Abstract
BackgroundAcquisition of human immunodeficiency virus type 1 (HIV-1) infection is mediated by a combination of characteristics of the infectious and the susceptible member of a transmission pair, including human behavioral and genetic factors, as well as viral fitness and tropism. Here we report on the impact of established and potential new HLA class I determinants of heterosexual HIV-1 acquisition in the HIV-1-exposed seronegative (HESN) partners of serodiscordant Zambian couples.Methodology/Principal FindingsWe assessed the relationships of behavioral and clinically documented risk factors, index partner viral load, and host genetic markers to HIV-1 transmission among 568 cohabiting couples followed for at least nine months. We genotyped subjects for three classical HLA class I genes known to influence immune control of HIV-1 infection. From 1995 to December 2006, 240 HESNs seroconverted and 328 remained seronegative. In Cox proportional hazards models, HLA-A*68:02 and the B*42-C*17 haplotype in HESN partners were significantly and independently associated with faster HIV-1 acquisition (relative hazards = 1.57 and 1.55; p = 0.007 and 0.013, respectively) after controlling for other previously established contributing factors in the index partner (viral load and specific class I alleles), in the HESN partner (age, gender), or in the couple (behavioral and clinical risk score). Few if any previously implicated class I markers were associated here with the rate of acquiring infection.Conclusions/SignificanceA few HLA class I markers showed modest effects on acquisition of HIV-1 subtype C infection in HESN partners of discordant Zambian couples. However, the striking disparity between those few markers and the more numerous, different markers found to determine HIV-1 disease course makes it highly unlikely that, whatever the influence of class I variation on the rate of infection, the mechanism mediating that phenomenon is identical to that involved in disease control.
Highlights
In sub-Saharan Africa, heterosexual exposure accounts for much of the spread of human immunodeficiency virus type 1 (HIV-1) infection, especially among HIV-1 discordant couples [1]
Occasional detection of HIV-1specific cytotoxic T-lymphocytes (CTLs) in genital mucosa of HIV-1-exposed seronegative (HESN) [29] has been taken to imply a role for Human leukocyte antigen (HLA) class I alleles in preventing viruses from disseminating and inducing systemic antibody responses, but multiple studies have not shown enough consistency to establish unequivocally the involvement of HLA class I polymorphisms in variable susceptibility to HIV infection [30]
We analyzed 568 HIV-1 serodiscordant couples with complete HLA class I genotyping as well as adequate follow-up between 1995 and 2006 (Figure 1). These couples included 240 who seroconverted (SCs) with viruses closely linked to those found in their index partners and 328 susceptibles who were persistently HESN during quarterly follow-up visits
Summary
In sub-Saharan Africa, heterosexual exposure accounts for much of the spread of human immunodeficiency virus type 1 (HIV-1) infection, especially among HIV-1 discordant couples [1]. Human leukocyte antigen (HLA) class I genes in the major histocompatibility complex (MHC) are important determinants of effective immune surveillance Their allelic variants have been associated with various outcomes in the natural course of HIV-1 infection, including viremia and disease progression (time to manifest immunodeficiency after infection) [9,10,11,12,13,14,15]. Acquisition of human immunodeficiency virus type 1 (HIV-1) infection is mediated by a combination of characteristics of the infectious and the susceptible member of a transmission pair, including human behavioral and genetic factors, as well as viral fitness and tropism. We report on the impact of established and potential new HLA class I determinants of heterosexual HIV-1 acquisition in the HIV-1-exposed seronegative (HESN) partners of serodiscordant Zambian couples
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