Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection

TLDR

The precise identification of the HIV‑1 envelope glycoprotein (Env) responsible for productive clinical infection could be instrumental in elucidating the molecular basis of HIV‑1 transmission and in designing effective vaccines. The study aimed to develop a mathematical model of random viral evolution and, together with phylogenetic tree construction, analyze 3,449 complete env sequences from 102 acutely infected subjects. Using single‑genome amplification, a mathematical model of random evolution, and phylogenetic tree construction, the authors examined env sequences to infer transmission dynamics. The analysis revealed that most subjects were infected by a single founder virus with Poisson‑distributed mutations and star‑like phylogeny, while 24 subjects had multiple founders; transmitted Envs were CCR5‑dependent, masked coreceptor sites, and showed modest resistance to fusion inhibitors and broadly neutralizing antibodies, indicating a brief window of vulnerability before peak viremia.

Abstract

The precise identification of the HIV-1 envelope glycoprotein (Env) responsible for productive clinical infection could be instrumental in elucidating the molecular basis of HIV-1 transmission and in designing effective vaccines. Here, we developed a mathematical model of random viral evolution and, together with phylogenetic tree construction, used it to analyze 3,449 complete env sequences derived by single genome amplification from 102 subjects with acute HIV-1 (clade B) infection. Viral env genes evolving from individual transmitted or founder viruses generally exhibited a Poisson distribution of mutations and star-like phylogeny, which coalesced to an inferred consensus sequence at or near the estimated time of virus transmission. Overall, 78 of 102 subjects had evidence of productive clinical infection by a single virus, and 24 others had evidence of productive clinical infection by a minimum of two to five viruses. Phenotypic analysis of transmitted or early founder Envs revealed a consistent pattern of CCR5 dependence, masking of coreceptor binding regions, and equivalent or modestly enhanced resistance to the fusion inhibitor T1249 and broadly neutralizing antibodies compared with Envs from chronically infected subjects. Low multiplicity infection and limited viral evolution preceding peak viremia suggest a finite window of potential vulnerability of HIV-1 to vaccine-elicited immune responses, although phenotypic properties of transmitted Envs pose a formidable defense.