HIV-1 Viremia Prevents the Establishment of Interleukin 2–producing HIV-specific Memory CD4+ T Cells Endowed with Proliferative Capacity

Abstract

CD4+ T cell responses are associated with disease control in chronic viral infections. We analyzed human immunodeficiency virus (HIV)-specific responses in ten aviremic and eight viremic patients treated during primary HIV-1 infection and for up to 6 yr thereafter. Using a highly sensitive 5-(and-6)-carboxyfluorescein diacetate-succinimidyl ester–based proliferation assay, we observed that proliferative Gag and Nef peptide-specific CD4+ T cell responses were 30-fold higher in the aviremic patients. Two subsets of HIV-specific memory CD4+ T cells were identified in aviremic patients, CD45RA− CCR7+ central memory cells (Tcm) producing exclusively interleukin (IL)-2, and CD45RA− CCR7− effector memory cells (Tem) that produced both IL-2 and interferon (IFN)-γ. In contrast, in viremic, therapy-failing patients, we found significant frequencies of Tem that unexpectedly produced exclusively IFN-γ. Longitudinal analysis of HIV epitope–specific CD4+ T cells revealed that only cells that had the capacity to produce IL-2 persisted as long-term memory cells. In viremic patients the presence of IFN-γ–producing cells was restricted to periods of elevated viremia. These findings suggest that long-term CD4+ T cell memory depends on IL-2–producing CD4+ T cells and that IFN-γ only–producing cells are short lived. Our data favor a model whereby competent HIV-specific Tcm continuously arise in small numbers but under persistent antigenemia are rapidly induced to differentiate into IFN-γ only–producing cells that lack self-renewal capacity.

MVA-nef induces HIV-1-specific polyfunctional and proliferative T-cell responses revealed by the combination of short- and long-term immune assays

“…20,29,42 HIV-1 viremia, in particular, impedes the establishment of IL-2-producing HIV-1-specific memory CD4 T cells endowed with proliferative capacity. 43 Several lines of evidence indicate that the proliferative capacity is maintained in primary and nonprogressive HIV-1 infection and impaired in chronic progressive infection. 16,20,44 Whether the proliferative impairment is reversible by endogenous or exogenous To account for multiple comparisons, differences between the functional groups were assessed by nonparametric KruskalWallis test for four-way comparison, followed by a pairwise Mann-Whitney test.…”

Polyfunctional HCV‐specific T‐cell responses are associated with effective control of HCV replication

“…Recent studies have indeed shown that the proliferation capacity of virus-specific CD4 and CD8 T cells is dependent upon the presence of IL-2-producing cells and that the presence of virus-specific proliferating cells is associated with control of virus replication [22,24,25]. Both CD4 1 ( Fig.…”

“…In particular, it has been shown that immune responses associated with effective virus clearance or control (low to undetectable viral load) were predominantly composed of polyfunctional CD4 1 and CD8 1 T cells. Polyfunctionality has been defined by the ability of both CD4 1 and CD8 1 T cells to produce cytokines such as IL-2 and IFN-g and to proliferate [22][23][24][25]. Other cytokines such as MIP-1b and TNF-a and functions such as degranulation activity and perforin expression are instrumental to better characterize the functional profile of T cells but do not discriminate between polyfunctional and ''only effector'' T-cell responses.…”

Programmed Death 1 Expression on HIV-Specific CD4+ T Cells Is Driven by Viral Replication and Associated with T Cell Dysfunction

“…We have previously shown that HIV-specific CD4 ϩ T cells are skewed by viral replication toward an effector memory T (T Em ) cell 3 phenotype as identified by the loss of CCR7 and the acquisition of CD57 (1,2). HIV-specific CD4 ϩ T Em cells from subjects with chronic HIV infection proliferate poorly and lack the ability to secrete IL-2 (2-4).…”