenetic clusters of similar diversity to the group M subtypes [22].
Inter-subtype and intra-subtype recombination may occur within dual-infected individuals to generate novel recombinant strains, even between highly diverse viruses such as those belonging to different groups [23,24]. There are currently 10 CRFs responsible for sub-epidemics worldwide (http://hiv-web.lanl.gov/CRFs/CRFs.html). In 1995, it was estimated that recombinant viruses accounted for up to 15% of global infections [25], and we have shown that up to 20% of heterosexual infections in the United Kingdom may be attributable to recombinant viral strains [26]. Additional CRFs and mosaics continue to be characterized, such as the recent discovery of a C/D CRF (CRF10_CD) found among perinatally infected infants in Tanzania [27], and an A/J recombinant infecting pregnant women in Cameroon [28]. Given the continued global spread of HIV-1, it is likely that recombinants will play an increasing role in the generation of HIV-1 diversity [6,23].
Genetic sequencing is the definitive method for subtyping [29]. Despite advances in long-polymerase chain reaction (PCR) technology [30], practical limitations have historically led to a subtype being assigned based on single genomic regions, most commonly env, gag, or _pol_[31]. There are several available techniques for subtype assignation, and deciding which is appropriate will often depend on the objectives of the surveillance strategy (Table 1).
HIV-1 subtype classification techniques.
Serological assays have proved useful for screening populations of limited subtype diversity, especially where one subtype predominates [32,33]. However, such assays are not applicable where multiple subtypes co-circulate as they can lead to subtype misclassification [34-36]. In such circumstances, PCR-based subtyping approaches, most commonly the heteroduplex mobility assay, have been widely applied [37-41]. In addition, by obtaining partial sequences from different gene regions, most commonly gag and env, recombinant prevalences can be estimated and potentially interesting genomes identified [26,39-41].
Epidemiology and global distribution of subtypes
There have been numerous descriptions of the HIV-1 genetic diversity within populations [5,6,42]. However, most studies have derived estimates using unsystematic, opportunistic sampling frames with relatively small numbers of specimens [43-46]. As such, current understanding of the distribution of HIV-1 subtypes may inadequately represent the worldwide diversity of the virus [6]. In particular, reporting bias can distort the global description through an over-representation of unusual subtypes and limited surveillance of populations with a more homogeneous subtype profile. Equally, the complex distribution of HIV across different transmission modes and sexual groups, coupled with the fact that transmission rates may differ within groups even within a single country or locality, complicates the surveillance of HIV infection.
The greatest genetic diversity is observed among HIV-1 strains from Africa [47] where transmission occurs primarily via heterosexual, iatrogenic (blood transfusion) and mother-to-child routes [48]. Distinct geographic subtype patterns are seen within Africa, with subtypes A and D most prevalent in Eastern Africa [49,50], subtype A in Western Africa [51,52], and subtype C in South Africa [53], although the epidemic in the latter region appears to be increasing in diversity, with subtypes A, B, D and recombinant forms now prevalent [39,54](Fig. 1). Phylogenetic analysis of the gag gene from isolates obtained from Senegal, Cameroon, Gabon, and Djibouti has suggested that between 60 and 84% of subtype A viruses circulating in Africa may in fact be similar to CRF_02AG [55], and not 'pure' subtype A viruses as previously described.
Geographical distribution of HIV-1 major (M) group subtypes. For clarity, only the most prevalent subtypes are shown. CRF, circulating recombinant form.
In Asia, an epidemic spread of HIV-1 is occurring with fewer co-circulating subtypes than in Africa. The epidemics in India and China are dominated by subtype C, the most prevalent subtype worldwide, which is thought to account for approximately 50% of infections [56,57]. Subtypes A, B, and recombinant strains have also been identified [56]. In contrast, two strains, subtypes B and CRF_01AE, co-circulate within the injecting drug user (IDU) population in Thailand [58]. These two subtypes have also been shown to co-circulate among Thai fishermen [59].
The original spread of HIV-1 in North America, Western Europe, and Australia was of subtype B strains among the MSM and IDU populations [14,60]. Heterosexual spread is increasing in these regions with non-B subtypes and recombinant strains observed, mostly among individuals with epidemiological links to areas where multiple subtypes co-circulate [26,43,44,61-65]. Most South American viruses appear to be subtype B, although there also the epidemic is increasing in diversity with subtypes A, C, and F, and recombinant viruses being reported [66,67].
The continued global expansion of subtypes has created the potential for recombinant virus generation and transmission, and the number of reports of recombinant infections is increasing. In part, this is due to improvements in surveillance methodology, and recombinant strains have been detected in many countries [26,31,55,67-71]. Intersubtype recombinant forms now appear to be circulating among IDU in China (B/C) [56], North Vietnam and Southeast Asia (CRF_01AE) [72], Argentina (B/F) [73], and Russia (A/B) [70].
Public health implications of genetic diversity
The genetic variability of infectious pathogens, and any consequent phenotypic variation, poses a significant challenge to disease control and surveillance [74,75]. Differences between subtypes in their viral properties can be argued from several lines of evidence. HIV-1 and HIV-2 show approximately ∼50% similarity at the nucleotide level [14] and differ in their pathogenicity and transmissibility [76,77]. While both are zoonoses [7,8], neither virus appears harmful to their natural primate hosts [78], and yet they are pathogenic when transferred to foreign primate host species [79]. In addition, the extraordinarily rapid rate of HIV-1 evolution in humans, estimated at around 0.0024 substitutions per base pair per year [9], coupled with the recombination events that may introduce large-scale genetic changes, creates the conditions for increased viral evolution. Interventions such as antiviral drug therapies may further accelerate genetic change through the preferential selection of resistant strains [80]. As we will describe, such variability may impact on vaccine modelling and diagnostic testing, the generation of antiviral resistance, and aid the surveillance of transmission patterns within the epidemic.
Selection of candidate vaccines
The development of a protective vaccine remains the greatest challenge in the global battle against HIV-1. It has been hindered by the lack of a suitable animal model, the limited understanding of the markers of protective immunity, and the intracellular mode of transmission and persistent nature of HIV infection in the immune system [81]. Several approaches have been applied to the development of vaccines with varying degrees of success, including epitope vaccines [82,83], live vector constructs containing various combinations of env, gag, pol, and _nef_[84,85], DNA vaccine constructs [86,87], live attenuated _nef_-deletion vaccines [88], and whole-killed viral constructs [89].
The genetic variability of HIV-1 complicates vaccine development [90]. The ability of HIV-1 to mutate rapidly during the course of infection can result in the generation of escape mutants that evade host immune recognition [91]. The generation of a quasi-species of genome sequences over the duration of infection [92], coupled with the extent of diversity of the genome, raises the probability that an immunogen specific to a single viral subtype may not elicit an immune response that targets all viral strains. Despite this, approaches that utilize well-conserved viral proteins such as the regulatory proteins Tat and Rev, or accessory proteins such as Nef, Vif, Vpr and Vpu, may prove less susceptible to mutations than approaches that utilize structural proteins such as Env. For example, the HIV-1 regulatory protein Tat has been shown to possess limited antigenic polymorphism across geographically diverse strains representing subtypes A, B, C, D, F, and G [93], and to elicit both a humoral and cellular specific immune response in animal models [86,94].
The majority of candidate vaccines currently undergoing trials have been developed using subtype B viral strains (most commonly HXB2 or MN), representing the predominant type in North America and Europe. Their ability to elicit a cross-subtype response is not yet fully understood. Some studies have suggested neutralizing antibodies to be subtype specific [95,96], while others have indicated that cross-clade cytotoxic T-lymphocyte responses may occur [97,98]. Trials of a subunit vaccine containing gp120 env subunits from subtypes B (MN) and CRF_01AE (CM244) among IDU in Thailand have suggested dual-antibody responses may be generated [99]. However, the extent to which epitopes are conserved across subtypes remains unclear. Whatever vaccine strategy is adopted, information on local subtype prevalence, incidence, and genetic diversity within the population will prove crucial, as will close monitoring for vaccine failures.
Impact on HIV testing
It is essential that commercially available assays are capable of diagnosing infection in all HIV-1-positive individuals, including those infected with less prevalent, more diverse subtypes. If this is not the case, accurate patient diagnosis, serosurveillance, and clinical assessment are all threatened. Equally, reports that some viral subtypes can 'escape' HIV testing may damage public confidence in health services or even the belief that HIV is pathogenic.
The genetic variability of HIV-1 has been shown to affect the accuracy and sensitivity of diagnostic assays [100-113]. The principal method of HIV diagnosis is the detection of HIV antibodies, but the antigenic epitopes used in such tests may not detect more diverse viral strains. Early diagnostic assays using synthetic peptides or recombinant antigens failed to identify group O and HIV-2 infections, a feature overcome by the incorporation of antigens appropriate for these variants into later generations of tests [114]. A recent study of six United States Food and Drug Administration licensed HIV-1 immunoassays suggested that all were capable of detecting infections with subtypes A-G, J and group O [102]. Cross-reactivity has also been observed between highly divergent group N sera and group M test antigens [15,115].
The detection of newly acquired HIV-1 infections is of paramount importance in the control and management of the epidemic. Such estimates allow primary prevention strategies, and aid in the treatment of infected individuals. Recent HIV-1 seroconversions have been found with the use of serological tests based on sensitive versus less-sensitive (detuned) antibody reactivities: early antibodies are present at lower levels and are not detected in the less-sensitive detuned assays [112,113,116]. However, subtype-specific differences in this type of assay have been described, with subtypes B and E giving different window periods of infection (155 and 270 days, respectively) [113]. Also, the 3A11-LS (Abbott, Abbott Park, Illinois, USA) assay has been shown to misdiagnose late-stage infections in a small proportion of subtype E infections [113], and to misclassify infections from some patients with late-stage AIDS [112]. At present, such detuned assays are based on modified commercial assays that utilize a subtype B derived antigen. Therefore, for them to be confidently applied in settings where non-B subtypes are common, appropriate cutoffs and window periods for all HIV-1 subtypes must be determined.
In some circumstances, such as for the diagnosis of infection among infants born to HIV-positive mothers or for early HIV diagnosis, it is more appropriate to detect viral antigens directly rather than anti-HIV antibodies [117]. Recently, a comparison of four commercially available p24 antigen assays has shown the sensitivity for detection of diverse samples to vary between assays [118]. The most recent diagnostic assays (fourth generation) combine the detection of anti-HIV antibodies and p24 antigen within a single test. These have been shown to narrow the window period of infection (the time between infection and reactivity in a screening test) by up to 9 days [119,120]. Such assays have therefore been recommended as initial screening tests for early infections. The use of PCR for proviral DNA detection appears more sensitive than p24 antigen assays, but here too diverse subtypes have been shown to give false-negative results [106,107,121]. In summary, therefore, commercial diagnostic tests for both HIV antibodies, HIV-1 proteins such as p24, and for HIV-1 DNA and RNA by PCR may all have reduced sensitivity for certain variants of HIV-1.
Assays that quantify the viral load within an individual play a key role in monitoring disease progression and aiding prognosis. High viral load during the acute phase and before seroconversion has been linked with more rapid disease progression [122], decreased numbers of peripheral CD4 T cells [123], increased sexual and vertical transmission [124,125], and failure of antiviral therapy [126]. Currently, four types of assay are available for viral load quantification: Amplicor HIV-1 Monitor v.1.5 (Monitor; Roche Diagnostics, Branchburg, New Jersey, USA) [127], nucleic acid sequence-based amplification (NASBA; Organon Teknika, Boxtel, The Netherlands) [128,129], HIV-1 Quantiplex branched DNA (bDNA; Chiron Diagnostics, Emeryville, California, USA) [130,131], and the LCx HIV RNA Quantitative assay (LCx; Abbott) [132]. The methodology employed for viral load quantification differs between these assays. Both the Monitor and NASBA assays use amplification of a region of the gag gene from viral RNA, with the Monitor assay generating and then amplifying DNA whereas NASBA amplifies multiple copies of viral RNA. Both the bDNA and LCx assays target the pol gene, with the bDNA assay utilizing sequential hybridization of multiple probes to target sequences and the LCx assay employing a competitive RT-PCR approach.
The ability of these assays to reliably quantify viral load from non-B subtype infections has been examined in several studies [100,104,105,109,132-135]. Subtype-associated differences in sensitivity, particularly for subtypes A and G, have been described [100,104,133]. For example, a study comparing the quantification of RNA from samples of subtypes A-H showed a failure of detection of RNA in some samples of subtype A and G with early versions of the Monitor and NASBA assays [133]. Current versions of the LCx, bDNA, and Monitor assays have been shown to reliably quantify HIV-1 RNA from subtype A-G infections [109].
The use of PCR may lead to errors in viral load quantification due to mismatches between the primer and the template [109,110]. Primer mismatches have been linked to the failure to quantify viral load from group O infections by the Monitor assay, infections that were detected by the LCx assay [109]. Such problems may be reduced, however, by the continual updating of primers/probes and assay conditions that take into account the genetic diversity of HIV-1. For example, the addition of new primer sets to the original Monitor assay was shown to increase its ability to reliably quantify subtypes A and E [105]. Diagnostic assays that utilize primers located in the conserved pol gene, such as the LCx assay, have also been shown to amplify examples of the highly divergent group N viruses [136]. In areas where subtype variability is greatest, therefore, an assay that targets a highly conserved target region, such as pol, may provide the most reliable estimates of viral load. Alternatively, a non-PCR approach such as the bDNA assay may also provide accurate results [105].
There is a need for well-characterized viral genome sequences of different subtypes to accurately compare the performance of various tests. A quality control panel containing HIV-1 isolates initially classified as subtypes A-G on the basis of phylogenetic analysis of their gag and/or env genes is available for this purpose [110]. However, further analysis of the gag, pol, and env regions from this panel has shown it to contain four intersubtype recombinants and two group O viruses, highlighting the need for complete genome characterization of putative reference strains [109]. The increasing genetic diversity of HIV-1 means that the evaluation and modification of nucleic-acid based diagnostic viral load and detection assays needs to be an ongoing process to ensure reproducible quantification for all HIV-1 strains.
Genetic markers of antiviral resistance
The emergence and transmission of HIV-1 resistance to antivirals in areas where those therapies are commonly used poses a serious challenge to individual patient management [137]. Detecting the phenotypic expression of resistance by growth of virus is difficult, and therefore genetic markers associated with resistance are monitored by sequencing. A review of the genetic basis of antiviral resistance is beyond the scope of this article and is available elsewhere [80]. It is reasonable to expect subtype-associated differences in antiviral resistance given that diverse viral forms such as HIV-1 group O have been shown to possess inherent resistance to non-nucleoside reverse transcriptase inhibitors [138]. The high level of genetic diversity of HIV-1, coupled with the fast turnover of virions, has been shown to lead to the rapid generation of drug-resistant strains [139].
The introduction of sequence-based assays as an aid to the clinical management of infection, as well as studies of antiviral resistance in treatment-naïve populations of heterogeneous subtype, has allowed a more complete picture of subtype-associated mutation patterns to emerge. Naturally occurring drug resistance mutations have been demonstrated among drug-naïve individuals infected with subtypes F and G [140,141], and mutations associated with resistance to protease inhibitors (PRI) have been shown in PRI-naïve individuals to be more prevalent among non-B subtypes than among subtype B strains [142]. Furthermore, individuals infected with subtypes A-D and CRF_01AE may possess naturally occurring mutations at sites that contribute to PRI resistance in subtype B viruses [143]. However, contradictory evidence is provided by several studies that have demonstrated no difference in the key resistance mutation profiles among individuals infected with a range of subtypes and recombinant virus [26,144]. Therefore, further research is required to determine what, if any, role the subtype may play in the development of primary antiviral resistance.
Subtype-associated differences may exist among the secondary (minor) drug resistance mutations. The M36I protease resistance mutation is present in subtype C viruses from untreated individuals, both in the United Kingdom and elsewhere [26,145,146]. Secondary mutations contributing to both protease (M36I and M46L) and RT (A98S and T200A) inhibitor resistance have also been found to be more common among non-B subtypes compared with subtype B viruses [144]. A 6-year study of drug resistance in primary HIV-1 infections in the United Kingdom has shown that, among persons infected with a subtype B virus, the risk of being infected with a drug-resistant virus has increased with time [137]. Monitoring the transmission of drug-resistant variants may therefore become necessary if the treatment of newly infected individuals is not to be compromised.
Molecular markers of transmission patterns
The characterization of circulating viral strains can perform an important role in the tracking of the epidemic. For example, the genetic variability of HIV-1 can be used to study transmission patterns, both to indicate individual transmission events [147-149] and to monitor the more general spread of the epidemic. Recent individual transmission events can be detected with great precision, although it is often difficult to determine the direction of infection. In one recent Scottish case, research data from genetic typing led to the criminal prosecution of a person who infected his partner when seemingly aware of his HIV-positive status. Epidemiological studies incorporating subtype characterization has allowed detection of the introduction of distinct HIV-1 subtypes into China, Thailand, the Philippines and several African countries [56,150-152]. In some instances, subtype may be associated with a particular route of transmission, such as in Thailand where subtypes B (in MSM and IDU) and CRF_01AE (in heterosexuals) were independently introduced over a similar time period, although these subtype patterns are now less distinct [58,150,153]. Phylogenetic evidence has also dated the introduction of the founder subtype CRF_01AE virus into the heterosexual Thai population to around 1986-1987 [9].
Biological variation: transmissibility
The possibility that HIV subtype may influence viral transmissibility and pathogenicity has been suggested [42,154,155]. Many other factors influence HIV-1 transmission including co-infection with other sexually transmitted diseases, host-immune and protective factors (as diverse as HIV co-receptor mutations and male circumcision) and the risk behaviours of the individual [155]. These variables confound attempts to determine the effect of subtype on viral transmissibility. For example, the co-existence of the two epidemics in Thailand and some growth properties of subtype CRF_01AE in Langerhans cells [156] led to the erroneous hypothesis of a greater transmissibility of subtype CRF_01AE viruses. However, the laboratory findings could not be substantiated [157,158] and the epidemiological evidence supports founder effects for the historical presence of CRF_01AE in different populations [159,160]. There is now crossover between these two subtypes and populations.
Studies of per-sex-act transmission probabilities in populations where HIV-1 subtype B predominates have suggested lower transmission rates than those where non-B subtypes are most prevalent [161,162]. Recently, a study in Tanzania suggested maternal subtype may play a role in vertical transmission, with subtypes A, C, and recombinant viruses being more likely to be perinatally transmitted than subtype D, possibly due to the use of the co-receptor CCR5 [163]. A consistent subtype-associated difference in transmissibility has yet to be proven, however, with similar rates of both sexual and vertical transmission, irrespective of subtype, having been observed [164,165]. Indeed, the co-existence of many HIV-1 subtypes rather than just one or a few would suggest that subtype alone is unlikely to be the main factor in viral transmissibility. In conclusion, this suggests that any differences are more likely to be due to factors other than viral subtype, such as higher prevalences of other sexually transmitted infections where non-B subtypes predominate [166]. The lack of conclusive evidence for an association between subtype and transmission does not preclude the existence of such an effect, but implies that recognizing it will require studies utilizing epidemiological, molecular, immunological and statistical methods in those areas where multiple subtypes co-circulate.
Biological variation: pathogenicity
The rate of disease progression among HIV-1-infected individuals varies widely [155,167,168]. As well as antiretroviral treatment, progression is influenced by host factors including chemokine co-receptor and human leukocyte antigen genotype [13,169], the route of transmission and age at time of infection [170], the presence of another sexually transmitted disease [171], ethnicity and individual socio-economic conditions [172], and viral characteristics [173].
The influence of subtype on viral pathogenicity has been investigated in several studies. It has been suggested that the chemokine co-receptor may differ between subtypes with, for example, the X4 (CXCR4) phenotype (previously called rapid/high or syncytium inducing) being under-represented among subtype C isolates [174-176]. While the X4 phenotype has been associated with disease progression among individuals infected with subtype B, there is no evidence that subtype C viruses are less pathogenic than other subtypes. A link has been suggested between the presence of an additional NF-κB site among subtype C viruses and enhanced viral transcription and replication [175,176]. However, sequence analysis of subtype C isolates from Zambia, India, Tanzania, South Africa, Brazil, and China has revealed that this extra site is present in only a small number of subtype C viruses [177]. This finding emphasizes the need to analyse large numbers of sequences before drawing conclusions about differences in subtype-specific biological properties.
Studies of the relationship between HIV-1 subtype and disease progression have produced contradictory results. One study, comparing Swedish patients infected with subtype B strains and Africans resident in Sweden infected predominantly with non-B subtype virus, found no difference in the rate of CD4 cell loss or disease progression over a 2-year period [178]. Similarly, two further studies of disease progression, one comparing subtype B-infected native Israelis and subtype C-infected Ethiopian immigrants in Israel [179] and another comparing people infected with either subtype B or CRF_01AE in Thailand [180], have found no differences in rates of progression. However, a cohort study of female sex workers in Senegal indicated that individuals infected with non-A subtypes progressed faster to disease than those infected with subtype A [181].
Several studies have indicated a more rapid rate of disease progression among people infected in Africa compared with those infected in Western Europe and the United States [167,181,182]. However, a lack of association between host ethnicity (taken as a marker for viral subtype) and disease progression has been shown in several studies [171,172,178]. It is therefore unclear to what extent such differences may be explained by environmental factors such as the quality of medical services, access to antiretroviral regimens, and the prevalence of concomitant infections, as opposed to viral and/or host factors [155].
Epidemiological surveillance strategies
The impact of the genetic diversity of HIV-1 on public health measures (summarized in Table 2) necessitates surveillance strategies that systematically sample and characterize representative strains from populations at varying risks of infection. However, to date, most available subtype data has been derived from studies that employ unsystematic, opportunistic sampling frames (Table 3).
Role of systematic surveillance of HIV-1 subtypes.
Sources of specimens for HIV-1 subtype surveillance.
The surveillance strategy chosen for monitoring HIV-1 diversity will depend on the particular objectives of the programme (Table 3). Prospective cohort studies have been applied in several countries; however, these are costly and often not entirely representative of persons at highest risk of infection [59,151]. Therefore, a number of countries have begun to sample blood collections for subtyping of all, or a sample of, newly diagnosed individuals (C. Archibald, R. Janssen, personal communication, 2000). This strategy may not be applicable in resource-poor settings where the majority of new infections are occurring, however, as it may miss trends in undiagnosed infections.
The implementation of unlinked, anonymous surveillance of population groups at varying risks of infection has been shown to produce minimally biased estimates of subtype prevalence (Table 3)[183-185]. By these means, for example, it is known in the United Kingdom that approximately 25% of HIV-1-seropositive individuals are infected with a non-B subtype [185]. In addition, up to 20% of the infections in heterosexuals in the United Kingdom are with a recombinant non-B subtype virus [26]. While such studies have proved useful in estimating incidence and in detecting the presence of new subtypes and recombinants, they can be costly and logistically difficult to undertake. Obtaining samples that are representative of populations is desirable but often difficult to achieve, and a pragmatic approach has been to utilize consistent sampling frames so as to detect important changes over time [46,59,186].
Conclusion
The genetic variability of HIV-1 determines the way in which the epidemic is monitored, and is also a significant factor in the management of individual infections. HIV-1 diversity is likely to play a role in the generation of secondary anti-viral resistance, although to date there is less convincing evidence of significant differences in transmissibility or pathogenicity of the subtypes. Numerous epidemiological studies have provided a picture of the global subtype distribution and these show increasing evidence of the importance of HIV-1 recombinants. Knowledge of the subtype distribution is of importance in the development of vaccines and is essential to ensure that tests used to diagnose and guide clinical and therapeutic monitoring of HIV infections remain fully sensitive and specific. Viral sequencing has proved useful in determining epidemiological linkage between infected individuals, and subtype surveillance serves as a guide to transmission patterns at broader levels. From this, a comprehensive picture of the worldwide pandemic can be obtained by combining epidemiological, molecular, and demographic data.
Epidemiological surveillance protocols therefore need to incorporate molecular techniques that are appropriate to the subtype prevalence in the population of interest, and which also retain the ability to detect the introduction of novel subtypes. The reliance of the majority of current algorithms on subtyping a single genomic region diminishes their ability to detect unusual and new recombinant strains that may be biologically important. Sequencing multiple loci may also be epidemiologically informative for detecting transmission patterns. The development of algorithms that utilize several regions of the genome, and where necessary incorporate sequencing, will play an important role in future surveillance of the epidemic.
To obtain a comprehensive picture of the diversity of HIV within a population, attempts should be made to prospectively sample a representative cross-section of individuals, incorporating groups at varying risk of infection, as well as cases with diverse modes of transmission. It is important that sampling strategies include and identify recent infections so as to provide a measure of current transmission patterns. However, recent seroconvertors are not always easy to detect, particularly in those groups not recognized to be at high risk of HIV infection, where diagnosis may not occur until late in the course of infection. The use of serological tests for HIV incidence, the so-called detuned antibody assays, may make the detection of recent infections easier. The collection of epidemiological and demographic data at source for each specimen is also necessary to enhance the future understanding of transmission patterns based on the subtypes of HIV-1.
Acknowledgements
The authors thank Philip Mortimer, John Parry, and Gary Murphy for their critical appraisals of this review. K.L.B. is supported by the Department of Health, and I.D.T. is supported by a University of Cambridge, Department of Clinical Medicine and Clinical Veterinary Medicine Simms Fund Scholarship. They also thank the many contributors to the Unlinked Anonymous HIV Prevalence Monitoring Programme throughout England and Wales, and especially the HIV Surveillance Group, Sexually Transmitted and Blood Borne Virus Laboratory, CPHL.
References
1. World Health Organization. The World Health Report 1999.〈http://www.who.int/whr/1999/en/report.htm〉.
2. Chin J. Public health surveillance of AIDS and HIV infections.Bull WHO 1990, **68:**529-536.
3. Temin HM. Retrovirus variation and reverse transcription: abnormal strand transfers result in retrovirus genetic variation.Proc Natl Acad Sci USA 1993, **90:**6900-6903.
4. Robertson DL, Anderson JP, Bradac JA, et al. A Reference Guide to HIV-1 Classification; 2000. 〈http://hiv-web.lanl.gov/immunology/articles/nomenclature/Nomen.html〉.
5. Peeters M, Sharp PM. Genetic diversity of HIV-1: the moving target.AIDS 2000, **14:**S129-S140.
6. McCutchan FE. Understanding the genetic diversity of HIV-1.AIDS 2000, **14:**S31-S44.
7. Hirsch VM, Olmsted RA, Murphey-Corb M, Purcell RH, Johnson PR. An African primate lentivirus (SIVsm) closely related to HIV-2.Nature 1989, **339:**389-392.
8. Gao F, Bailes E, Robertson DL, et al.Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes.Nature 1999, **397:**436-441.
9. Korber B, Muldoon M, Theiler J, et al.Timing the ancestor of the HIV-1 pandemic strains.Science 2000, **288:**1789-1796.
10. Zhu T, Korber BT, Nahmias AJ, Hooper E, Sharp PM, Ho DD. An African HIV-1 sequence from 1959 and implications for the origin of the epidemic.Nature 1998, **391:**594-597.
11. Roberts JD, Bebenek K, Kunkel TA. The accuracy of reverse transcriptase from HIV-1.Science 1988, **242:**1171-1173.
12. Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection.Nature 1995, **373:**123-126.
13. Michael NL. Host genetic influences on HIV-1 pathogenesis.Curr Opin Immunol 1999, **11:**466-474.
14. Myers G, Korber B, Wain-Hobson S, Smith RF, Pavlaks GN. Human Retroviruses and AIDS. Los Alamos, NM: Los Alamos National Laboratory; 1999.
15. Simon F, Mauclere P, Roques P, et al.Identification of a new human immunodeficiency virus type 1 distinct from group M and group O.Nat Med 1998, **4:**1032-1037.
16. Gurtler L, Hauser P, Eberle J, et al.A new subtype of human immunodeficiency virus type 1 (MVP-5180) from Cameroon.J Virol 1994, **68:**1581-1585.
17. Robertson DL, Anderson JP, Bradac JA, et al.HIV-1 nomenclature proposal.Science 2000, **288:**55-57.
18. Paraskevis D, Magiorkinis M, Vandamme AM, Kostrikis LG, Hatzakis A. Re-analysis of human immunodeficiency virus type 1 isolates from Cyprus and Greece, initially designated 'subtype I', reveals a unique complex A/G/H/K/? mosaic pattern.J Gen Virol 2001, **82:**575-580.
19. Carr JK, Salminen MO, Koch C, et al.Full-length sequence and mosaic structure of a human immunodeficiency virus type 1 isolate from Thailand.J Virol 1996, **70:**5935-5943.
20. Triques K, Bourgeois A, Saragosti S, et al.High diversity of HIV-1 subtype F strains in Central Africa.Virology 1999, **259:**99-109.
21. Triques K, Bourgeois A, Vidal N, et al.Near-full-length genome sequencing of divergent African HIV type 1 subtype F viruses leads to the identification of a new HIV type 1 subtype designated K.AIDS Res Hum Retroviruses 2000, **16:**139-151.
22. Janssens W, Heyndrickx L, Van der Auwera G, et al.Interpatient genetic variability of HIV-1 group O.AIDS 1999, **13:**41-48.
23. Robertson DL, Sharp PM, McCutchan FE, Hahn BH. Recombination in HIV-1.Nature 1995, **374:**124-126.
24. Peeters M, Liegeois F, Torimiro N, et al.Characterization of a highly replicative intergroup M/O human immunodeficiency virus type 1 recombinant isolated from a Cameroonian patient.J Virol 1999, **73:**7368-7375.
25. Robertson DL, Hahn BH, Sharp PM. Recombination in AIDS viruses.J Mol Evol 1995, **40:**249-259.
26. Barlow KL, Tatt ID, Cane PA, Pillay D, Clewley JP. Recombinant strains of HIV type 1 in the United Kingdom.AIDS Res Hum Retroviruses 2001, **17:**467-474.
27. Koulinska IN, Ndung'u T, Mwakagile D, et al.A new human immunodeficiency virus type 1 circulating recombinant form from Tanzania.AIDS Res Hum Retroviruses 2001, **17:**423-431.
28. Tscherning-Casper C, Dolcini G, Mauclere P, et al.Evidence of the existence of a new circulating recombinant form of HIV type 1 subtype A/J in Cameroon.AIDS Res Hum Retroviruses 2000, **16:**1313-1318.
29. Laukkanen T, Albert J, Liitsola K, et al.Virtually full-length sequences of HIV type 1 subtype J reference strains.AIDS Res Hum Retroviruses 1999, **15:**293-297.
30. Salminen MO, Johansson B, Sonnerborg A, et al.Full-length sequence of an Ethiopian human immunodeficiency virus type 1 (HIV-1) isolate of genetic subtype C.AIDS Res Hum Retroviruses 1996, **12:**1329-1339.
31. Louwagie J, McCutchan FE, Peeters M, et al.Phylogenetic analysis of gag genes from seventy international HIV-1 isolates provides evidence for multiple genotypes.AIDS 1993, **7:**769-780.
32. Simon F, Loussert-Ajaka I, Damond F, Saragosti S, Barin F, Brun-Vezinet F. HIV type 1 diversity in northern Paris, France.AIDS Res Hum Retroviruses 1996, **12:**1427-1433.
33. Murphy G, Belda FJ, Pau CP, Clewley JP, Parry JV. Discrimination of subtype B and non-subtype B strains of human immunodeficiency virus type 1 by serotyping: correlation with genotyping.J Clin Microbiol 1999, **37:**1356-1360.
34. Plantier JC, Damond F, Lasky M, et al.V3 serotyping of HIV-1 infection: correlation with genotyping and limitations.J AIDS Hum Retrovirol 1999, **20:**432-441.
35. Cheingsong-Popov R, Osmanov S, Pau CP, et al.Serotyping of HIV type 1 infections: definition, relationship to viral genetic subtypes, and assay evaluation.AIDS Res Hum Retroviruses 1998, **14:**311-318.
36. Nkengasong JN, Willems B, Janssens W, et al.Lack of correlation between V3-loop peptide enzyme immunoassay serologic subtyping and genetic sequencing.AIDS 1998, **12:**1405-1412.
37. Barlow KL, Green J, Clewley JP. Viral genome characterisation by the heteroduplex mobility and heteroduplex tracking assays.Rev Med Virol 2000, **10:**321-335.
38. Belda FJ, Barlow KL, Clewley JP. Subtyping HIV-1 by improved resolution of heteroduplexes on agarose gels.J AIDS Hum Retrovirol 1997, **16:**218-219.
39. Bredell H, Hunt G, Morgan B, Tiemessen CT, Martin DJ, Morris L. Identification of HIV type 1 intersubtype recombinants in South Africa using env and gag heteroduplex mobility assays.AIDS Res Hum Retroviruses 2000, **16:**493-497.
40. Heyndrickx L, Janssens W, Zekeng L, et al.Simplified strategy for detection of recombinant human immunodeficiency virus type 1 group M isolates by gag/env heteroduplex mobility assay.J Virol 2000, **74:**363-370.
41. Tatt ID, Barlow KL, Clewley JP. A gag gene heteroduplex mobility assay for subtyping HIV-1.J Virol Methods 2000, **87:**41-51.
42. European Commission and Joint United Nations Programme on HIV/AIDS. HIV-1 subtypes: implications for epidemiology, pathogenicity, vaccines and diagnostics. Workshop Report from the European Commission (DG XII, INCO-DC) and the Joint United Nations Programme on HIV/AIDS.AIDS 1997, **11:**17-36.
43. Arnold C, Barlow KL, Parry JV, Clewley JP. At least five HIV-1 sequence subtypes (A, B, C, D, A/E) occur in England.AIDS Res Hum Retroviruses 1995, **11:**427-429.
44. Clewley JP, Arnold C, Barlow KL, Grant PR, Parry JV. Diverse HIV-1 genetic subtypes in UK [letter].Lancet 1996, **347:**1487.
45. Holguin A, Rodes B, Soriano V. Recombinant human immunodeficiency viruses type 1 circulating in Spain.AIDS Res Hum Retroviruses 2000, **16:**505-511.
46. Hussein M, Abebe A, Pollakis G, et al.HIV-1 subtype C in commercial sex workers in Addis Ababa, Ethiopia.J AIDS 2000, **23:**120-127.
47. Vidal N, Peeters M, Mulanga-Kabeya C, et al.Unprecedented degree of human immunodeficiency virus type 1 (HIV-1) group M genetic diversity in the Democratic Republic of Congo suggests that the HIV-1 pandemic originated in Central Africa.J Virol 2000, **74:**10498-10507.
49. Carr JK, Laukkanen T, Salminen MO, et al.Characterization of subtype A HIV-1 from Africa by full genome sequencing.AIDS 1999, **13:**1819-1826.
50. Rayfield MA, Downing RG, Baggs J, et al.A molecular epidemiologic survey of HIV in Uganda.AIDS 1998, **12:**521-527.
51. Ishikawa K, Janssens W, Brandful J, et al.Genetic and phylogenetic analysis of HIV type 1 env subtypes in Ghana, West Africa.AIDS Res Hum Retroviruses 1996, **12:**1575-1578.
52. Howard TM, Rasheed S. Genomic structure and nucleotide sequence analysis of a new HIV type 1 subtype A strain from Nigeria.AIDS Res Hum Retroviruses 1996, **12:**1413-1425.
53. Bredell H, Williamson C, Sonnenberg P, Martin DJ, Morris L. Genetic characterization of HIV type 1 from migrant workers in three South African gold mines.AIDS Res Hum Retroviruses 1998, **14:**677-684.
54. van Harmelen J, van der Ryst E, Wood R, Lyons SF, Williamson C. Restriction fragment length polymorphism analysis for rapid gag subtype determination of human immunodeficiency virus type 1 in South Africa.J Virol Methods 1999, **78:**51-59.
55. Montavon C, Toure-Kane C, Liegeois F, et al.Most env and gag subtype A HIV-1 viruses circulating in West and West Central Africa are similar to the prototype AG recombinant virus IBNG.J AIDS 2000, **23:**363-374.
56. Piyasirisilp S, McCutchan FE, Carr JK, et al.A recent outbreak of human immunodeficiency virus type 1 infection in southern China was initiated by two highly homogeneous, geographically separated strains, circulating recombinant form AE and a novel BC recombinant.J Virol 2000, **74:**11286-11295.
57. Lole KS, Bollinger RC, Paranjape RS, et al.Full-length human immunodeficiency virus type 1 genomes from subtype C-infected seroconverters in India, with evidence of intersubtype recombination.J Virol 1999, **73:**152-160.
58. Wasi C, Herring B, Raktham S, et al.Determination of HIV-1 subtypes in injecting drug-users in Bangkok, Thailand, using peptide-binding enzyme immunoassay and heteroduplex mobility assay: evidence of increasing infection with HIV-1 subtype E.AIDS 1995, **9:**843-849.
59. Entz AT, Ruffolo VP, Chinveschakitvanich V, Soskolne V, van Griensven GJ. HIV-1 prevalence, HIV-1 subtypes and risk factors among fishermen in the Gulf of Thailand and the Andaman Sea.AIDS 2000, **14:**1027-1034.
60. Distler O, McQueen PW, Tsang ML, et al.Characterization of the V3 region of HIV-1 isolates from Sydney, Australia.AIDS Res Hum Retroviruses 1995, **11:**423-425.
61. Couturier E, Damond F, Roques P, et al.HIV-1 diversity in France, 1996-1998. The AC 11 laboratory network.AIDS 2000, **14:**289-296.
62. Irwin KL, Pau CP, Lupo D, et al.Presence of human immunodeficiency virus (HIV) type 1 subtype A infection in a New York community with high HIV prevalence: a sentinel site for monitoring HIV genetic diversity in North America.J Infect Dis 1997, **176:**1629-1633.
63. Belda FJ, Barlow KL, Murphy G, Parry JV, Clewley JP. A dual subtype B/E HIV type 1 infection with a novel V3 loop crown motif among infections acquired in Thailand and imported into England.AIDS Res Hum Retroviruses 1998, **14:**911-916.
64. Dietrich U, Ruppach H, Gehring S, et al.Large proportion of non-B HIV-1 subtypes and presence of zidovudine resistance mutations among German seroconvertors.AIDS 1997, **11:**1532-1533.
65. Alaeus A, Leitner T, Lidman K, Albert J. Most HIV-1 genetic subtypes have entered Sweden.AIDS 1997, **11:**199-202.
66. Laukkanen T, Carr JK, Janssens W, et al.Virtually full-length subtype F and F/D recombinant HIV-1 from Africa and South America.Virology 2000, **269:**95-104.
67. Ramos A, Tanuri A, Schechter M, et al.Dual and recombinant infections: an integral part of the HIV-1 epidemic in Brazil.Emerg Infect Dis 1999, **5:**65-74.
68. Cornelissen M, Kampinga G, Zorgdrager F, Goudsmit J. Human immunodeficiency virus type 1 subtypes defined by env show high frequency of recombinant gag genes.J Virol 1996, **70:**8209-8212.
69. Oelrichs RB, Workman C, Laukkanen T, McCutchan FE, Deacon NJ. A novel subtype A/G/J recombinant full-length HIV type 1 genome from Burkina Faso.AIDS Res Hum Retroviruses 1998, **14:**1495-1500.
70. Liitsola K, Holm K, Bobkov A, et al.An AB recombinant and its parental HIV type 1 strains in the area of the former Soviet Union: low requirements for sequence identity in recombination.AIDS Res Hum Retroviruses 2000, **16:**1047-1053.
71. Montavon C, Bibollet-Ruche F, Robertson D, et al.The identification of a complex A/G/I/J recombinant HIV type 1 virus in various West African countries.AIDS Res Hum Retroviruses 1999, **15:**1707-1712.
72. Kato K, Kusagawa S, Motomura K, et al.Closely related HIV-1 CRF01_AE variant among injecting drug users in Northern Vietnam: evidence of HIV spread across the Vietnam-China Border.AIDS Res Hum Retroviruses 2001, **17:**113-123.
73. Thomson MM, Villahermosa ML, Vazquez-de-Parga E, et al.Widespread circulation of a B/F intersubtype recombinant form among HIV-1-infected individuals in Buenos Aires, Argentina.AIDS 2000, **14:**897-899.
74. Bellini WJ, Rota PA. Genetic diversity of wild-type measles viruses: implications for global measles elimination programs.Emerg Infect Dis 1998, **4:**29-35.
75. Gensheimer KF, Fukuda K, Brammer L, Cox N, Patriarca PA, Strikas RA. Preparing for pandemic influenza: the need for enhanced surveillance.Emerg Infect Dis 1999, **5:**297-299.
76. Kanki PJ, Travers KU, MBoup S, et al.Slower heterosexual spread of HIV-2 than HIV-1.Lancet 1994, **343:**943-946.
77. Marlink R, Kanki P, Thior I, et al.Reduced rate of disease development after HIV-2 infection as compared to HIV-1.Science 1994, **265:**1587-1590.
78. Broussard SR, Staprans SI, White R, Whitehead EM, Feinberg MB, Allan JS. Simian immunodeficiency virus replicates to high levels in naturally infected African green monkeys without inducing immunologic or neurologic disease.J Virol 2001, **75:**2262-2275.
79. Wei Q, Fultz PN. Extensive diversification of human immunodeficiency virus type 1 subtype B strains during dual infection of a chimpanzee that progressed to AIDS.J Virol 1998, **72:**3005-3017.
80. Pillay D, Taylor S, Richman DD. Incidence and impact of resistance against approved antiretroviral drugs.Rev Med Virol 2000, **10:**231-253.
81. McMichael AJ, Hanke T. Is an HIV vaccine possible?Nat Med 1999, **5:**612-614.
82. Ensoli B, Cafaro A. Control of viral replication and disease onset in cynomolgus monkeys by HIV-1 TAT vaccine.J Biol Regulat Homeost Agents 2000, **14:**22-26.
83. Xiao Y, Liao M, Lu Y, Dierich MP, Chen YH. Epitope-vaccines: a new strategy to induce high levels of neutralizing antibodies against HIV-1.Immunobiology 2000, **201:**323-331.
84. Clements-Mann ML, Weinhold K, Matthews TJ, et al.Immune responses to human immunodeficiency virus (HIV) type 1 induced by canarypox expressing HIV-1MN gp120, HIV-1SF2 recombinant gp120, or both vaccines in seronegative adults.J Infect Dis 1998, **177:**1230-1246.
85. Corey L, McElrath MJ, Weinhold K, et al.Cytotoxic T cell and neutralizing antibody responses to human immunodeficiency virus type 1 envelope with a combination vaccine regimen.J Infect Dis 1998, **177:**301-309.
86. Caselli E, Betti M, Grossi MP, et al.DNA immunization with HIV-1 tat mutated in the trans activation domain induces humoral and cellular immune responses against wild-type Tat.J Immunol 1999, **162:**5631-5638.
87. Ayyavoo V, Kudchodkar S, Ramanathan MP, et al.Immunogenicity of a novel DNA vaccine cassette expressing multiple human immunodeficiency virus (HIV-1) accessory genes.AIDS 2000, **14:**1-9.
88. Daniel MD, Kirchhoff F, Czajak SC, Sehgal PK, Desrosiers RC. Protective effects of a live attenuated SIV vaccine with a deletion in the nef gene.Science 1992, **258:**1938-1941.
89. Moss RB, Diveley J, Jensen FC, Gouveia E, Carlo DJ. Human immunodeficiency virus (HIV)-specific immune responses are generated with the simultaneous vaccination of a gp120-depleted, whole-killed HIV-1 immunogen with cytosine-phosphorothioate-guanine dinucleotide immunostimulatory sequences of DNA.J Hum Virol 2001, **4:**39-43.
90. Nathanson N, Mathieson BJ. Biological considerations in the development of a human immunodeficiency virus vaccine.J Infect Dis 2000, **182:**579-589.
91. Borrow P, Lewicki H, Wei X, et al.Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virusNat Med 1997, **3:**205-211.
92. Domingo E, Menendez-Arias L, Quinones-Mateu ME, et al.Viral quasispecies and the problem of vaccine-escape and drug-resistant mutants.Prog Drug Res 1997, **48:**99-128.
93. Goldstein G, Tribbick G, Manson K. Two B cell epitopes of HIV-1 Tat protein have limited antigenic polymorphism in geographically diverse HIV-1 strains.Vaccine 2001, **19:**1738-1746.
94. Cafaro A, Caputo A, Fracasso C, et al.Control of SHIV-89.6P-infection of cynomolgus monkeys by HIV-1 Tat protein vaccine.Nat Med 1999, **5:**643-650.
95. Mascola JR, Louwagie J, McCutchan FE, et al.Two antigenically distinct subtypes of human immunodeficiency virus type 1: viral genotype predicts neutralization serotype.J Infect Dis 1994, **169:**48-54.
96. Dorrell L, Dong T, Ogg GS, et al.Distinct recognition of non-clade B human immunodeficiency virus type 1 epitopes by cytotoxic T lymphocytes generated from donors infected in Africa.J Virol 1999, **73:**1708-1714.
97. Cao H, Mani I, Vincent R, et al.Cellular immunity to human immunodeficiency virus type 1 (HIV-1) clades: relevance to HIV-1 vaccine trials in Uganda.J Infect Dis 2000, **182:**1350-1356.
98. van der Groen G, Nyambi PN, Beirnaert E, et al.Genetic variation of HIV type 1: relevance of interclade variation to vaccine development.AIDS Res Hum Retroviruses 1998, **14:**S211-S221.
99. Berman PW, Huang W, Riddle L, et al.Development of bivalent (B/E) vaccines able to neutralize CCR5-dependent viruses from the United States and Thailand.Virology 1999, **265:**1-9.
100. Alaeus A, Lilja E, Herman S, Spadoro J, Wang J, Albert J. Assay of plasma samples representing different HIV-1 genetic subtypes: an evaluation of new versions of the amplicor HIV-1 monitor assay.AIDS Res Hum Retroviruses 1999, **15:**889-894.
101. Dorn J, Masciotra S, Yang C, et al.Analysis of genetic variability within the immunodominant epitopes of envelope gp41 from human immunodeficiency virus type 1 (HIV-1) group M and its impact on HIV-1 antibody detection.J Clin Microbiol 2000, **38:**773-780.
102. Koch WH, Sullivan PS, Roberts C, et al.Evaluation of United States-licensed human immunodeficiency virus immunoassays for detection of group M viral variants.J Clin Microbiol 2001, **39:**1017-1020.
103. Nolte FS, Boysza J, Thurmond C, Clark WS, Lennox JL. Clinical comparison of an enhanced-sensitivity branched-DNA assay and reverse transcription-PCR for quantitation of human immunodeficiency virus type 1 RNA in plasma.J Clin Microbiol 1998, **36:**716-720.
104. Holguin A, de Mendoza C, Soriano V. Comparison of three different commercial methods for measuring plasma viraemia in patients infected with non-B HIV-1 subtypes.Eur J Clin Microbiol Infect Dis 1999, **18:**256-259.
105. Parekh B, Phillips S, Granade TC, Baggs J, Hu DJ, Respess R. Impact of HIV type 1 subtype variation on viral RNA quantitation.AIDS Res Hum Retroviruses 1999, **15:**133-142.
106. Arnold C, Barlow KL, Kaye S, Loveday C, Balfe P, Clewley JP. HIV type 1 sequence subtype G transmission from mother to infant: failure of variant sequence species to amplify in the Roche Amplicor Test.AIDS Res Hum Retroviruses 1995, **11:**999-1001.
107. Barlow KL, Tosswill JH, Parry JV, Clewley JP. Performance of the Amplicor human immunodeficiency virus type 1 PCR and analysis of specimens with false-negative results.J Clin Microbiol 1997, **35:**2846-2853.
108. Triques K, Coste J, Perret JL, et al.Efficiencies of four versions of the AMPLICOR HIV-1 MONITOR test for quantification of different subtypes of human immunodeficiency virus type 1.J Clin Microbiol 1999, **37:**110-116.
109. Swanson P, Soriano V, Devare SG, Hackett J. Comparative performance of three viral load assays on human immunodeficiency virus type 1 (HIV-1) isolates representing group M (subtypes A to G) and group O: LCx HIV RNA quantitative, AMPLICOR HIV-1 MONITOR version 1.5, and Quantiplex HIV-1 RNA version 3.0.J Clin Microbiol 2001, **39:**862-870.
110. Michael NL, Herman SA, Kwok S, et al.Development of calibrated viral load standards for group M subtypes of human immunodeficiency virus type 1 and performance of an improved AMPLICOR HIV-1 MONITOR test with isolates of diverse subtypes.J Clin Microbiol 1999, **37:**2557-2563.
111. Coste J, Montes B, Reynes J, et al.Effect of HIV-1 genetic diversity on HIV-1 RNA quantification in plasma: comparative evaluation of three commercial assaysJ AIDS Hum Retrovirol 1997, **15:**174-175.
112. Janssen RS, Satten GA, Stramer SL, et al.New testing strategy to detect early HIV-1 infection for use in incidence estimates and for clinical and prevention purposes.JAMA 1998, **280:**42-48.
113. Parekh BS, Hu DJ, Vanichseni S, et al.Evaluation of a sensitive/less-sensitive testing algorithm using the 3A11-LS assay for detecting recent HIV seroconversion among individuals with HIV-1 subtype B or E infection in Thailand.AIDS Res Hum Retroviruses 2001, **17:**453-458.
114. Schable C, Zekeng L, Pau CP, et al.Sensitivity of United States HIV antibody tests for detection of HIV-1 group O infections.Lancet 1994, **344:**1333-1334.
115. Masciotra S, Rudolph DL, van der Groen G, Yang C, Lal RB. Serological detection of infection with diverse human and simian immunodeficiency viruses using consensus env peptides.Clin Diagn Lab Immunol 2000, **7:**706-709.
116. Murphy G, Parry JV, Gupta SB, et al.Test of HIV incidence shows continuing HIV transmission in homosexual/bisexual men in England and Wales.Commun Dis Public Health 2001, **4:**33-37.
117. Reisler RB, Thea DM, Pliner V, et al.Early detection of reverse transcriptase activity in plasma of neonates infected with HIV-1: a comparative analysis with RNA-based and DNA-based testing using polymerase chain reaction.J Acquir Immune Defic Syndr 2001, **26:**93-102.
118. Fransen K, Beelaert G, van der Groen G. Evaluation of four HIV antigen tests.J Virol Methods 2001, **93:**189-193.
119. Giles RE, Burgess C, Perry KR, Parry JV. Vironostika HIV Uni-Form II Ag/Ab.MDA Report, MDA/99/51. London: Medical Devices Agency; 1999.
120. Perry KR, Kenny C, Parry JV, Mortimer PP. bioMerieux VIDAS HIV DUO.MDA Report, MDA/99/69. London: Medical Devices Agency; 1999.
121. Barlow KL, Tosswill JH, Clewley JP. Analysis and genotyping of PCR products of the Amplicor HIV-1 kit.J Virol Methods 1995, **52:**65-74.
122. Bruisten SM, Frissen PH, Van Swieten P, et al.Prospective longitudinal analysis of viral load and surrogate markers in relation to clinical progression in HIV type 1-infected persons.AIDS Res Hum Retroviruses 1997, **13:**327-335.
123. Riddler SA, Mellors JW. HIV-1 viral load and clinical outcome: review of recent studies.AIDS 1997, **11:**S141-S148.
124. Coll O, Hernandez M, Boucher CA, et al.Vertical HIV-1 transmission correlates with a high maternal viral load at delivery.J AIDS Hum Retrovirol 1997, **14:**26-30.
125. Pedraza MA, del Romero J, Roldan F, et al.Heterosexual transmission of HIV-1 is associated with high plasma viral load levels and a positive viral isolation in the infected partner.J AIDS 1999, **21:**120-125.
126. Mellors JW, Rinaldo CR, Gupta P, White RM, Todd JA, Kingsley LA. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma.Science 1996, **272:**1167-1170.
127. Mulder J, McKinney N, Christopherson C, Sninsky J, Greenfield L, Kwok S. Rapid and simple PCR assay for quantitation of human immunodeficiency virus type 1 RNA in plasma: application to acute retroviral infection.J Clin Microbiol 1994, **32:**292-300.
128. Kievits T, van Gemen B, van Strijp D, et al.NASBA isothermal enzymatic in vitro nucleic acid amplification optimized for the diagnosis of HIV-1 infection.J Virol Methods 1991, **35:**273-286.
129. de Baar MP, Timmermans EC, Bakker M, de Rooij E, van Gemen B, Goudsmit J. One-tube real-time isothermal amplification assay to identify and distinguish human immunodeficiency virus type 1 subtypes A, B, and C and circulating recombinant forms AE and AG.J Clin Microbiol 2001, **39:**1895-1902.
130. Pachl C, Todd JA, Kern DG, et al.Rapid and precise quantification of HIV-1 RNA in plasma using a branched DNA signal amplification assay.J AIDS Hum Retrovirol 1995, **8:**446-454.
131. Todd J, Pachl C, White R, et al.Performance characteristics for the quantitation of plasma HIV-1 RNA using branched DNA signal amplification technology.J AIDS Hum Retrovirol 1995, **10(suppl 2):**S35-S44.
132. Swanson P, Harris BJ, Holzmayer V, Devare SG, Schochetman G, Hackett J. Quantification of HIV-1 group M (subtypes A-G) and group O by the LCx HIV RNA quantitative assay.J Virol Methods 2000, **89:**97-108.
133. Coste J, Montes B, Reynes J, et al.Comparative evaluation of three assays for the quantitation of human immunodeficiency virus type 1 RNA in plasma.J Med Virol 1996, **50:**293-302.
134. Holguin A, Aracil B, Alvarez A, Barros C, Soriano V. Prevalence of human immunodeficiency virus type 1 (HIV-1) non-B subtypes in foreigners living in Madrid, Spain, and comparison of the performances of the AMPLICOR HIV-1 MONITOR version 1.0 and the new automated version 1.5.J Clin Microbiol 2001, **39:**1850-1854.
135. de Baar MP, van Dooren MW, de Rooij E, et al.Single rapid real-time monitored isothermal RNA amplification assay for quantification of human immunodeficiency virus type 1 isolates from groups M, N, and O.J Clin Microbiol 2001, **39:**1378-1384.
136. Ernest I, Alexandre I, Zammatteo N, et al.Quantitative assay for group M (subtype A-H) and group O HIV-1 RNA detection in plasma.J Virol Methods 2001, **93:**1-14.
137. UK Collaborative Group on Monitoring the Transmission of HIV Drug Resistance. Analysis of prevalence of HIV-1 drug resistance in primary infections in the United Kingdom.BMJ 2001, **322:**1087-1088.
138. Descamps D, Collin G, Letourneur F, et al.Susceptibility of human immunodeficiency virus type 1 group O isolates to antiretroviral agents: in vitro phenotypic and genotypic analyses.J Virol 1997, **71:**8893-8898.
139. Coffin JM. HIV-1 population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy.Science 1995, **267:**483-489.
140. Apetrei C, Descamps D, Collin G, et al.Human immunodeficiency virus type 1 subtype F reverse transcriptase sequence and drug susceptibility.J Virol 1998, **72:**3534-3538.
141. Descamps D, Apetrei C, Collin G, Damond F, Simon F, Brun-Vezinet F. Naturally occurring decreased susceptibility of HIV-1 subtype G to protease inhibitors.AIDS 1998, **12:**1109-1111.
142. Pieniazek D, Rayfield M, Hu DJ, et al.Protease sequences from HIV-1 group M subtypes A-H reveal distinct amino acid mutation patterns associated with protease resistance in protease inhibitor-naive individuals worldwide.AIDS 2000, **14:**1489-1495.
143. Cornelissen M, van den Burg R, Zorgdrager F, Lukashov V, Goudsmit J. pol gene diversity of five human immunodeficiency virus type 1 subtypes: evidence for naturally occurring mutations that contribute to drug resistance, limited recombination patterns, and common ancestry for subtypes B and D.J Virol 1997, **71:**6348-6358.
144. Perez-Alvarez L, Cuevas MT, Villahermosa ML, et al.Prevalence of drug resistance mutations in B, non-B subtypes, and recombinant forms of human immunodeficiency virus type 1 in infected individuals in Spain (Galicia).J Hum Virol 2001, **4:**35-38.
145. Cane PA, de Ruiter A, Rice P, Wiselka M, Fox R, Pillay D. Resistance-associated mutations in the human immunodeficiency virus type 1 subtype C protease gene from treated and untreated patients in the United Kingdom.J Clin Microbiol 2001, **39:**2652-2654.
146. Shafer RW, Chuang TK, Hsu P, White CB, Katzenstein DA. Sequence and drug susceptibility of subtype C protease from human immunodeficiency virus type 1 seroconverters in Zimbabwe.AIDS Res Hum Retroviruses 1999, **15:**65-69.
147. Martlew VJ, Carey P, Tong CY, et al.Post-transfusion HIV infection despite donor screening: a report of three cases.J Hosp Infect 2000, **44:**93-97.
148. Ou C-Y, Ciesielski CA, Myers G, et al.Molecular epidemiology of HIV transmission in a dental practice.Science 1992, **256:**1165-1171.
149. Arnold C, Balfe P, Clewley JP. Sequence distances between env genes of HIV-1 from individuals infected from the same source: implications for the investigation of possible transmission events.Virology 1995, **211:**198-203.
150. Ou C-Y, Takebe Y, Weniger BC, et al.Independent introduction of two major HIV-1 genotypes into distinct high-risk populations in Thailand.Lancet 1993, **341:**1171-1174.
151. Santiago ML, Santiago EG, Hafalla JC, et al.Molecular epidemiology of HIV-1 infection in the Philippines, 1985 to 1997: transmission of subtypes B and E and potential emergence of subtypes C and F.J AIDS Hum Retrovirol 1998, **18:**260-269.
152. Ellenberger DL, Pieniazek D, Nkengasong J, et al.Genetic analysis of human immunodeficiency virus in Abidjan, Ivory Coast reveals predominance of HIV type 1 subtype A and introduction of subtype G.AIDS Res Hum Retroviruses 1999, **15:**3-9.
153. Kunanusont C, Foy HM, Kreiss JK, et al.HIV-1 subtypes and male-to-female transmission in Thailand.Lancet 1995, **345:**1078-1083.
154. Neilson JR, John GC, Carr JK, et al.Subtypes of human immunodeficiency virus type 1 and disease stage among women in Nairobi, Kenya.J Virol 1999, **73:**4393-4403.
155. Hu DJ, Buve A, Baggs J, van der Groen G, Dondero TJ. What role does HIV-1 subtype play in transmission and pathogenesis? An epidemiological perspective editorial.AIDS 1999, **13:**873-881.
156. Soto-Ramirez LE, Renjifo B, McLane MF, et al.HIV-1 Langerhans' cell tropism associated with heterosexual transmission of HIV.Science 1996, **271:**1291-1293.
157. Dittmar MT, Simmons G, Hibbitts S, et al.Langerhans cell tropism of human immunodeficiency virus type 1 subtype A through F isolates derived from different transmission groups.J Virol 1997, **71:**8008-8013.
158. Pope M, Frankel SS, Mascola JR, et al.Human immunodeficiency virus type 1 strains of subtypes B and E replicate in cutaneous dendritic cell-T-cell mixtures without displaying subtype-specific tropism.J Virol 1997, **71:**8001-8007.
159. Limpakarnjanarat K, Ungchusak K, Mastro TD, et al.The epidemiological evolution of HIV-1 subtypes B and E among heterosexuals and injecting drug users in Thailand, 1992-1997.AIDS 1998, **12:**1108-1109.
160. Mastro TD, Kunanusont C, Dondero TJ, Wasi C. Why do HIV-1 subtypes segregate among persons with different risk behaviors in South Africa and Thailand?AIDS 1997, **11:**113-116.
161. Cameron DW, Simonsen JN, D'Costa LJ, et al.Female to male transmission of human immunodeficiency virus type 1: risk factors for seroconversion in men.Lancet 1989, **2:**403-407.
162. van Harmelen J, Wood R, Lambrick M, Rybicki EP, Williamson AL, Williamson C. An association between HIV-1 subtypes and mode of transmission in Cape Town, South Africa.AIDS 1997, **11:**81-87.
163. Renjifo B, Fawzi W, Mwakagile D, et al.Differences in perinatal transmission among human immunodeficiency virus type 1 genotypes.J Hum Virol 2001, **4:**16-25.
164. Mastro TD, de Vincenzi I. Probabilities of sexual HIV-1 transmission.AIDS 1996, **10:**S75-S82.
165. Shaffer N, Roongpisuthipong A, Siriwasin W, et al.Maternal virus load and perinatal human immunodeficiency virus type 1 subtype E transmission, Thailand. Bangkok Collaborative Perinatal HIV Transmission Study Group.J Infect Dis 1999, **179:**590-599.
166. Fleming DT, Wasserheit JN. From epidemiological synergy to public health policy and practice: the contribution of other sexually transmitted diseases to sexual transmission of HIV infection.Sex Transm Infect 1999, **75:**3-17.
167. Galai N, Kalinkovich A, Burstein R, Vlahov D, Bentwich Z. African HIV-1 subtype C and rate of progression among Ethiopian immigrants in Israel.Lancet 1997, **349:**180-181.
168. Morgan D, Maude GH, Malamba SS, et al.HIV-1 disease progression and AIDS-defining disorders in rural Uganda.Lancet 1997, **350:**245-250.
169. Cohen OJ, Kinter A, Fauci AS. Host factors in the pathogenesis of HIV disease.Immunol Rev 1997, **159:**31-48.
170. Pezzotti P, Phillips AN, Dorrucci M, et al.Category of exposure to HIV and age in the progression to AIDS: longitudinal study of 1199 people with known dates of seroconversion.BMJ 1996, **313:**583-586.
171. Chaisson RE, Keruly JC, Moore RD. Race, sex, drug use, and progression of human immunodeficiency virus disease.N Eng J Med 1995, **333:**751-756.
172. Samson M, Libert F, Doranz BJ, et al.Resistance to HIV-1 infection in caucasian individuals bearing mutant alleles of the CCR-5 chemokine receptor gene.Nature 1996, **382:**722-725.
173. Fauci AS. Host factors and the pathogenesis of HIV-induced disease.Nature 1996, **384:**529-534.
174. Tscherning C, Alaeus A, Fredriksson R, et al.Differences in chemokine coreceptor usage between genetic subtypes of HIV-1.Virology 1998, **241:**181-188.
175. Abebe A, Demissie D, Goudsmit J, et al.HIV-1 subtype C syncytium- and non-syncytium-inducing phenotypes and coreceptor usage among Ethiopian patients with AIDS.AIDS 1999, **13:**1305-1311.
176. Peeters M, Vincent R, Perret JL, et al.Evidence for differences in MT2 cell tropism according to genetic subtypes of HIV-1: syncytium-inducing variants seem rare among subtype C HIV-1 viruses.J AIDS Hum Retrovirol 1999, **20:**115-121.
177. Rodenburg CM, Li Y, Trask SA, et al.Near full-length clones and reference sequences for subtype C isolates of HIV type 1 from three different continents.AIDS Res Hum Retroviruses 2001, **17:**161-168.
178. Alaeus A, Lidman K, Bjorkman A, Giesecke J, Albert J. Similar rate of disease progression among individuals infected with HIV-1 genetic subtypes A-D.AIDS 1999, **13:**901-907.
179. Weisman Z, Kalinkovich A, Borkow G, Stein M, Greenberg Z, Bentwich Z. Infection by different HIV-1 subtypes (B and C) results in a similar immune activation profile despite distinct immune backgrounds.J AIDS 1999, **21:**157-163.
180. Amornkul PN, Tansuphasawadikul S, Limpakarnjanarat K, et al.Clinical disease associated with HIV-1 subtype B′ and E infection among 2104 patients in Thailand.AIDS 1999, **13:**1963-1969.
181. Kanki PJ, Hamel DJ, Sankale JL, et al.Human immunodeficiency virus type 1 subtypes differ in disease progression.J Infect Dis 1999, **179:**68-73.
182. Anzala OA, Nagelkerke NJ, Bwayo JJ, et al.Rapid progression to disease in African sex workers with human immunodeficiency virus type 1 infection.J Infect Dis 1995, **171:**686-689.
183. Nicoll A, Gill N, Goldberg D, Peckham C. The ethics of unlinked anonymous testing. Surveys provide essential information [letter].BMJ 2000, **320:**1275.
184. Nicoll A, Gill ON, Peckham CS, et al.The public health applications of unlinked anonymous seroprevalence monitoring for HIV in the United Kingdom.Int J Epidemiol 2000, **29:**1-10.
185. Parry JV, Murphy G, Barlow KL, et al.National surveillance of HIV-1 subtypes for England and Wales: design, methods, and initial findings.J AIDS 2001, **26:**381-388.
186. Motomura K, Kusagawa S, Kato K, et al.Emergence of new forms of human immunodeficiency virus type 1 intersubtype recombinants in central Myanmar.AIDS Res Hum Retroviruses 2000, **16:**1831-1843.
187. Gao F, Robertson DL, Carruthers CD, et al.A comprehensive panel of near-full-length clones and reference sequences for non-subtype B isolates of human immunodeficiency virus type 1.J Virol 1998, **72:**5680-5698.
188. Luo C-C, Downing RG, Dela Torre N, et al.The development and evaluation of a probe hybridisation method for subtyping HIV type 1 infection in Uganda.AIDS Res Hum Retroviruses 1998, **14:**691-694.
189. Kostrikis LG, Shin S, Ho DD. Genotyping HIV-1 and HCV strains by a combinatorial DNA melting assay (COMA).Mol Med 1998, **4:**443-453.
Keywords:
HIV-1; subtype; recombination; genetic diversity; epidemiology; public health; surveillance
© 2001 Lippincott Williams & Wilkins, Inc.