Signatures in Simian Immunodeficiency Virus SIVsmE660 Envelope gp120 Are Associated with Mucosal Transmission but Not Vaccination Breakthrough in Rhesus Macaques

Abstract

Mucosal surfaces are vulnerable to human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV) infection IMPORTANCEMost HIV-1 infections occur across a mucosal barrier, and it is therefore important to understand why these sites are vulnerable and how to protect them with a vaccine. To gain insight into these questions, we studied rhesus macaques that were vaccinated with SIVmac239 and unvaccinated controls to determine whether the SIVsmE660 viral variants that infected these two groups were different. We did not find differences between viral variants in the absence versus presence of vaccination-induced immunity, but we did find that the SIVsmE660 viral variants that infected the monkeys, regardless of vaccination, were different from the dominant population found in the viral challenge inoculum. Our data suggest that the mucosal environments of the vagina and rectum both impose a strong selection for the SIVsmE660 variants in the challenge inoculum that are most like SIV and HIVs that circulate in nature.T he majority of human immunodeficiency virus type 1 (HIV-1) transmission events occur across the genital or rectal mucosa and involve a reduction in the diversity of the infecting viral quasispecies (1). This genetic bottleneck of HIV-1 transmission has been attributed to various features of the HIV-1 envelope (Env) glycoproteins (2-8), resistance to interferon (7, 9), and a selection bias toward consensus residues that confer increased in vivo fitness (10). These studies notwithstanding, it has been difficult to pinpoint the attributes that directly facilitate transmission of a particular HIV-1 variant from a genetically diverse quasispecies. A primary focus of nonhuman primate simian immunodeficiency virus (SIV) challenge models is therefore to recapitulate the critical events that occur during HIV-1 transmission so that any observed effect, including protection, is accurately reflected by the model. An approach in which rhesus macaques are inoculated intravaginally or intrarectally at regular intervals with a relatively low dose of SIV has been shown to recapitulate the hallmark reduction in viral diversity characteristic of HIV-1 transmission (11)(12)(13)(14). As a result, the repeated, low-dose challenge method has become widely accepted and commonly utilized to model protection against mucosal SIV infection (14-32). Despite these numerous studies, the characteristics of the virus that influence intravaginal and intrarectal transmission and protection are incompletely understood.We previously demonstrated that an SIVmac239-based regimen consisting of two DNA primes followed by two modified vaccinia virus Ankara (MVA) boosts provided significant protection against repeated, low-dose SIVsmE660 intrarectal challenge. Including granulocyte-macrophage colony-stimulating factor (GM-CSF) or CD40 ligand (CD40L) as an adjuvant with the DNA Citation Smith SA, Kilgore KM, Kasturi SP, Pulendran B, Hunter E, Amara RR, Derdeyn CA. 2016. Signatures in simian immunodeficiency virus SIVsmE660 envelop...

Adenovirus prime, Env protein boost vaccine protects against neutralization-resistant SIVsmE660 variants in rhesus monkeys

“…While these authors found an enrichment in all transmission events for A/K viruses, there was no increase in selection in vaccinated animals. It was suggested that all founder viruses are enriched for the A/K genotype1819. While we also found an enrichment in the A/K genotype compared to the stock, the vaccine effect we report here was a statistically significant increase in the A/K genotype in vaccinated animals compared to sham controls.…”

Diversification in the HIV-1 Envelope Hyper-variable Domains V2, V4, and V5 and Higher Probability of Transmitted/Founder Envelope Glycosylation Favor the Development of Heterologous Neutralization Breadth

“…Because nucleotide-based dN/dS analyses are problematic when resampling the same population over short periods of time [83], and do not fully reflect the range of diversity that occurs within Env at the amino acid level (conservative vs. non-conservative amino acid changes, insertions and deletions, alterations to glycosylation sites), we developed and implemented a novel approach for statistically quantifying early Env diversity. First, FASTA amino acid alignments of the T/F Envs and early Envs from the same patient were subjected to Sequence Harmony analysis to identify amino acid positions that were significantly different between the two groups of sequences (Z-score ≤ -3) [38,63,84]. As a proof of concept for this approach, we first analyzed sequences from subject R880F, whose early neutralizing antibody responses and escape pathways had been previously mapped in our laboratory in great detail [11].…”

CD8 + Lymphocytes Are Required for Maintaining Viral Suppression in SIV-Infected Macaques Treated with Short-Term Antiretroviral Therapy

“…Single genome analysis of plasma-derived SIV was performed essentially as described previously (Burton et al, 2015; Smith et al, 2016). Additional details can be found in the Supplemental Experimental Procedures.…”