The rapid and extensive spread of the human immunodeficiency virus (HIV) epidemic provides a rare opportunity to witness host–pathogen co-evolution involving humans. A focal point is the interaction between genes encoding human leukocyte antigen (HLA) and those encoding HIV proteins. HLA molecules present fragments (epitopes) of HIV proteins on the surface of infected cells to enable immune recognition and killing by CD8+ T cells; particular HLA molecules, such as HLA-B*57, HLA-B*27 and HLA-B*51, are more likely to mediate successful control of HIV infection1. Mutation within these epitopes can allow viral escape from CD8+ T-cell recognition. Here we analysed viral sequences and HLA alleles from >2,800 subjects, drawn from 9 distinct study cohorts spanning 5 continents. Initial analysis of the HLA-B*51-restricted epitope, TAFTIPSI (reverse transcriptase residues 128–135), showed a strong correlation between the frequency of the escape mutation I135X and HLA-B*51 prevalence in the 9 study cohorts (P = 0.0001). Extending these analyses to incorporate other well-defined CD8+ T-cell epitopes, including those restricted by HLA-B*57 and HLA-B*27, showed that the frequency of these epitope variants (n = 14) was consistently correlated with the prevalence of the restricting HLA allele in the different cohorts (together, P < 0.0001), demonstrating strong evidence of HIV adaptation to HLA at a population level. This process of viral adaptation may dismantle the well-established HLA associations with control of HIV infection that are linked to the availability of key epitopes, and highlights the challenge for a vaccine to keep pace with the changing immunological landscape presented by HIV.

For this review of genetic susceptibility to human immunodeficiency virus type 1 infection, far more information was available on factors involved in acquisition of the virus by an uninfected "recipient" than on propagation by the infected "donor." Genetic variation presumably alters transmission from an infected host primarily by regulating the replication of virus and the concentration of particles circulating in blood and mucosal secretions of the potential donor. Thus, the effects of host genetic variation on transmission are inextricably bound to the well-established and powerful effects on virus load at different stages of infection. Teasing apart the effects in both donors and recipients has been and will continue to be quite difficult.

Polymorphic products of genes in the HLA region contributing to variability in the course of human immunodeficiency virus type 1 (HIV-1) infection were identified by screening 375 Caucasian seroconverters who were aggregated from 3 cohorts. AIDS-free time was related to numerous (15) class I alleles, alone or in conjunction with transporter protein variants, to homozygosity at the A or B locus, and to alleles of two class II haplotypes. A prognostic scoring algorithm derived from the 3 cohorts captured multiple HLA contributions to protection or to risk (relative hazard=0.57-60 per unit increase in score, all P<<.001). The impact of HLA was strong and appeared independent of the effects of chemokine receptor/ligand polymorphisms and antiretroviral treatment. The algorithm also predicted divergent rates of CD4+ cell decline in 2 other groups, totaling 227 seropositive persons (P=.06 - <.001). Confirmation of these relationships should encourage investigation of HIV-1 antigen processing and presentation mediated by polymorphisms in the HLA region.

African-Americans (AFAM) and Hispanics (HIS) represent only 13% and 12% of the U.S. population but 54% and 19%, respectively, of annually incident HIV-1 infections in the United States. The 88 patients in the current study were from U.S. racial or ethnic minority groups (72% African-American, 17% Hispanic), female (85%), and adolescent (mean age 20 years). Their HLA allele distributions were distinct from patterns in U.S. whites. Overall, HIV-1-specific T cell responses were observed in 91% of participants: 75% recognized peptides in Gag, 67% Pol, 57% Nef, and 41% Env. The patients recognized 87 (36%) of 244 Gag, Pol, Env, or Nef peptides tested. Similar to what has been seen in white cohorts, epitope-rich peptide clusters were identified within conserved functional domains in Gag matrix, Gag capsid, Pol reverse transcriptase, and Nef. Peptides representing variable regions from within the B subtype or with more changes from the B subtype consensus sequence were less likely to stimulate a positive T cell response. A small percentage (17%) of unique T cell responses was found in this cohort that displayed no previously known T cell epitopes. Dominant responses generally overlapped with epitope-rich regions in HIV-1 described previously for whites, although many of these peptides were likely restricted by HLA class I alleles not previously associated with these epitopes. Hence host genetic variation among different racial groups may have less impact on the utility of candidate HIV-1 vaccines than previously suspected.

Numerous reports have suggested that immunogenetic factors may influence HIV-1 acquisition, yet replicated findings that translate between study cohorts remain elusive. Our work aimed to test several hypotheses about genetic variants within the IL10-IL24 gene cluster that encodes interleukin (IL)-10, IL-19, IL-20, and IL-24. In aggregated data from 515 Rwandans and 762 Zambians with up to 12 years of follow-up, 190 single nucleotide polymorphisms (SNPs) passed quality control procedures. When HIV-1-exposed seronegative subjects (n = 486) were compared with newly seroconverted individuals (n = 313) and seroprevalent subjects (n = 478) who were already infected at enrollment, rs12407485 (G>A) in IL19 showed a robust association signal in adjusted logistic regression models (odds ratio = 0.64, P = 1.7 × 10−4, and q = 0.033). Sensitivity analyses demonstrated that (i) results from both cohorts and subgroups within each cohort were highly consistent; (ii) verification of HIV-1 infection status after enrollment was critical; and (iii) supporting evidence was readily obtained from Cox proportional hazards models. Data from public databases indicate that rs12407485 is part of an enhancer element for three transcription factors. Overall, these findings suggest that molecular features at the IL19 locus may modestly alter the establishment of HIV-1 infection.