HIV-1 DNA sequence diversity and evolution during acute subtype C infection

Guinevere Q Lee,Krista L Dong,Joshua M Chevalier,Kamini Gounder,Mathias Lichterfeld,Bruce D Walker,Thumbi Ndung'u,Xu G Yu,Kavidha Reddy,Kevin B Einkauf

doi:10.1038/s41467-019-10659-2

Abstract

Little is known about the genotypic make-up of HIV-1 DNA genomes during the earliest stages of HIV-1 infection. Here, we use near-full-length, single genome next-generation sequencing to longitudinally genotype and quantify subtype C HIV-1 DNA in four women identified during acute HIV-1 infection in Durban, South Africa, through twice-weekly screening of high-risk participants. In contrast to chronically HIV-1-infected patients, we found that at the earliest phases of infection in these four participants, the majority of viral DNA genomes are intact, lack APOBEC-3G/F-associated hypermutations, have limited genome truncations, and over one year show little indication of cytotoxic T cell-driven immune selections. Viral sequence divergence during acute infection is predominantly fueled by single-base substitutions and is limited by treatment initiation during the earliest stages of disease. Our observations provide rare longitudinal insights of HIV-1 DNA sequence profiles during the first year of infection to inform future HIV cure research.

Highlights

Little is known about the genotypic make-up of HIV-1 DNA genomes during the earliest stages of HIV-1 infection
We provide a longitudinal evaluation of HIV-1 DNA sequences in four subtype C HIV-1-infected individuals identified at stages II and V of acute infection
Pt 1 and Pt 2 were both captured at stage II of acute HIV-1 infection (Supplementary Table 1): Pt 1 immediately initiated antiretroviral therapy after first detection of HIV-1 plasma viremia, with raltegravir withdrawn 90 days after viral suppression, whereas Pt 2 remained untreated according to the treatment guidelines at the time of diagnosis for the entire follow-up period of 328 days

Summary

Introduction

Little is known about the genotypic make-up of HIV-1 DNA genomes during the earliest stages of HIV-1 infection. Studies to evaluate longitudinal decay dynamics of early HIV-1 reservoirs have relied on PCR-based techniques such as quantitative PCR (qPCR) and/or droplet digital PCR (ddPCR) which both capture short portions of HIV-1 DNA genomes These methods are limited by the fact that over 90% of the viral DNA genomes in long-term treated chronically-infected patients are defective and replication-incompetent, and are more likely to represent fossils of the replicative history of HIV-1 in a given patient, rather than a functionally-relevant viral reservoir able to fuel rebound viremia[21]. This study design has enabled us to identify individuals within days after HIV-1 transmission, and to capture

Methods

Results

Conclusion