HIV-Induced T-Cell Activation/Exhaustion in Rectal Mucosa Is Controlled Only Partially by Antiretroviral Treatment

• Published in: PloS one Vol. 7; no. 1; p. e30307
• Main Authors: Rueda, Cesar Mauricio, Velilla, Paula Andrea, Chougnet, Claire A., Montoya, Carlos Julio, Rugeles, Maria Teresa
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.01.2012; Public Library of Science (PLoS)
• Subjects: Active control; Adult; Aging; Anti-HIV Agents - therapeutic use; Antigens; Antiretroviral agents; Antiretroviral drugs; Antiretroviral Therapy, Highly Active; Biology; Blood; Care and treatment; CD25 antigen; CD4 antigen; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - metabolism; CD8 antigen; CD8-Positive T-Lymphocytes - drug effects; CD8-Positive T-Lymphocytes - metabolism; Cell activation; Chronic infection; CTLA-4 Antigen - metabolism; CTLA-4 protein; Cytokines; Cytomegalovirus; Cytometry; Cytotoxicity; Development and progression; Drug therapy; Esophagus; Exhaustion; Female; Flow Cytometry; Forkhead Transcription Factors - metabolism; Foxp3 protein; GATA-3 protein; Gene expression; Granzymes - metabolism; Growth factors; Gut-associated lymphoid tissues; Health aspects; Highly active antiretroviral therapy; Histocompatibility antigen HLA; HIV; HIV Infections - drug therapy; HIV Infections - immunology; HIV Infections - physiopathology; HLA-DR Antigens - metabolism; Human immunodeficiency virus; Humans; Immune response; Infections; Infectious diseases; Interleukin-2 Receptor alpha Subunit - metabolism; Leukocytes (mononuclear); Lymphatic system; Lymphocyte Activation - drug effects; Lymphocytes; Lymphocytes T; Lymphoid cells; Lymphoid tissue; Lymphoid Tissue - drug effects; Lymphoid Tissue - metabolism; Male; Medicine; Middle Aged; Mucosa; Mucous Membrane - drug effects; Mucous Membrane - metabolism; Patients; PD-1 protein; Peripheral blood mononuclear cells; Polarization; Programmed Cell Death 1 Receptor - metabolism; Rectum; Rectum - cytology; Replication; RNA; T cell receptors; T cells; T-Lymphocytes - drug effects; T-Lymphocytes - metabolism; Tissues; Tuberculosis; Virus replication; Colombia; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0030307

Peripheral blood T-cells from untreated HIV-1-infected patients exhibit reduced immune responses, usually associated with a hyperactivated/exhausted phenotype compared to HAART treated patients. However, it is not clear whether HAART ameliorates this altered phenotype of T-cells in the gastrointestinal-associated lymphoid tissue (GALT), the main site for viral replication. Here, we compared T-cells from peripheral blood and GALT of two groups of chronically HIV-1-infected patients: untreated patients with active viral replication, and patients on suppressive HAART. We characterized the T-cell phenotype by measuring PD-1, CTLA-4, HLA-DR, CD25, Foxp3 and granzyme A expression by flow cytometry; mRNA expression of T-bet, GATA-3, ROR-γt and Foxp3, and was also evaluated in peripheral blood mononuclear cells and rectal lymphoid cells. In HIV-1+ patients, the frequency of PD-1(+) and CTLA-4(+) T-cells (both CD4+ and CD8+ T cells) was higher in the GALT than in the blood. The expression of PD-1 by T-cells from GALT was higher in HIV-1-infected subjects with active viral replication compared to controls. Moreover, the expression per cell of PD-1 and CTLA-4 in CD4(+) T-cells from blood and GALT was positively correlated with viral load. HAART treatment decreased the expression of CTLA-4 in CD8(+) T cells from blood and GALT to levels similar as those observed in controls. Frequency of Granzyme A(+) CD8(+) T-cells in both tissues was low in the untreated group, compared to controls and HAART-treated patients. Finally, a switch towards Treg polarization was found in untreated patients, in both tissues. Together, these findings suggest that chronic HIV-1 infection results in an activated/exhausted T-cell phenotype, despite T-cell polarization towards a regulatory profile; these alterations are more pronounced in the GALT compared to peripheral blood, and are only partiality modulated by HAART.