Integration features of intact latent HIV-1 in CD4+ T cell clones contribute to viral persistence.

Amy S Huang,Lillian B Cohn,Mila Jankovic,Victor Ramos,Thiago Y Oliveira,Michel C Nussenzweig,Christian Gaebler

doi:10.1084/jem.20211427

Abstract

Latent intact HIV-1 proviruses persist in a small subset of long-lived CD4+ T cells that can undergo clonal expansion in vivo. Expanded clones of CD4+ T cells dominate latent reservoirs in individuals on long-term antiretroviral therapy (ART) and represent a major barrier to HIV-1 cure. To determine how integration landscape might contribute to latency, we analyzed integration sites of near full length HIV-1 genomes from individuals on long-term ART, focusing on individuals whose reservoirs are highly clonal. We find that intact proviruses in expanded CD4+ T cell clones are preferentially integrated within Krüppel-associated box (KRAB) domain-containing zinc finger (ZNF) genes. ZNF genes are associated with heterochromatin in memory CD4+ T cells; nevertheless, they are expressed in these cells under steady-state conditions. In contrast to genes carrying unique integrations, ZNF genes carrying clonal intact integrations are down-regulated upon cellular activation. Together, the data suggest selected genomic sites, including ZNF genes, can be especially permissive for maintaining HIV-1 latency during memory CD4+ T cell expansion.

Highlights

Antiretroviral therapy (ART) is highly effective in suppressing is driven by antigen exposure
The analysis focused on six individuals whose intact and replication competent proviruses had been extensively characterized through direct sequencing and viral outgrowth
To analyze HIV-1 sequences and determine their corresponding site of chromosomal integration, genomic DNA from CD4+ T cells was diluted to single proviral genome level and subjected to whole genome amplification (WGA; Fig. 1 A)

Summary

Introduction

Proviruses persist in CD4+ T cells and can be reactivated upon. The latent reactivated are not well understood. When considering all incompartment has an estimated half-life of 4–18 yr 2003) and represents the primary barrier to HIV-1 cure. Whether long half-life of the latent reservoir, including infected cell these genes contribute to integration, selection, or latency reproliferation. This idea is counterintuitive because mains unknown

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Results

Conclusion