title: HIV-induced T-cell activation/exhaustion in rectal mucosa is controlled only partially by antiretroviral treatment.
abstract: 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.
authors.affiliation: Grupo Inmunovirologia, Universidad de Antioquia, Medellín, Antioquia, Colombia.
authors.forename: Cesar Mauricio
authors.initials: CM
authors.lastname: Rueda
authors.forename: Paula Andrea
authors.initials: PA
authors.lastname: Velilla
authors.forename: Claire A
authors.initials: CA
authors.lastname: Chougnet
authors.forename: Carlos Julio
authors.initials: CJ
authors.lastname: Montoya
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Rugeles
mesh_terms: D000328:Adult; D019380:Anti-HIV Agents / Q000627:therapeutic use; D023241:Antiretroviral Therapy, Highly Active; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D060908:CTLA-4 Antigen / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000378:metabolism; D053804:Granzymes / Q000378:metabolism; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000503:physiopathology*; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008221:Lymphoid Tissue / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009092:Mucous Membrane / Q000187:drug effects / Q000378:metabolism; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism; D012007:Rectum / Q000166:cytology*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D019380:Anti-HIV Agents; D060908:CTLA-4 Antigen; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D006684:HLA-DR Antigens; D053645:Interleukin-2 Receptor alpha Subunit; C105992:PDCD1 protein, human; D061026:Programmed Cell Death 1 Receptor; D053804:Granzymes