Heterosexual Transmission of Subtype C HIV-1 Selects Consensus-Like Variants without Increased Replicative Capacity or Interferon-α Resistance.

Martin J Deymier,Dario A Dilernia,Susan A Allen,Persephone Borrow,Eric Hunter,Zachary Ende,William Kilembe,Angharad E Fenton-May,Michael H Malim

doi:10.1371/journal.ppat.1005154

Martin J Deymier, Dario A Dilernia + Show 7 more

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https://doi.org/10.1371/journal.ppat.1005154

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Journal: PLoS pathogens	Publication Date: Sep 17, 2015
Citations: 78	License type: CC BY 4.0

Affiliation: Emory University, University of Oxford

Abstract

Heterosexual transmission of HIV-1 is characterized by a genetic bottleneck that selects a single viral variant, the transmitted/founder (TF), during most transmission events. To assess viral characteristics influencing HIV-1 transmission, we sequenced 167 near full-length viral genomes and generated 40 infectious molecular clones (IMC) including TF variants and multiple non-transmitted (NT) HIV-1 subtype C variants from six linked heterosexual transmission pairs near the time of transmission. Consensus-like genomes sensitive to donor antibodies were selected for during transmission in these six transmission pairs. However, TF variants did not demonstrate increased viral fitness in terms of particle infectivity or viral replicative capacity in activated peripheral blood mononuclear cells (PBMC) and monocyte-derived dendritic cells (MDDC). In addition, resistance of the TF variant to the antiviral effects of interferon-α (IFN-α) was not significantly different from that of non-transmitted variants from the same transmission pair. Thus neither in vitro viral replicative capacity nor IFN-α resistance discriminated the transmission potential of viruses in the quasispecies of these chronically infected individuals. However, our findings support the hypothesis that within-host evolution of HIV-1 in response to adaptive immune responses reduces viral transmission potential.

Highlights

HIV-1 transmission is characterized by an extreme genetic bottleneck, the basis of which is unclear
Despite the available HIV-1 diversity present in a chronically infected individual, single viral variants are transmitted in 80–90% of heterosexual transmission events
Genetic & Phenotypic Characteristics of Transmitted HIV-1 Variants part by the International AIDS Vaccine Initiative (SAA), whose work is made possible by generous support from many donors including: the Bill & Melinda Gates Foundation; the Ministry of Foreign Affairs of Denmark; Irish Aid; the Ministry of Finance of Japan; the Ministry of Foreign Affairs of the Netherlands; the Norwegian Agency for Development Cooperation (NORAD); the United Kingdom Department for International Development (DFID), and the United States Agency for International Development (USAID)

Summary

Introduction

HIV-1 transmission is characterized by an extreme genetic bottleneck, the basis of which is unclear Studies of both the highly diverse envelope glycoprotein [1,2,3] and full HIV-1 genomes [4] demonstrated that 80–90% of heterosexual transmissions are initiated by a single virus variant selected from the diverse viral quasispecies present in the chronically infected transmitting partner. Reported characteristics of TF virus Envs include a selection for CCR5-tropism [2,20], a predominance of shorter and less glycosylated Env proteins [1,11,15,18,19], a preference for binding α4β7 [10,21] and a selection for more ancestral variants [8,22] These studies observed selection of viral traits, others found that acute and chronic variants had similar characteristics. Studies of env only clones from acute infection compared with chronic control viruses have shown similar CD4 T cell subset tropism, low macrophage tropism, and a lack of effect of blocking α4β7 on infection [25]

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