Journal Article

Magnitude and Complexity of Rectal Mucosa HIV-1-Specific CD8+ T-Cell Responses during Chronic Infection Reflect Clinical Status

Braun, Jerome V., Shacklett, Barbara L., Young, Delandy H., Pollard, Richard B., Critchfield, J. William, Hayes, Timothy L., Garcia, Juan C.

2008

Overview

The intestinal mucosa displays robust virus replication and pronounced CD4+ T-cell loss during acute human immunodeficiency virus type 1 (HIV-1) infection. The ability of HIV-specific CD8+ T-cells to modulate disease course has prompted intensive study, yet the significance of virus-specific CD8+ T-cells in mucosal sites remains unclear. We evaluated five distinct effector functions of HIVgag-specific CD8+ T-cells in rectal mucosa and blood, individually and in combination, in relationship to clinical status and antiretroviral therapy (ART). In subjects not on ART, the percentage of rectal Gag-specific CD8+ T-cells capable of 3, 4 or 5 simultaneous effector functions was significantly related to blood CD4 count and inversely related to plasma viral load (PVL) (p<0.05). Polyfunctional rectal CD8+ T-cells expressed higher levels of MIP-1beta and CD107a on a per cell basis than mono- or bifunctional cells. The production of TNFalpha, IFN-gamma, and CD107a by Gag-specific rectal CD8+ T-cells each correlated inversely (p<0.05) with PVL, and MIP-1beta expression revealed a similar trend. CD107a and IFN-gamma production were positively related to blood CD4 count (p<0.05), with MIP-1beta showing a similar trend. IL-2 production by rectal CD8+ T-cells was highly variable and generally low, and showed no relationship to viral load or blood CD4 count. The polyfunctionality of rectal Gag-specific CD8+ T-cells appears to be related to blood CD4 count and inversely related to PVL. The extent to which these associations reflect causality remains to be determined; nevertheless, our data suggest a potentially important role for mucosal T-cells in limiting virus replication during chronic infection.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Anti-Retroviral Agents - therapeutic use / Antiretroviral agents / Antiretroviral drugs / Antiretroviral therapy / Blood / CD4 antigen / CD4-Positive T-Lymphocytes - drug effects / CD4-Positive T-Lymphocytes - immunology / CD8 antigen / CD8-Positive T-Lymphocytes - drug effects / CD8-Positive T-Lymphocytes - immunology / Chronic Disease / Chronic infection / Cohort Studies / Cytokines / Cytotoxicity / Disease Progression / Drug therapy / Female / Flow cytometry / Gag protein / Health aspects / Health Status / Highly active antiretroviral therapy / HIV / HIV Infections - blood / HIV Infections - drug therapy / HIV Infections - immunology / HIV Infections - pathology / HIV Seropositivity - blood / HIV Seropositivity - immunology / HIV-1 - immunology / Human immunodeficiency virus / Humans / Immunity, Mucosal - drug effects / Immunity, Mucosal - immunology / Immunology / Immunology/Immune Response / Infection / Infections / Infectious diseases / Infectious Diseases/HIV Infection and AIDS / Infectious Diseases/Sexually Transmitted Diseases / Interferon / Interleukin 2 / Intestinal Mucosa - drug effects / Intestinal Mucosa - immunology / Intestine / Lymphocyte Count / Lymphocytes / Lymphocytes T / Male / Medical research / Medicine / Mucosa / Mutation / Plasma / Rectum / Rectum - immunology / Rectum - pathology / Replication / T cell receptors / T cells / Tumor necrosis factor-α / Viral Load / Virology/Immunodeficiency Viruses / Virus replication / Viruses / γ-Interferon