HLA Allele Sharing and HIV Type 1 Viremia in Seroconverting Zambians with Known Transmitting Partners

Abstract

Rapid HIV type 1 (HIV-1) mutation coupled with immune evasion poses a major obstacle to effective interventions. In particular, transmission of HIV-1 from a donor partner (transmitter) to a recipient (seroconverter) with similar antigen-presenting molecules (i.e., human leukocyte antigens, HLA) may favor or expedite viral adaptation to host immune responses. Our PCR-based HLA-A, HLA-B, and HLA-DRB1 genotyping for 115 Zambian couples with documented intracouple HIV-1 (mostly clade C) transmission revealed that single-locus HLA allele sharing ranged from 28 to 36%. Different degrees of allele sharing, at single or multiple HLA loci between donor-recipient pairs, were associated with only modest increases in seroconverter RNA level (+0.04 to + 0.24 log(10) copies/mL, p > 0.25). Thus, partial HLA allele sharing commonly seen in Zambian couples did not appear to confer unequivocal early advantage for viral replication in the newly seroconverting subjects. However, correlation of virus loads in seroconverters with those of their known index partners (adjusted Pearson r = 0.21, p = 0.03) did imply that viral characteristics can independently contribute to variability in plasma virus load.

Cumulative Impact of Host and Viral Factors on HIV-1 Viral-Load Control during Early Infection

“…In contrast, a more significant VL correlation was shown for a transmission pair cohort of men who have sex with men (MSM) in San Francisco (21), and a phylogenetic analysis of MSM in the Swiss HIV Cohort Study concluded that up to half of the variance in set-point VL can be heritable (22). These observations reinforced the hypothesis that the genetic characteristics of the transmitted founder virus could be an important determinant for defining the early set-point VL in the linked SC (18,19,21,22). The contribution of the virus may, however, be modulated by human genetic factors in both the SC and the TSP.…”

“…This observation is consistent with our previous studies of the ZEHRP cohort and with other studies of heterosexual cohorts of limited size. These studies demonstrated a relatively weak correlation between VLs in TSPs and SCs in linked heterosexual transmission partners (18)(19)(20). In contrast, a more significant VL correlation was shown for a transmission pair cohort of men who have sex with men (MSM) in San Francisco (21), and a phylogenetic analysis of MSM in the Swiss HIV Cohort Study concluded that up to half of the variance in set-point VL can be heritable (22).…”

“…Gender has also been observed to modulate VL in both early and chronic infections in antiretroviral-naïve and -treated populations (29-31), although the exact mechanism for this is not known (32). Finally, sharing of HLA-I alleles between the TSP and the SC can lead to reduced control of virus following transmission because of the existence of CTL escape mutations selected in the TSP that reduce the efficacy of the de novo immune response (11,19,33). In our current study of 195 phylogenetically linked heterosexual transmission couples, we had a sufficiently large population to document for the first time that while the phenotype of the transmitted founder virus had a significant impact on early set-point VL, the gender of the SC as well as the immunogenetic characteristics of both the TSP and the SC significantly and independently modulated this effect.…”

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

“…Host factors ranged from coreceptor gene (e.g., CCR5) polymorphisms to HLA variants (24,50,83,84). The importance of viral characteristics is reflected by a correlation between donor and recipient VL after controlling for the effects of age and gender, as well as HLA (85). Supporting evidence from several recent studies suggests that the magnitude of the influence of the transmitted virus on the recipient's VL can be highly variable (26,27).…”

“…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).…”