Abstract
BackgroundSevere genetic bottleneck occurs during HIV-1 sexual transmission whereby most infections are initiated by a single transmitted/founder (T/F) virus. Similar observations had been made in nonhuman primates exposed mucosally to SIV/SHIV. We previously reported variable clinical outcome in rhesus macaques inoculated intravaginally (ivg) with a high dose of R5 SHIVSF162P3N. Given the potential contributions of viral diversity to HIV-1 persistence and AIDS pathogenesis and recombination between retroviral genomes increases the genetic diversity, we tested the hypothesis that transmission of multiple variants contributes to heightened levels of virus replication and faster disease progression in the SHIVSF162P3N ivg-infected monkeys.ResultsWe found that the differences in viral replication and disease progression between the transiently viremic (TV; n = 2), chronically-infected (CP; n = 8) and rapid progressor (RP; n = 4) ivg-infected macaques cannot be explained by which variant in the inoculum was infecting the animal. Rather, transmission of a single variant was observed in both TV rhesus, with 1–2 T/F viruses found in the CPs and 2–4 in all four RP macaques. Moreover, the genetic relatedness of the T/F viruses in the CP monkeys with multivariant transmission was greater than that seen in the RPs. Biological characterization of a subset of T/F envelopes from chronic and rapid progressors revealed differences in their ability to mediate entry into monocyte-derived macrophages, with enhanced macrophage tropism observed in the former as compared to the latter.ConclusionOur study supports the tenet that sequence diversity of the infecting virus contributes to higher steady-state levels of HIV-1 virus replication and faster disease progression and highlights the role of macrophage tropism in HIV-1 transmission and persistence.
Highlights
Severe genetic bottleneck occurs during human immunodeficiency virus type 1 (HIV-1) sexual transmission whereby most infections are initiated by a single transmitted/founder (T/F) virus
Since recombination between retroviral genomes is estimated to exceed the rate of mutation [31,32,33,34], and extensive recombination among HIV-1 quasispecies has been shown to contribute to viral diversity in infected patients [22,35], it is reasonable to hypothesize that transmission of multiple variants facilitates the generation of genetic variations and increase in viral fitness, leading to heightened levels of virus replication and rapid disease progression
Cell count compared to women who were infected with a single viral genotype [19]. Our study extends these early observations by showing that the number of variants, sequence diversity and macrophage tropism of the T/F populations contribute to higher steady-state levels of HIV-1 virus replication and faster disease progression
Summary
Severe genetic bottleneck occurs during HIV-1 sexual transmission whereby most infections are initiated by a single transmitted/founder (T/F) virus. Since recombination between retroviral genomes is estimated to exceed the rate of mutation [31,32,33,34], and extensive recombination among HIV-1 quasispecies has been shown to contribute to viral diversity in infected patients [22,35], it is reasonable to hypothesize that transmission of multiple variants facilitates the generation of genetic variations and increase in viral fitness, leading to heightened levels of virus replication and rapid disease progression We tested this hypothesis by investigating the population size and characteristics of the T/F viruses in R5 SHIVSF162P3N intravaginally infected macaques with variable clinical outcome
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