Identification of a CCR5-Expressing T Cell Subset That Is Resistant to R5-Tropic HIV Infection

Kyra Oswald-Richter,Todd Hulgan,Spyros A Kalams,Stacy M Grill,Michelle Tseng,Derya Unutmaz,Mindy Leelawong,David W Haas

doi:10.1371/journal.ppat.0030058

Abstract

Infection with HIV-1 perturbs homeostasis of human T cell subsets, leading to accelerated immunologic deterioration. While studying changes in CD4+ memory and naïve T cells during HIV-1 infection, we found that a subset of CD4+ effector memory T cells that are CCR7−CD45RO−CD45RA+ (referred to as TEMRA cells), was significantly increased in some HIV-infected individuals. This T cell subset displayed a differentiated phenotype and skewed Th1-type cytokine production. Despite expressing high levels of CCR5, TEMRA cells were strikingly resistant to infection with CCR5 (R5)–tropic HIV-1, but remained highly susceptible to CXCR4 (X4)–tropic HIV-1. The resistance of TEMRA cells to R5-tropic viruses was determined to be post-entry of the virus and prior to early viral reverse transcription, suggesting a block at the uncoating stage. Remarkably, in a subset of the HIV-infected individuals, the relatively high proportion of TEMRA cells within effector T cells strongly correlated with higher CD4+ T cell numbers. These data provide compelling evidence for selection of an HIV-1–resistant CD4+ T cell population during the course of HIV-1 infection. Determining the host factors within TEMRA cells that restrict R5-tropic viruses and endow HIV-1–specific CD4+ T cells with this ability may result in novel therapeutic strategies against HIV-1 infection.

Highlights

Chronic immune activation and homeostatic disturbance of T cell subsets that accompany viral replication are hallmarks of HIV-1 infection [1,2,3,4]
In this manuscript we identify a subset of human CD4þ T cells, which we termed effector memory CD45RAþ T cell (TEMRA) cells, that express CCR5 but still remain resistant to infection
We show that HIV-1 infection is blocked in TEMRA cells after entry of the virus, but before it has a chance to integrate into the cellular genome

Summary

Introduction

Chronic immune activation and homeostatic disturbance of T cell subsets that accompany viral replication are hallmarks of HIV-1 infection [1,2,3,4]. Human T cells are categorized as naıve (TN) and memory (TM) subsets based on expression of CD45RA and CD45RO isoforms, respectively [5,6,7,8]. Sallusto and colleagues defined two CD4þ memory T cell subsets, termed central memory (TCM) and effector memory (TEM) cells [8]. TCM cells express high levels of CCR7 and lack potent effector functions. It has been proposed that TCM cells are responsible for maintaining long-term memory, and upon re-exposure to antigens, differentiate into TEM cells with effector functions. Prior studies indicated that HIV-1 preferentially infects memory, rather than naıve CD4þ T cells [11,12,13,14,15,16], possibly because of exclusive expression of the HIV-1 coreceptor CCR5 on memory T cells. TEM cells are enriched for expression of CCR5 relative to other CD4 memory cells [17,18], suggesting that they may be primary targets for CCR5-tropic (R5-tropic) viruses that predominate in most infected persons

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Discussion

Conclusion