Quantitative and Qualitative Assessment of Human Immunodeficiency Virus Type 1 (HIV‐1)–Specific CD4⁺T Cell Immunity togagin HIV‐1–Infected Individuals with Differential Disease Progression: Reciprocal Interferon‐γ and Interleukin‐10 Responses

Abstract

The human immunodeficiency virus type 1 (HIV-1)-specific CD4(+) T cell response was investigated in 33 untreated HIV-1-infected individuals, using highly sensitive ELISPOT assays and intracellular flow cytometry. The median frequencies of interferon (IFN)-gamma-producing HIV-1 gag-specific CD4(+) T cells did not correlate significantly with control of viral replication or progression. HIV-1 gag-specific interleukin (IL)-4-producing cells were rarely detected. Circulating frequencies of CD4(+) T cells constitutively producing IL-10, however, were significantly higher in individuals with progression or active replication. In 17 of 30 HIV-1-infected individuals, gag antigen was observed to induce IL-10 production from CD4(+) T cells. In 2 individuals, early treatment of acute HIV-1 infection "rescued" low to undetectable gag-specific IFN-gamma-producing CD4(+) T cell responses and dramatically down-regulated constitutive IL-10 production from circulating CD4(+) T cells. The detection of HIV-1-specific IL-10-inducing CD4(+) T cells in HIV-1-infected individuals suggests that HIV-1 may directly subvert specific immune responses by IL-10 induction.

HIV-Specific TGF-β-Positive CD4+T Cells Do Not Express Regulatory Surface Markers and Are Regulated by CTLA-4

“…IL-10-producing HIV-specific CD4 þ Treg suppress HIV-specific T cell function in vitro, 46,47 and their detection is associated with progressive HIV disease. 10,37,48,49 We found no significant IL-10 production by the HIV-specific TGF-b-positive CD4 þ T cells in our study. We proposed that the concomitant presence of suppressor IL-10-positive CD8 þ T cells and HIV-specific TGF-b-positive CD4 þ T cells may promote additive suppression of HIV-specific T cell responses.…”

HIV-1-Specific Memory CD4+ T Cells Are Phenotypically Less Mature Than Cytomegalovirus-Specific Memory CD4+ T Cells

“…Most HIV-1-infected individuals show poor or absent proliferative responses to HIV-1, even on successful antiretroviral therapy (2)(3)(4). Although IFN-␥-producing CD4 ϩ T cells directed against HIV-1 are detectable in individuals at all stages of disease (5)(6)(7)(8), the intensity of the HIV-1-specific IFN-␥ CD4 ϩ T cell response does not correlate with viral load or disease progression (6,7). These findings indicate that the majority of HIV-1-infected individuals have circulating HIV-1-specific memory CD4 ϩ T cells that are functionally defective.…”

HIV-Specific IL-10-Positive CD8+ T Cells Suppress Cytolysis and IL-2 Production by CD8+ T Cells

“…Previous studies have found that the proliferation of CD4 ϩ T cells from HIV-infected individuals was inversely associated with the levels of IL-10 and that responses were partially restored by anti-IL-10 Abs (17,18). In addition, a higher frequency of CD4 ϩ T cells producing IL-10 was associated with a more progressive HIV disease (19).…”