High-Level Variability in the ORF-K1 Membrane Protein Gene at the Left End of the Kaposi’s Sarcoma-Associated Herpesvirus Genome Defines Four Major Virus Subtypes and Multiple Variants or Clades in Different Human Populations (original) (raw)
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Journal of virology, 1997
Previous analysis of the majority of Kaposi's sarcoma (KS) tumors, in both AIDS and non-AIDS populations, has revealed the consistent presence of two small subsegments (open reading frame 25/26 [ORF25/26] and ORF75) of a novel human gamma class herpesvirus genome referred to as KSHV or HHV-8. We have carried out DNA sequence comparisons with DNAs encompassing a total of 2,500 bp each over three separate PCR-amplified fragments from KS lesions and body cavity-based lymphoma (BCBL) samples from 12 distinct patients, including four African and two classical or endemic non-AIDS KS samples. The results revealed differences at 37 of 2,500 nucleotide positions (i.e., 1.5% overall variation). However, the 12 HHV-8 genomes examined fell into three distinct but very narrow subgroupings (A, B, and C strains). All A strain isolates differed from B strain isolates at 16 positions, but of the eight U.S. samples tested, six were A strains, and these differed at no more than two positions among...
Virology, 2010
Human herpesvirus-8 (HHV-8) variants have been found heterogeneously distributed among human populations living in diverse geographic regions, but their differential pathogenicity in Kaposi's sarcoma development remains controversial. In the present study, HHV-8 variant distribution has been analyzed in classic, iatrogenic, endemic as well as epidemic Kaposi's sarcoma (KS) during pre-AIDS and AIDS period in countries with different KS incidence rate. DNA samples from cutaneous KS lesions of 68 patients living in Africa (n = 23, Cameroon, Kenya and Uganda), Europe (n = 34, Greece and Italy) and North America (n = 11) have been subjected to PCR amplification of HHV-8 ORF 26, T0.7, K1 and K14.1/15, followed by direct nucleotide sequencing and phylogenetic analysis. Among the 23 African samples, the majority of HHV-8 ORF 26 variants clustered with the subtype R (n = 12) and B (n = 5). Conversely, the viral sequences obtained from 45 European and North European tumors belonged mainly to subtype A/C (n = 36). In general, HHV-8 and K1 variant clustering paralleled that of ORF 26 and T0.7. Genotyping of the K14.1/15 loci revealed a large predominance of P subtype in all tumors. In conclusion, comparison of the HHV-8 sequences from classic or endemic versus AIDS-associated KS showed a strong linkage of the HHV-8 variants with specific populations, which has not changed during AIDS epidemic.
Journal of virology, 1999
Kaposi's sarcoma (KS)-associated herpesvirus or human herpesvirus 8 (HHV8) DNA is found consistently in nearly all classical, endemic, transplant, and AIDS-associated KS lesions, as well as in several AIDS-associated lymphomas. We have previously sequenced the genes for the highly variable open reading frame K1 (ORF-K1) protein from more than 60 different HHV8 samples and demonstrated that they display up to 30% amino acid variability and cluster into four very distinct evolutionary subgroups (the A, B, C, and D subtypes) that correlate with the major migrationary diasporas of modern humans. Here we have extended this type of analysis to six other loci across the HHV8 genome to further evaluate overall genotype patterns and the potential for chimeric genomes. Comparison of the relatively conserved ORF26, T0.7/K12, and ORF75 gene regions at map positions 0. 35, 0.85, and 0.96 revealed typical ORF-K1-linked subtype patterns, except that between 20 and 30% of the genomes analyzed p...
Virology, 2022
Kaposi sarcoma (KS)-associated herpesvirus (KSHV/HHV-8) was first sequenced from the body cavity (BC) lymphoma cell line, BC-1, in 1996. Few other KSHV genomes have been reported. Our knowledge of sequence variation for this virus remains spotty. This study reports additional genomes from historical US patient samples and from African KS biopsies. It describes an assay that spans regions of the virus that cannot be covered by short read sequencing. These include the terminal repeats, the LANA repeats, and the origins of replication. A phylogenetic analysis, based on 107 genomes, identified three distinct clades; one containing isolates from USA/ Europe/Japan collected in the 1990s and two of Sub-Saharan Africa isolates collected since 2010. This analysis indicates that the KSHV strains circulating today differ from the isolates collected at the height of the AIDS epidemic. This analysis helps experimental designs and potential vaccine studies.
Journal of Clinical Virology, 2007
A human gamma class herpesvirus within the rhadinovirus family known as Kaposi's sarcomaassociated herpesvirus (KSHV) or human herpesvirus 8 (HHV8) is now fully accepted as the etiological agent of both Kaposi's sarcoma (KS) and primary effusion lymphoma (PEL), as well as of some cases of multicentric Castleman's didease (MCD). The rates of these diseases are greatly increased in certain AIDS subpopulations (epidemic form), less so in organ transplant patients (iatrogenic form), and they also occur in rare non-AIDS associated cases, usually in elderly men (classical form). KSHV DNA can be detected in virtually all KS lesions and PEL cell lines, and in many MCD biopsies, and often also in PBMC or saliva from these same patients, from asymptomatic dual HIV and KSHV seropositive AIDS patients, and in febrile children in Africa undergoing primary KSHV infections. However, except in sub-Saharan Africa (>50%) and parts of the Mediterranean and Middle East (15%), most human populations show only 1 to <3% seropositivity rates and KSHV DNA is rarely detectable in PBMC and saliva samples from healthy individuals.
Journal of Clinical Virology, 2002
Background: the genomes of human Kaposi's sarcoma-associated herpesvirus (KSHV) display several levels of DNA sequence heterogeneity and subgrouping that show distinctive clustering patterns in related human populations. The four major subtype patterns for the hypervariable ORF-K1 protein correlate closely with the principal diasporas resulting from the migration of modern humans out of East Africa and suggest that KSHV is an ancient human virus that is transmitted primarily in a familial fashion with consequent very low recombination rates. However, chimeric www.elsevier.com/locate/jcv : S 1 3 8 6 -6 5 3 2 ( 0 1 ) 0 0 2 0 5 -0 J. Zong et al. / Journal of Clinical Virology 23 (2002) 119-148 120 genomes have also been detected, especially with regard to the presence of P versus M alleles of the ORF-K15 gene. Objecti6es: to understand further the genetic organization and evolutionary history of KSHV, especially with regard to possible new subtypes, recombinant genomes, constant region loci and clustering in particular ethnic groups or among classic versus epidemic cases in the same geographic area. Study design: direct PCR DNA sequencing was carried out on the ORF-K1 and ORF-K15 genes at the extreme left and right hand sides, as well as on six other internal loci of diagnostic samples collected from 70 new KSHV-positive patients in Israel, South Korea, Sicily, Scandinavia, Brazil, Uganda, South Africa and the US. Results and conclusions: our overall results from more than 135 KSHV genomes from many different human population groups now provides evidence for seven distinct subtypes of KSHV genomes (referred to as A/P, B/P, C/P, D/P, M, N and Q). However, the two most closely related subtypes (A/P and C/P) are only differentiated at the LHS side of the genome, and the three most distantly related forms (M, N and Q) appear to exist only as small chimeric segments that are remnants from the RHS of more ancient forms of the virus. By analyzing multiple conserved loci across the B subtype genomes that predominate in sub-Saharan Africa, we can also now recognize three to four distinct B genome subgroups with varying patterns of inter and intratypic mosaicism. Analysis of classic KS genomes from Israel has revealed that the ORF-K1 clade referred to as A1% predominates in Ashkenazi Jewish immigrants from Russia, whereas C2 and C6 variants predominate in North African Sephardi Jews. A variety of chimeric genomes containing C2 or C3 ORF-K1 genes are disseminated among classic KS cases throughout Europe and Asia including Israel, Sicily, Scandinavia, South Korea, and Taiwan. Comparison of the genomes from classic versus AIDS-associated KSHV in the US indicates that it was derived originally by reactivation and spread of a subset of the endogenous viruses carried by descendants of immigrants from endemic areas of Northern and Eastern Europe, the Mediterranean and sub-Saharan Africa.
Anticancer research
Kaposi's sarcoma-associated herpesvirus (KSHV)/human herpesvirus 8 (HHV-8) is consistently found in almost all observed Kaposi's sarcomas (KS), whether AIDS-associated, iatrogenic or classic. To our knowledge no data are available on the genetic polymorphism of HHV-8 from Greece. We report the study of 15 renal transplant recipients with KS, 5 with AIDS-associated KS, 11 with classic KS and 60 healthy individuals from Greece. Polymerase chain reaction (PCR) was carried out on DNA extracted from peripheral-blood mononuclear cells (PBMC) or KS cutaneous biopsies, using specific primers for the HHV-8, KS330 fragment from ORF-26 (233 bp) and the highly variable region (VR1) from ORF-K1 (363 bp). HHV-8 DNA was detected in 30 out of 31 (97%) KS cases, regardless of their clinico-pathological subtype and in 10 out of 60 (16.7%) healthy individuals. Sequencing of the ORF26 fragment demonstrated that the 40 HHV-8 strains were of the A and C sub-types. Furthermore, sequencing of the O...
Genotypic distribution of HHV-8 in AIDS individuals without and with Kaposi sarcoma
Medicine, 2016
AIDS-associated Kaposi's sarcoma (AIDS-KS) caused by human herpes virus 8 (HHV-8) is the most severe and resistant form of KS tumor. Our aim was to verify whether there is an association between HHV-8 variability and development of AIDS-KS in Brazil by comparing the HHV-8 variability between individuals without and with KS. Saliva samples and blood, when available, were analyzed by PCR techniques for detection of the fragments of ORF K1 of HHV-8, which were then genotyped and analyzed regarding the genetic variability. Our study described 106 positive cases for HHV-8 in the saliva from 751 AIDS patients without previous KS. In addition, we performed a phylogenetic analysis of HHV-8 in 34 of the 106 AIDS patients without KS and in 33 of the 37 patients with active KS. The distribution of HHV-8 genotypes A, B, C, and F in AIDS individuals was indistinguishable by comparing non-KS and KS groups, as well as regarding ethnicity. Considering the KS group, genotype B was associated with better prognosis of KS tumor. Interestingly, we found a particular profile of diversity within clade C and 2 recombinant patterns of HHV-8 in the saliva of AIDS individuals without KS. We emphasize the need to achieve standard genotyping protocol for ORF K1 amplification, thus allowing for substantial detection of HHV-8 variants. Our findings can shed light on the role of HHV-8 variability in the pathogenesis of AIDS-KS. Abbreviations: AIDS-KS = acquired immunodeficiency syndrome associated Kaposi's sarcoma, cART = combination antiretroviral therapy, EDTA = ethylene diamine tetra acetic acid, EPA = evolutionary placement algorithm, HHV-8 = human herpesvirus type 8, HIV Tat = Tat protein involved in the replication of immunodeficiency virus type 1, IFA = immunofluorescence assay, KS = Kaposi's sarcoma, LANA = latency-associated nuclear antigen, ML = maximum likelihood, ORF = open reading frame, PBMCs = peripheral blood mononuclear cells.