Rare HIV-1 transmitted/founder lineages identified by deep viral sequencing contribute to rapid shifts in dominant quasispecies during acute and early infection

Abstract

In order to inform the rational design of HIV-1 preventive and cure interventions it is critical to understand the events occurring during acute HIV-1 infection (AHI). Using viral deep sequencing on six participants from the early capture acute infection RV217 cohort, we have studied HIV-1 evolution in plasma collected twice weekly during the first weeks following the advent of viremia. The analysis of infections established by multiple transmitted/founder (T/F) viruses revealed novel viral profiles that included: a) the low-level persistence of minor T/F variants, b) the rapid replacement of the major T/F by a minor T/F, and c) an initial expansion of the minor T/F followed by a quick collapse of the same minor T/F to low frequency. In most participants, cytotoxic T-lymphocyte (CTL) escape was first detected at the end of peak viremia downslope, proceeded at higher rates than previously measured in HIV-1 infection, and usually occurred through the exploration of multiple mutational pathways within an epitope. The rapid emergence of CTL escape variants suggests a strong and early CTL response. Minor T/F viral strains can contribute to rapid and varied profiles of HIV-1 quasispecies evolution during AHI. Overall, our results demonstrate that early, deep, and frequent sampling is needed to investigate viral/host interaction during AHI, which could help identify prerequisites for prevention and cure of HIV-1 infection.

Caution is needed in interpreting HIV transmission chains by ultradeep sequencing

“…Resistant variants are generally less fit than wild-type variants. On the other hand, rapid change of minority variants levels during early infection had been reported [42], supporting viral lineage modifications in response to adaptive immunity or consistent with the hypothesis that fitness-impacting mutations are efficiently and rapidly removed.…”

In vitro replicative fitness of early Transmitted founder HIV-1 variants and sensitivity to Interferon alpha

“…Concurrently, the virus evolves over some time by incorporating mutations to escape drug or humoral immune pressure and ensure its survival and fitness 3 . Understanding the key events occurring during acute HIV-1 infection, that play a key role in determining the course of the disease 4 , is therefore crucial for identification of an effective vaccine strategy that can protect against HIV-1 or other alternative prevention approaches 1 . Further, the phenotypic traits of infectious viral variants associated with enhanced mucosal transmission need to be identified and characterized 5 .…”

“…The different stages of HIV-1 infection are classified as primary/acute, asymptomatic/latent, and later/end-stage disease (AIDS). Acute infection is often associated with very high viral load 6 and rapid depletion of CD4 + T cells 4 , while chronic HIV-1 infection is characterized by higher genotypic and phenotypic diversity 7 . Identifying the mechanisms involved in the interaction between the virus and the host during the acute phase of infection can provide a critical opportunity to prevent transmission of HIV infection.…”

Next-generation sequencing of HIV-1 single genome amplicons

“…The plasticity of HIV-1 quasispecies allows them to infect different cell targets [8], escape host immunity [9], and resist inhibition by ART [10]. A major challenge for the study of this high level of genetic diversity is the limited capacity of bulk PCR/sequencing techniques to capture the complexity of the viral quasispecies [11].…”