Complexity of the Inoculum Determines the Rate of Reversion of SIV Gag CD8 T Cell Mutant Virus and Outcome of Infection

Abstract

Escape mutant (EM) virus that evades CD8+ T cell recognition is frequently observed following infection with HIV-1 or SIV. This EM virus is often less replicatively “fit” compared to wild-type (WT) virus, as demonstrated by reversion to WT upon transmission of HIV to a naïve host and the association of EM virus with lower viral load in vivo in HIV-1 infection. The rate and timing of reversion is, however, highly variable. We quantified reversion to WT of a series of SIV and SHIV viruses containing minor amounts of WT virus in pigtail macaques using a sensitive PCR assay. Infection with mixes of EM and WT virus containing ≥10% WT virus results in immediate and rapid outgrowth of WT virus at SIV Gag CD8 T cell epitopes within 7 days of infection of pigtail macaques with SHIV or SIV. In contrast, infection with biologically passaged SHIV _mn229 viruses with much smaller proportions of WT sequence, or a molecular clone of pure EM SIV _mac239, demonstrated a delayed or slow pattern of reversion. WT virus was not detectable until ≥8 days after inoculation and took ≥8 weeks to become the dominant quasispecies. A delayed pattern of reversion was associated with significantly lower viral loads. The diversity of the infecting inoculum determines the timing of reversion to WT virus, which in turn predicts the outcome of infection. The delay in reversion of fitness-reducing CD8 T cell escape mutations in some scenarios suggests opportunities to reduce the pathogenicity of HIV during very early infection.

Author Summary

Understanding how to contain HIV replication by the immune system is a key goal of vaccine strategies. HIV frequently mutates to avoid immune recognition, but this may come at a “fitness cost”, weakening the virus. When HIV is transmitted to a new host, the mutations often revert back to wild-type, allowing the virus to regain a fitter state. We found that when multiple HIV-like viruses are transmitted to monkeys, containing both mutant and wild-type, reversion to wild-type is very rapid and the fitter virus results in higher viral levels. In contrast, when only escape mutant virus initiates the infection, reversion to wild-type is delayed to later during early infection, and lower levels of virus result. Our results suggest that the composition of the infecting virus plays a role in determining the outcome of HIV infections. Strategies to maintain weakened virus strains during the early HIV infection may help the host control virus replication.