Identification of five different Patr class I molecules that bind HLA supertype peptides and definition of their peptide binding motifs

We have sequenced the Pan troglodytes class I (Patr) molecules from three common chimpanzees and expressed them as single molecules in a class I-deficient cell line. These lines were utilized to obtain purified class I molecules to define the peptide binding motifs associated with five different Patr molecules. Based on these experiments, as well as analysis of the predicted structure of the B and F polymorphic MHC pockets, we classified five Patr molecules (Patr-A*0101, Patr-B*0901, Patr-B*0701, Patr-A*0602, and Patr-B*1301) within previously defined supertype specificities associated with HLA class I molecules (HLA-A3, -B7, -A1, and -A24 supertypes). The overlap in the binding repertoire between specific HLA and Patr class I molecules was in the range of 33 to 92%, depending on the particular Patr molecule as assessed by the binding of HIV-, hepatitis B virus-, and hepatitis C virus-derived epitopes. Finally, live cell binding assays of nine chimpanzee-derived B cell lines demonstrated that HLA supertype peptides bound to Patr class I molecules with frequencies in the 20-50% range.     

Foci of endemic simian immunodeficiency virus infection in wild-living eastern chimpanzees (Pan troglodytes schweinfurthii)

Simian immunodeficiency virus of chimpanzees (SIVcpz) is the immediate precursor to human immunodeficiency virus type 1 (HIV-1), yet remarkably, the distribution and prevalence of SIVcpz in wild ape populations are unknown. Studies of SIVcpz infection rates in wild chimpanzees are complicated by the species' endangered status and by its geographic location in remote areas of sub-Saharan Africa. We have developed sensitive and specific urine and fecal tests for SIVcpz antibody and virion RNA (vRNA) detection and describe herein the first comprehensive prevalence study of SIVcpz infection in five wild Pan troglodytes schweinfurthii communities in east Africa. In Kibale National Park in Uganda, 31 (of 52) members of the Kanyawara community and 39 (of approximately 145) members of the Ngogo community were studied; none were found to be positive for SIVcpz infection. In Gombe National Park in Tanzania, 15 (of 20) members of the Mitumba community, 51 (of 55) members of the Kasekela community, and at least 10 (of approximately 20) members of the Kalande community were studied. Seven individuals were SIVcpz antibody and/or vRNA positive, and two others had indeterminate antibody results. Based on assay sensitivities and the numbers and types of specimens analyzed, we estimated the prevalence of SIVcpz infection to be 17% in Mitumba (95% confidence interval, 10 to 40%), 5% in Kasekela (95% confidence interval, 4 to 7%), and 30% in Kalande (95% confidence interval, 15 to 60%). For Gombe as a whole, the SIVcpz prevalence was estimated to be 13% (95% confidence interval, 7 to 25%). SIVcpz infection was confirmed in five chimpanzees by PCR amplification of partial pol and gp41/nef sequences which revealed a diverse group of viruses that formed a monophyletic lineage within the SIVcpzPts radiation. Although none of the 70 Kibale chimpanzees tested SIVcpz positive, we estimated the likelihood that a 10% or higher prevalence existed but went undetected because of sampling and assay limitations; this possibility was ruled out with 95% certainty. These results indicate that SIVcpz is unevenly distributed among P. t. schweinfurthii in east Africa, with foci or "hot spots" of SIVcpz endemicity in some communities and rare or absent infection in others. This situation contrasts with that for smaller monkey species, in which infection rates by related SIVs are generally much higher and more uniform among different groups and populations. The basis for the wide variability in SIVcpz infection rates in east African apes and the important question of SIVcpz prevalence in west central African chimpanzees (Pan troglodytes troglodytes) remain to be elucidated.     

An early HIV mutation within an HLA-B*57-restricted T cell epitope abrogates binding to the killer inhibitory receptor 3DL1

Mutations within MHC class I-restricted epitopes have been studied in relation to T cell-mediated immune escape, but their impact on NK cells via interaction with killer Ig-like receptors (KIRs) during early HIV infection is poorly understood. In two patients acutely infected with HIV-1, we observed the appearance of a mutation within the B*57-restricted TW10 epitope (G9E) that did not facilitate strong escape from T cell recognition. The NK cell receptor KIR3DL1, carried by these patients, is known to recognize HLA-B*5703 and is associated with good control of HIV-1. Therefore, we tested whether the G9E mutation influenced the binding of HLA-B*5703 to soluble KIR3DL1 protein by surface plasmon resonance, and while the wild-type sequence and a second (T3N) variant were recognized, the G9E variant abrogated KIR3DL1 binding. We extended the study to determine the peptide sensitivity of KIR3DL1 interaction with epitopes carrying mutations near the C termini of TW10 and a second HLA-B*57-restricted epitope, IW9. Several amino acid changes interfered with KIR3DL1 binding, the most extreme of which included the G9E mutation commonly selected by HLA-B*57. Our results imply that during HIV-1 infection, some early-emerging variants could affect KIR-HLA interaction, with possible implications for immune recognition.     

Nef proteins from simian immunodeficiency virus-infected chimpanzees interact with p21-activated kinase 2 and modulate cell surface expression of various human receptors

The accessory Nef protein allows human immunodeficiency virus type 1 (HIV-1) to persist at high levels and to cause AIDS in infected humans. The function of HIV-1 group M subtype B nef alleles has been extensively studied, and a variety of in vitro activities believed to be important for viral pathogenesis have been established. However, the function of nef alleles derived from naturally simian immunodeficiency virus (SIV)-infected chimpanzees, the original host of HIV-1, or from the HIV-1 N and O groups resulting from independent zoonotic transmissions remains to be investigated. In the present study we demonstrate that SIVcpz and HIV-1 group N or O nef alleles down-modulate CD4, CD28, and class I or II MHC molecules and up-regulate surface expression of the invariant chain (Ii) associated with immature major histocompatibility complex (MHC) class II. Furthermore, the ability of Nef to interact with the p21-activated kinase 2 was generally conserved. The functional activity of HIV-1 group N and O nef genes did not differ significantly from group M nef alleles. However, SIVcpz nef genes as a group showed a 1.8- and 2.0-fold-higher activity in modulating CD28 (P = 0.0002) and Ii (P = 0.016) surface expression, respectively, but were 1.7-fold less active in down-regulating MHC class II molecules (P = 0.006) compared to HIV-1 M nef genes. Our finding that primary SIVcpz nef alleles derived from naturally infected chimpanzees modulate the surface expression of various human cellular receptors involved in T-cell activation and antigen presentation suggests that functional nef genes helped the chimpanzee virus to persist efficiently in infected humans immediately after zoonotic transmission.     

Impact of simian immunodeficiency virus infection on chimpanzee population dynamics

Like human immunodeficiency virus type 1 (HIV-1), simian immunodeficiency virus of chimpanzees (SIVcpz) can cause CD4+ T cell loss and premature death. Here, we used molecular surveillance tools and mathematical modeling to estimate the impact of SIVcpz infection on chimpanzee population dynamics. Habituated (Mitumba and Kasekela) and non-habituated (Kalande) chimpanzees were studied in Gombe National Park, Tanzania. Ape population sizes were determined from demographic records (Mitumba and Kasekela) or individual sightings and genotyping (Kalande), while SIVcpz prevalence rates were monitored using non-invasive methods. Between 2002-2009, the Mitumba and Kasekela communities experienced mean annual growth rates of 1.9% and 2.4%, respectively, while Kalande chimpanzees suffered a significant decline, with a mean growth rate of -6.5% to -7.4%, depending on population estimates. A rapid decline in Kalande was first noted in the 1990s and originally attributed to poaching and reduced food sources. However, between 2002-2009, we found a mean SIVcpz prevalence in Kalande of 46.1%, which was almost four times higher than the prevalence in Mitumba (12.7%) and Kasekela (12.1%). To explore whether SIVcpz contributed to the Kalande decline, we used empirically determined SIVcpz transmission probabilities as well as chimpanzee mortality, mating and migration data to model the effect of viral pathogenicity on chimpanzee population growth. Deterministic calculations indicated that a prevalence of greater than 3.4% would result in negative growth and eventual population extinction, even using conservative mortality estimates. However, stochastic models revealed that in representative populations, SIVcpz, and not its host species, frequently went extinct. High SIVcpz transmission probability and excess mortality reduced population persistence, while intercommunity migration often rescued infected communities, even when immigrating females had a chance of being SIVcpz infected. Together, these results suggest that the decline of the Kalande community was caused, at least in part, by high levels of SIVcpz infection. However, population extinction is not an inevitable consequence of SIVcpz infection, but depends on additional variables, such as migration, that promote survival. These findings are consistent with the uneven distribution of SIVcpz throughout central Africa and explain how chimpanzees in Gombe and elsewhere can be at equipoise with this pathogen.     

Conserved MHC class I peptide binding motif between humans and rhesus macaques

Since the onset of the HIV pandemic, the use of nonhuman primate models of infection has increasingly become important. An excellent model to study HIV infection and immunological responses, in particular cell-mediated immune responses, is SIV infection of rhesus macaques. CTL epitopes have been mapped using SIV-infected rhesus macaques, but, to date, a peptide binding motif has been described for only one rhesus class I MHC molecule, Mamu-A*01. Herein, we have established peptide-live cell binding assays for four rhesus MHC class I molecules: Mamu-A*11, -B*03, -B*04, and -B*17. Using such assays, peptide binding motifs have been established for all four of these rhesus MHC class I molecules. With respect to the nature and spacing of crucial anchor positions, the motifs defined for Mamu-B*04 and -B*17 present unique features not previously observed for other primate species. The motifs identified for Mamu-A*11 and -B*03 are very similar to the peptide binding motifs previously described for human HLA-B*44 and -B*27, respectively. Accordingly, naturally processed peptides derived from HLA-B*44 and HLA-B*27 specifically bind Mamu-A*11 and Mamu-B*03, respectively, indicating that conserved MHC class I binding capabilities exist between rhesus macaques and humans. The definition of four rhesus MHC class I-specific motifs expands our ability to accurately detect and quantitate immune responses to MHC class I-restricted epitopes in rhesus macaques and to rationally design peptide epitope-based model vaccine constructs destined for use in nonhuman primates.     

Contrasting effects of natural selection on human and chimpanzee CC chemokine receptor 5

Human immunodeficiency virus type 1 (HIV-1) evolved via cross-species transmission of simian immunodeficiency virus (SIVcpz) from chimpanzees (Pan troglodytes). Chimpanzees, like humans, are susceptible to infection by HIV-1. However, unlike humans, infected chimpanzees seldom develop immunodeficiency when infected with SIVcpz or HIV-1. SIVcpz and most strains of HIV-1 require the cell-surface receptor CC chemokine receptor 5 (CCR5) to infect specific leukocyte subsets, and, subsequent to infection, the level of CCR5 expression influences the amount of HIV-1 entry and the rate of HIV-1 replication. Evidence that variants in the 5' cis-regulatory region of CCR5 (5'CCR5) affect disease progression in humans suggests that variation in CCR5 might also influence the response of chimpanzees to HIV-1/SIVcpz. To determine whether patterns of genetic variation at 5'CCR5 in chimpanzees are similar to those in humans, we analyzed patterns of DNA sequence variation in 37 wild-born chimpanzees (26 P. t. verus, 9 P. t. troglodytes, and 2 P. t. schweinfurthii), along with previously published 5'CCR5 data from 112 humans and 50 noncoding regions in the human and chimpanzee genomes. These analyses revealed that patterns of variation in 5'CCR5 differ dramatically between chimpanzees and humans. In chimpanzees, 5'CCR5 was less diverse than 80% of noncoding regions and was characterized by an excess of rare variants. In humans, 5'CCR5 was more diverse than 90% of noncoding regions and had an excess of common variants. Under a wide range of demographic histories, these patterns suggest that, whereas human 5'CCR5 has been subject to balancing selection, chimpanzee 5'CCR5 has been influenced by a selective sweep. This result suggests that chimpanzee 5'CCR5 might harbor or be linked to functional variants that influence chimpanzee resistance to disease caused by SIVcpz/HIV-1.     

Nonstandard peptide binding revealed by crystal structures of HLA-B*5101 complexed with HIV immunodominant epitopes

The crystal structures of the human MHC class I allele HLA-B*5101 in complex with 8-mer, TAFTIPSI, and 9-mer, LPPVVAKEI, immunodominant peptide epitopes from HIV-1 have been determined by x-ray crystallography. In both complexes, the hydrogen-bonding network in the N-terminal anchor (P1) pocket is rearranged as a result of the replacement of the standard tyrosine with histidine at position 171. This results in a nonstandard positioning of the peptide N terminus, which is recognized by B*5101-restricted T cell clones. Unexpectedly, the P5 peptide residues appear to act as anchors, drawing the peptides unusually deeply into the peptide-binding groove of B51. The unique characteristics of P1 and P5 are likely to be responsible for the zig-zag conformation of the 9-mer peptide and the slow assembly of B*5101. A comparison of the surface characteristics in the alpha1-helix C-terminal region for B51 and other MHC class I alleles highlights mainly electrostatic differences that may be important in determining the specificity of human killer cell Ig-like receptor binding.     

Identification of domain boundaries within the N-termini of TAP1 and TAP2 and their importance in tapasin binding and tapasin-mediated increase in peptide loading of MHC class I

Before exit from the endoplasmic reticulum (ER), MHC class I molecules transiently associate with the transporter associated with antigen processing (TAP1/TAP2) in an interaction that is bridged by tapasin. TAP1 and TAP2 belong to the ATP-binding cassette (ABC) transporter family, and are necessary and sufficient for peptide translocation across the ER membrane during loading of MHC class I molecules. Most ABC transporters comprise a transmembrane region with six membrane-spanning helices. TAP1 and TAP2, however, contain additional N-terminal sequences whose functions may be linked to interactions with tapasin and MHC class I molecules. Upon expression and purification of human TAP1/TAP2 complexes from insect cells, proteolytic fragments were identified that result from cleavage at residues 131 and 88 of TAP1 and TAP2, respectively. N-Terminally truncated TAP variants lacking these segments retained the ability to bind peptide and nucleotide substrates at a level comparable to that of wild-type TAP. The truncated constructs were also capable of peptide translocation in vitro, although with reduced efficiency. In an insect cell-based assay that reconstituted the class I loading pathway, the truncated TAP variants promoted HLA-B*2705 processing to similar levels as wild-type TAP. However, correlating with the observed reduction in tapasin binding, the tapasin-mediated increase in processing of HLA-B*2705 and HLA-B*4402 was lower for the truncated TAP constructs relative to the wild type. Together, these studies indicate that N-terminal domains of TAP1 and TAP2 are important for tapasin binding and for optimal peptide loading onto MHC class I molecules.     

Simian immunodeficiency virus infection in wild-caught chimpanzees from cameroon

Simian immunodeficiency viruses (SIVcpz) infecting chimpanzees (Pan troglodytes) in west central Africa are the closest relatives to all major variants of human immunodeficiency virus type 1 ([HIV-1]; groups M, N and O), and have thus been implicated as the source of the human infections; however, information concerning the prevalence, geographic distribution, and subspecies association of SIVcpz still remains limited. In this study, we tested 71 wild-caught chimpanzees from Cameroon for evidence of SIVcpz infection. Thirty-nine of these were of the central subspecies (Pan troglodytes troglodytes), and 32 were of the Nigerian subspecies (Pan troglodytes vellerosus), as determined by mitochondrial DNA analysis. Serological analysis determined that one P. t. troglodytes ape (CAM13) harbored serum antibodies that cross-reacted strongly with HIV-1 antigens; all other apes were seronegative. To characterize the newly identified virus, 14 partially overlapping viral fragments were amplified from fecal virion RNA and concatenated to yield a complete SIVcpz genome (9,284 bp). Phylogenetic analyses revealed that SIVcpzCAM13 fell well within the radiation of the SIVcpzPtt group of viruses, as part of a clade including all other SIVcpzPtt strains as well as HIV-1 groups M and N. However, SIVcpzCAM13 clustered most closely with SIVcpzGAB1 from Gabon rather than with SIVcpzCAM3 and SIVcpzCAM5 from Cameroon, indicating the existence of divergent SIVcpzPtt lineages within the same geographic region. These data, together with evidence of recombination among ancestral SIVcpzPtt lineages, indicate long-standing endemic infection of central chimpanzees and reaffirm a west central African origin of HIV-1. Whether P. t. vellerosus apes are naturally infected with SIVcpz requires further study.     

Transmission of simian immunodeficiency virus SIVcpz and the evolution of infection in the presence and absence of concurrent human immunodeficiency virus type 1 infection in chimpanzees

Current data suggest that the human immunodeficiency virus type 1 (HIV-1) epidemic arose by transmission of simian immunodeficiency virus (SIV) SIVcpz from a subspecies of common chimpanzees (Pan troglodytes troglodytes) to humans. SIVcpz of chimpanzees is itself a molecular chimera of SIVs from two or more different monkey species, suggesting that recombination was made possible by coinfection of one individual animal with different lentiviruses. However, very little is known about SIVcpz transmission and the susceptibility to lentivirus coinfection of its natural host, the chimpanzee. Here, it is revealed that either infected plasma or peripheral blood mononuclear cells readily confer infection when exposure occurs by the intravenous or mucosal route. Importantly, the presence of preexisting HIV-1 infection did not modify the kinetics of SIVcpz infection once it was established by different routes. Although humoral responses appeared as early as 4 weeks postinfection, neutralization to SIVcpz-ANT varied markedly between animals. Analysis of the SIVcpz env sequence over time revealed the emergence of genetic viral variants and persistent SIVcpz RNA levels of between 10(4) and 10(5) copies/ml plasma regardless of the presence or absence of concurrent HIV-1 infection. These unique data provide important insight into possible routes of transmission, the kinetics of acute SIVcpz infection, and how readily coinfection with SIVcpz and other lentiviruses may be established as necessary preconditions for potential recombination.     

High prevalence of simian immunodeficiency virus infection in a community of savanna chimpanzees

Simian immunodeficiency virus of chimpanzees (SIVcpz) has a significant negative impact on the health, reproduction, and life span of chimpanzees, yet the prevalence and distribution of this virus in wild-living populations are still only poorly understood. Here, we show that savanna chimpanzees, who live in ecologically marginal habitats at 10- to 50-fold lower population densities than forest chimpanzees, can be infected with SIVcpz at high prevalence rates. Fecal samples were collected from nonhabituated eastern chimpanzees (Pan troglodytes schweinfurthii) in the Issa Valley (n = 375) and Shangwa River (n = 6) areas of the Masito-Ugalla region in western Tanzania, genotyped to determine the number of sampled individuals, and tested for SIVcpz-specific antibodies and nucleic acids. None of 5 Shangwa River apes tested positive for SIVcpz; however, 21 of 67 Issa Valley chimpanzees were SIVcpz infected, indicating a prevalence rate of 31% (95% confidence interval, 21% to 44%). Two individuals became infected during the 14-month observation period, documenting continuing virus spread in this community. To characterize the newly identified SIVcpz strains, partial and full-length viral sequences were amplified from fecal RNA of 10 infected chimpanzees. Phylogenetic analyses showed that the Ugalla viruses formed a monophyletic lineage most closely related to viruses endemic in Gombe National Park, also located in Tanzania, indicating a connection between these now separated communities at some time in the past. These findings document that SIVcpz is more widespread in Tanzania than previously thought and that even very low-density chimpanzee populations can be infected with SIVcpz at high prevalence rates. Determining whether savanna chimpanzees, who face much more extreme environmental conditions than forest chimpanzees, are more susceptible to SIVcpz-associated morbidity and mortality will have important scientific and conservation implications.     

Gorillas with spondyloarthropathies express an MHC class I molecule with only limited sequence similarity to HLA-B27 that binds peptides with arginine at P2

The human MHC class I gene, HLA-B27, is a strong risk factor for susceptibility to a group of disorders termed spondyloarthropathies (SpAs). HLA-B27-transgenic rodents develop SpAs, implicating HLA-B27 in the etiology of these disorders. Several nonhuman primates, including gorillas, develop signs of SpAs indistinguishable from clinical signs of humans with SpAs. To determine whether SpAs in gorillas have a similar HLA-B27-related etiology, we analyzed the MHC class I molecules expressed in four affected gorillas. Gogo-B01, isolated from three of the animals, has only limited similarity to HLA-B27 at the end of the alpha1 domain. It differs by several residues in the B pocket, including differences at positions 45 and 67. However, the molecular model of Gogo-B*0101 is consistent with a requirement for positively charged residues at the second amino acid of peptides bound by the MHC class I molecule. Indeed, the peptide binding motif and sequence of individual ligands eluted from Gogo-B*0101 demonstrate that, like HLA-B27, this gorilla MHC class I molecule binds peptides with arginine at the second amino acid position of peptides bound by the MHC class I molecule. Furthermore, live cell binding assays show that Gogo-B*0101 can bind HLA-B27 ligands. Therefore, although most gorillas that develop SpAs express an MHC class I molecule with striking differences to HLA-B27, this molecule binds peptides similar to those bound by HLA-B27.     

Mutually exclusive T-cell receptor induction and differential susceptibility to human immunodeficiency virus type 1 mutational escape associated with a two-amino-acid difference between HLA class I subtypes

The relative contributions of HLA alleles and T-cell receptors (TCRs) to the prevention of mutational viral escape are unclear. Here, we examined human immunodeficiency virus type 1 (HIV-1)-specific CD8(+) T-cell responses restricted by two closely related HLA class I alleles, B*5701 and B*5703, that differ by two amino acids but are both associated with a dominant response to the same HIV-1 Gag epitope KF11 (KAFSPEVIPMF). When this epitope is presented by HLA-B*5701, it induces a TCR repertoire that is highly conserved among individuals, cross-recognizes viral epitope variants, and is rarely associated with mutational escape. In contrast, KF11 presented by HLA-B*5703 induces an entirely different, more heterogeneous TCR beta-chain repertoire that fails to recognize specific KF11 escape variants which frequently arise in clade C-infected HLA-B*5703(+) individuals. These data show the influence of HLA allele subtypes on TCR selection and indicate that extensive TCR diversity is not a prerequisite to prevention of allowable viral mutations.     

HLA class I-associated diseases with a suspected autoimmune etiology: HLA-B27 subtypes as a model system

Although most autoimmune diseases are connected to major histocompatibility complex (MHC) class II alleles, a small number of these disorders exhibit a variable degree of association with selected MHC class I genes, like certain human HLA-A and HLA-B alleles. The basis for these associations, however, has so far remained elusive. An understanding might be obtained by comparing functional, biochemical, and biophysical properties of alleles that are minimally distinct from each other, but are nevertheless differentially associated to a given disease, like the HLA-B*27:05 and HLA-B*27:09 antigens, which differ only by a single amino acid residue (Asp116His) that is deeply buried within the binding groove. We have employed a number of approaches, including X-ray crystallography and isotope-edited infrared spectroscopy, to investigate biophysical characteristics of the two HLA-B27 subtypes complexed with up to ten different peptides. Our findings demonstrate that the binding of these peptides as well as the conformational flexibility of the subtypes is greatly influenced by interactions of the C-terminal peptide residue. In particular, a basic C-terminal peptide residue is favoured by the disease-associated subtype HLA-B*27:05, but not by HLA-B*27:09. This property appears also as the only common denominator of distinct HLA class I alleles, among them HLA-B*27:05, HLA-A*03:01 or HLA-A*11:01, that are associated with diseases suspected to have an autoimmune etiology. We postulate here that the products of these alleles, due to their unusual ability to bind with high affinity to a particular peptide set during positive T cell selection in the thymus, are involved in shaping an abnormal T cell repertoire which predisposes to the acquisition of autoimmune diseases.     

HIV-1 Replication Fitness of HLA-B*57/58:01 CTL Escape Variants Is Restored by the Accumulation of Compensatory Mutations in Gag

Expression of HLA-B*57 and the closely related HLA-B*58:01 are associated with prolonged survival after HIV-1 infection. However, large differences in disease course are observed among HLA-B*57/58:01 patients. Escape mutations in CTL epitopes restricted by these HLA alleles come at a fitness cost and particularly the T242N mutation in the TW10 CTL epitope in Gag has been demonstrated to decrease the viral replication capacity. Additional mutations within or flanking this CTL epitope can partially restore replication fitness of CTL escape variants. Five HLA-B*57/58:01 progressors and 5 HLA-B*57/58:01 long-term nonprogressors (LTNPs) were followed longitudinally and we studied which compensatory mutations were involved in the restoration of the viral fitness of variants that escaped from HLA-B*57/58:01-restricted CTL pressure. The Sequence Harmony algorithm was used to detect homology in amino acid composition by comparing longitudinal Gag sequences obtained from HIV-1 patients positive and negative for HLA-B*57/58:01 and from HLA-B*57/58:01 progressors and LTNPs. Although virus isolates from HLA-B*57/58:01 individuals contained multiple CTL escape mutations, these escape mutations were not associated with disease progression. In sequences from HLA-B*57/58:01 progressors, 5 additional mutations in Gag were observed: S126N, L215T, H219Q, M228I and N252H. The combination of these mutations restored the replication fitness of CTL escape HIV-1 variants. Furthermore, we observed a positive correlation between the number of escape and compensatory mutations in Gag and the replication fitness of biological HIV-1 variants isolated from HLA-B*57/58:01 patients, suggesting that the replication fitness of HLA-B*57/58:01 escape variants is restored by accumulation of compensatory mutations.     

Frequency of HLA-A*03 associates with HIV-1 infection in a Chinese cohort

During the early mid-1990s, a number of rural farmers across central China were employed to the unregulated plasmaselling-activity and many of them were infected by HIV-1. However, AIDS progression in the former blood donors (FBDs) is various. The aim of this study is to assess human leukocyte antigen (HLA) class I allele distribution in FBDs and evaluate its association with HIV-1 infection and disease progression. A total of 353 FBDs were enrolled in the cohort including 294 ART naïve HIV-1 seropositive and 59 HIV-1 seronegative age-matched subjects. The viral load and CD4/CD8 T cell counts were assessed in all subjects. Compared with HIV-seropositive group, the frequency of HLA-A*03 in control was significantly higher. After classifying the HLA-B alleles of the subjects according to the presence of Bw4/Bw6 serological epitopes, detrimental effect of HLA Bw6/ Bw6 homozygosity was also confirmed in the HIV-seropositive subjects. This study provides novel evidence on HLA class I allele distribution and association of HLA-A*03 frequency with HIV-1 infection and viremia in the HIV-1 infected FBDs, which may throw light on intervention strategy for the HIV-1 infection and our understanding how host immunity and genetic background affect HIV infection and AIDS progression.