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

Jianming Tang,Eric Hunter,Joseph Mulenga,Ilene Brill,Liangyuan Hu,Susan Allen,Wei Song,Paul K Farmer,Richard A Kaslow,Rakhi Malhotra

doi:10.1371/journal.pone.0009629

Jianming Tang, Eric Hunter + Show 8 more

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https://doi.org/10.1371/journal.pone.0009629

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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.

Highlights

Polymorphic human leukocyte antigen (HLA) molecules facilitate immune surveillance by presenting a wide spectrum of self and foreign antigens to T-cells and by serving as ligands for killer immunoglobulin-like receptors (KIRs) on natural killer (NK) cells
Overall Characteristics of HIV-1 Seropositive Zambians For this study, 784 HIV-1 seropositive Zambian adults consisted of 563 seroprevalent patients (SPs) who were seropositive at enrollment and 221 SCs who became seropositive during quarterly follow-up visits (Table 1)
At the time of viral load (VL) measurements, SPs had a median duration of follow-up (DOF) of 546 days, while SCs had a median duration of infection (DOI) of 229 days

Summary

Introduction

Polymorphic human leukocyte antigen (HLA) molecules facilitate immune surveillance by presenting a wide spectrum of self and foreign antigens to T-cells and by serving as ligands for killer immunoglobulin-like receptors (KIRs) on natural killer (NK) cells. In the context of human immunodeficiency virus type 1 (HIV1) infection, multiple HLA class I alleles have been shown to differentially influence viral pathogenesis, often as a result of their selective targeting of viral epitopes for cytotoxic T-lymphocyte (CTL) responses [6,7,8]. Such CTL responses frequently and often rapidly induce viral immune escape, regardless of patient populations or HIV-1 subtypes (clades) [8,9,10,11,12,13,14]. Immunogenetic research has established various human genetic factors, especially human leukocyte antigen (HLA) variants, as independent determinants of VL set-point

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