Viral and host determinants of HIV-1 pathogenesis : AIDS (original) (raw)
The HIV-1 pandemic is quite young, about 30 years old, an obviously too short period to allow the virus and its human host to reach an adaptative equilibrium. In this issue of AIDS, Müller et al. describe a fascinating study attempting to retrospectively assess temporal trends in HIV virulence in a prevalent cohort of HIV-infected individuals, by means of simple criteria (CD4 cell count, CD4: CD8 ratio, HIV-1 RNA) chosen as virulence proxies [1]. This study demonstrates that trends in virulence markers fluctuate over time [1]. The observation of long time intervals is therefore necessary to identify trends translating a significant biological event. In the study by Müller et al. of more than 800 North-west European patients none of the virulence markers correlated with the date of diagnosis, suggesting that either the virus has already reached its optimal virulence or that the slow temporal trend in virulence cannot be captured due to strong evolutionary constraints. In prevalent observational cohorts, variation in the disease stage at entry is a potential source of bias that may be taken into account by including only subjects with known dates of contamination. It should stressed also, that temporal trends of CD4 cell count, CD4 cell: CD8 cell ratio and HIV-1 RNA are the result of both viral factors of virulence and of host determinants of susceptibility.
Virulence is defined as viral characteristics responsible for disease. It is typically a multifactorial, polygenic phenomenon with consequences not only on pathogenesis but also on transmissibility. Viral fitness (in vivo) or replicative capacity (in vitro) reflect one of such viral events that may determine clinical progression [2]. A competitive in vitro assessment of the replicative capacity of historical HIV-1 strains (1986–1989) and of more recent primary isolates (2002–2003) suggested a recent attenuation of HIV-1 fitness and an incomplete adaptation of the virus to its human host [3]. In this study, historical HIV-1 isolates were also less sensitive to lamivudine than isolates involved in more recent infections. Although it is generally considered that antiretroviral resistance mutants of HIV-1 have a decreased replicative capacity, this observation together with other recent data [4] shows that a direct resistance–-fitness relationship is not universal. Indeed, HIV-1 isolates with enhanced replicative capacity and pathogenicity can be found in individuals with drug-resistant viruses [4].
Cellular tropism is also a likely HIV-1 virulence factor. Viruses using CXCR4 as a coreceptor are frequently encountered in late stages of the HIV disease. The detection of X4 viruses is associated with a rapid CD4 cell decline and a faster progression of the disease [5]. HIV-1 virulence is under the control of viral regulatory (tat, rev) and accessory genes (nef, vpr, vpu, vif) and gene products. As an example, the Tat protein has been shown to activate the transcription of several cellular genes and stimulate TNF-α production [6]. Furthermore, the Vif protein is a potent inhibitor of the cellular restriction factors APOBEC3G and APOBEC3F, a cytidine deaminase responsible for editing and elimination of hypermutated viral DNA transcripts [7,8]. Defective vif alleles can be identified in HIV-1 infected individuals and natural variation in Vif function may be responsible for impaired APOBEC3G function neutralization and promote viral diversity [9]. Entrapment of cellular components such as cyclophilin A into virions during the budding process is needed for infectiousness. When cyclophilin A is incorporated into HIV virions it interacts closely with the p24 region of p55. Disruption of this interaction considerably impairs viral replication [10]. Recently, by means of a regulatable expression system, increasing gp120 density on viral envelope was shown to be associated with an increased viral production [11].
However, the clinical expression of HIV-1 infection and the HIV-1-related immunodeficiency are not only driven by viral factors. Treatments, of course, and host susceptibility play also a crucial role. In the study by Müller et al., introduction of HAART in the mid-1990s did not seem to have impacted on a measurable change in virulence markers trends [1]. Polymorphism of chemokine receptor genes and their promoters [12], density of CCR5 on cell surface [13], APOBEC 3G/3F restriction, polymorphism of killer immunoglobulin-like receptors (KIR) [14], or HLA class I alleles [15] can all modify HIV disease progression. By evaluating trends in virulence by a retrospective cohort design, it is quite difficult to ensure that the impact of such host-susceptibility factors and therapeutics have a constant weight on the virulence markers measurements. For example, it is obvious that in the early stages of a new epidemic, the first infected individuals presenting with the disease are those expressing host factors favouring shorter incubation periods.
Although the study by Arien et al. focused on the evolution of viral replicative capacity only [3], the pioneering study by Müller et al. provides us with a first glance at the temporal evolution of the net effect of viral and host factors on the progression of HIV disease [1]. An underlying question raised by this study is whether simple immunological or virological proxies can adequately capture the whole complexity of HIV-1 virulence and host susceptibility. These proxies are certainly perfectible and it is quite likely that new tools will emerge in a very near future that should improve the assessment of the respective role of viral and host determinants of HIV-1 pathogenesis [16].
References
1. Müller V, Lederberger B, Perrin L, Klimkait T, Furrer H, Telenti A, et al. and the Swiss HIV Cohort Study. Stable virulence levels in two decades of the Swiss HIV Cohort Study.AIDS 2005; 20:00–00.
2. Barbour JD, Grant RM. The role of viral fitness in HIV pathogenesis. Curr HIV/AIDS Rep 2005; 2:29–34.
3. Arien KK, Troyer RM, Gali Y, Colebunders RL, Arts EJ, Vanham G. Replicative fitness of historical and recent HIV-1 isolates suggests HIV-1 attenuation over time. AIDS 2005; 19:1555–1564.
4. Solomon A, Lane N, Wightman F, Gorry PR, Lewin SR. Enhanced replicative capacity and pathogenicity of HIV-1 isolated from individuals infected with drug-resistant virus and declining CD4+ T-cell counts. J Acquir Immune Defic Syndr 2005; 40:140–148.
5. Richman DD, Bozzette SA. The impact of the syncytium-inducing phenotype of human immunodeficiency virus on disease progression. J Infect Dis 1994; 169:968–974.
6. Contreras X, Bennasser Y, Chazal N, Moreau M, Leclerc C, Tkaczuk J, et al. Human immunodeficiency virus type 1 Tat protein induces an intracellular calcium increase in human monocytes that requires DHP receptors: involvement in TNF-alpha production. Virology 2005; 332:316–328.
7. Argyris EG, Pomerantz RJ. HIV-1 Vif versus APOBEC3G: newly appreciated warriors in the ancient battle between virus and host. Trends Microbiol 2004; 12:145–148.
8. Huthoff H, Malim MH. Cytidine deamination and resistance to retroviral infection: towards a structural understanding of the APOBEC proteins. Virology 2005; 334:147–153.
9. Simon V, Zennou V, Murray D, Huang Y, Ho DD, Bieniasz PD. Natural variation in Vif: differential impact on APOBEC3G/3F and a potential role in HIV-1 diversification. PLoS Pathog 2005; 1:e6.
10. Franke EK, Luban J. Inhibition of HIV-1 replication by cyclosporin A or related compounds correlates with the ability to disrupt the Gag-cyclophilin A interaction. Virology 1996; 222:279–282.
11. Bachrach E, Dreja H, Lin YL, Mettling C, Pinet V, Corbeau P, Piechczyk M. Effects of virion surface gp120 density on infection by HIV-1 and viral production by infected cells. Virology 2005; 332:418–429.
12. Hladik F, Liu H, Speelmon E, Livingston-Rosanoff D, Wilson S, Sakchalathorn P, et al. Combined effect of CCR5-Delta32 heterozygosity and the CCR5 promoter polymorphism −2459 A/G on CCR5 expression and resistance to human immunodeficiency virus type 1 transmission. J Virol 2005; 79:11677–11684.
13. Lin Y-L, Mettling C, Portales P, Reynes J, Clot J, Corbeau P. Cell surface CCR5 density determines the postentry efficiency of R5 HIV-1 infection. Proc Natl Acad Sci USA 2002; 99:15590–15595.
14. Gaudieri S, DeSantis D, McKinnon E, Moore C, Nolan D, Witt CS, et al. Killer immunoglobulin-like receptors and HLA act both independently and synergistically to modify HIV disease progression. Genes Immun 2005; 6:683–690.
15. Kiepiela P, Leslie AJ, Honeyborne I, Ramduth D, Thobakgale C, Chetty S, et al. Dominant influence of HLA-B in mediating the potential co-evolution of HIV and HLA. Nature 2004; 432:769–775.
16. Julg B, Goebel FD. Susceptibility to HIV/AIDS: an individual characteristic we can measure? Infection 2005; 33:160–162.
Keywords:
virulence proxy; viral fitness; cellular restriction; host susceptibility factors
© 2006 Lippincott Williams & Wilkins, Inc.