OA21.01
Background: HIV escapes adaptive cellular immunity by selecting mutations that are associated with the individual's HLA-I alleles. These mutations can be transmitted but the impact of this process on pathogenesis is poorly understood.
Methods: In 169 transmission pairs, we studied the transmission of HIV polymorphisms in Gag, Pol and Nef by Sanger sequencing of population amplicons in the donor (D) and the linked-recipient (LR) (≤3 months post-transmission). Polymorphisms statistically-linked to HLA alleles or located in well-defined CTL epitopes were quantified according to each LR's HLA alleles and associated with their set-point VL and CD4 counts.
Results: The majority of polymorphisms (83.6%) were transmitted from the D to the LR and a significant fraction (17.3%) was already adapted to the LR's HLA (11.6% escape and 6.2% epitope-located). A Spearman correlation analysis showed that transmission of Pol polymorphisms irrelevant to the LR's HLA was associated with a diminished set-point VL (p=0.003). This association was lost (p=0.4) when other variables known to determine set-point VL (gender-p=0.01; B*57-p=0.02; HLA-B sharing-p=0.006; replicative capacity (RC)-p=0.008) were included in a Generalized Linear Model. An in-depth analysis of survival curves (log-rank test) for different CD4 endpoints (200–350 cells/ul) showed that the proportion of transmitted HLA-linked polymorphisms relevant to the LR' HLA in Gag was consistently associated with a faster CD4 decline (p=0.0004). When other factors (gender, protective alleles, allele sharing, RC and set-point VL) were considered in a Cox Proportional Hazard Model, the proportion of transmitted HLA-linked polymorphisms in Gag remained the only variable significantly associated with CD4 decline (p=0.03).
Conclusions: Because most Gag, Pol and Nef polymorphisms are transmitted, newly infected individuals can receive a pre-adapted variant that leads to an accelerated disease progression (faster CD4 decline) without showing a significant effect on set-point VL.
