Abstract
Initial studies of 88 transmission pairs in the Zambia Emory HIV Research Project cohort demonstrated that the number of transmitted HLA-B associated polymorphisms in Gag, but not Nef, was negatively correlated to set point viral load (VL) in the newly infected partners. These results suggested that accumulation of CTL escape mutations in Gag might attenuate viral replication and provide a clinical benefit during early stages of infection. Using a novel approach, we have cloned gag sequences isolated from the earliest seroconversion plasma sample from the acutely infected recipient of 149 epidemiologically linked Zambian transmission pairs into a primary isolate, subtype C proviral vector, MJ4. We determined the replicative capacity (RC) of these Gag-MJ4 chimeras by infecting the GXR25 cell line and quantifying virion production in supernatants via a radiolabeled reverse transcriptase assay. We observed a statistically significant positive correlation between RC conferred by the transmitted Gag sequence and set point VL in newly infected individuals (p = 0.02). Furthermore, the RC of Gag-MJ4 chimeras also correlated with the VL of chronically infected donors near the estimated date of infection (p = 0.01), demonstrating that virus replication contributes to VL in both acute and chronic infection. These studies also allowed for the elucidation of novel sites in Gag associated with changes in RC, where rare mutations had the greatest effect on fitness. Although we observed both advantageous and deleterious rare mutations, the latter could point to vulnerable targets in the HIV-1 genome. Importantly, RC correlated significantly (p = 0.029) with the rate of CD4+ T cell decline over the first 3 years of infection in a manner that is partially independent of VL, suggesting that the replication capacity of HIV-1 during the earliest stages of infection is a determinant of pathogenesis beyond what might be expected based on set point VL alone.
Highlights
Despite a diverse HIV-1 quasispecies within chronically infected individuals, a single variant establishes infection in the majority of heterosexual transmission cases, resulting in a severe genetic bottleneck [1,2,3]
Certain mutations in the main structural protein, Gag, driven by cytotoxic T lymphocytes are detrimental to viral replication, and we showed previously that, upon transmission, viruses with higher numbers of escape mutations in Gag were associated with lower early set point viral loads
We found that the replicative capacity conferred by the transmitted Gag correlated with set point viral loads in newly infected individuals, as well as with the viral load of the transmitting partner, and we identified previously unrecognized residues associated with increasing and decreasing replicative capacity
Summary
Despite a diverse HIV-1 quasispecies within chronically infected individuals, a single variant establishes infection in the majority of heterosexual transmission cases, resulting in a severe genetic bottleneck [1,2,3]. A more profound understanding of the interaction between host and viral characteristics and how they shape early pathogenesis and disease progression will be integral for understanding the trajectory and impact of early events after heterosexual transmission. While it is well established that host factors such as HLA-class I alleles can play a major role in determining clinical progression in those individuals recently infected with HIV-1 [4,5,6,7,8,9,10] the role of transmitted viral characteristics has been understudied due to the lack of suitable cohorts in which virus from both the donor and linked recipient are available.
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