Human Leukocyte Antigens and HIV Type 1 Viral Load in Early and Chronic Infection: Predominance of Evolving Relationships

Abstract

BackgroundDuring untreated, chronic HIV-1 infection, plasma viral load (VL) is a relatively stable quantitative trait that has clinical and epidemiological implications. Immunogenetic research has established various human genetic factors, especially human leukocyte antigen (HLA) variants, as independent determinants of VL set-point.Methodology/Principal FindingsTo identify and clarify HLA alleles that are associated with either transient or durable immune control of HIV-1 infection, we evaluated the relationships of HLA class I and class II alleles with VL among 563 seroprevalent Zambians (SPs) who were seropositive at enrollment and 221 seroconverters (SCs) who became seropositive during quarterly follow-up visits. After statistical adjustments for non-genetic factors (sex and age), two unfavorable alleles (A*3601 and DRB1*0102) were independently associated with high VL in SPs (p<0.01) but not in SCs. In contrast, favorable HLA variants, mainly A*74, B*13, B*57 (or Cw*18), and one HLA-A and HLA-C combination (A*30+Cw*03), dominated in SCs; their independent associations with low VL were reflected in regression beta estimates that ranged from −0.47±0.23 to −0.92±0.32 log10 in SCs (p<0.05). Except for Cw*18, all favorable variants had diminishing or vanishing association with VL in SPs (p≤0.86).Conclusions/SignificanceOverall, each of the three HLA class I genes had at least one allele that might contribute to effective immune control, especially during the early course of HIV-1 infection. These observations can provide a useful framework for ongoing analyses of viral mutations induced by protective immune responses.

Human Leukocyte Antigen Variants B*44 and B*57 Are Consistently Favorable during Two Distinct Phases of Primary HIV-1 Infection in Sub-Saharan Africans with Several Viral Subtypes

“…HLA genotyping. Allelic variants at three HLA class I loci (HLA-A, HLA-B, and HLA-C) were resolved to 4-digit specificities using a combination of PCRbased techniques (81,82). Reference to fully resolved alleles followed the revised nomenclature effective in April 2010 (55).…”

“…In most studies, a quantitative measure of VL is used without reference to estimated date of infection (EDI), under the assumption that patients are seldom observed during acute-phase (peak) infection and that the early chronic-phase (set-point) VL is usually stable for years in patients with no apparent manifestations of immunodeficiency. Factors known or suspected to influence VL range from viral mutations (changes in replication fitness or switches in coreceptor tropism) (15,28,39,72) to host genes that govern innate and adaptive immune responses (54,75,81,83,84,86).Within the human nuclear genome, human leukocyte antigen (HLA) class I genes are the most convincing (and universally applicable) quantitative trait loci for HIV-1 viremia (14,16,17,66). However, the individual HLA alleles, haplotypes, and supertypes with reported impacts on HIV-1 VL are not always clear because their distribution and patterns of linkage disequilibrium often differ from one population to another (7,53,63).…”

“…In most studies, a quantitative measure of VL is used without reference to estimated date of infection (EDI), under the assumption that patients are seldom observed during acute-phase (peak) infection and that the early chronic-phase (set-point) VL is usually stable for years in patients with no apparent manifestations of immunodeficiency. Factors known or suspected to influence VL range from viral mutations (changes in replication fitness or switches in coreceptor tropism) (15,28,39,72) to host genes that govern innate and adaptive immune responses (54,75,81,83,84,86).…”

“…However, the individual HLA alleles, haplotypes, and supertypes with reported impacts on HIV-1 VL are not always clear because their distribution and patterns of linkage disequilibrium often differ from one population to another (7,53,63). Consensus findings have been limited to a few variants like B*27 and B*57 (9,80), although more recent work based on African cohorts has yielded consensus results for additional variants, including A*74, B*13, and B*81, that are often favorable (49,81). The HLA class I heavy chains encoded by these alleles differentially present highly conserved viral epitopes for cytotoxic T-lymphocyte (CTL) responses (5,29,39).…”

“…We and others have reported previously that both host and viral factors can independently impact HIV-1 VL during the early and chronic phases of infection (54,81,84,85). Host factors ranged from coreceptor gene (e.g., CCR5) polymorphisms to HLA variants (24,50,83,84).…”