Mucosal T Helper 17 and T Regulatory Cell Homeostasis Correlate with Acute Simian Immunodeficiency Virus Viremia and Responsiveness to Antiretroviral Therapy in Macaques

• Published in: AIDS research and human retroviruses Vol. 35; no. 3; p. 295
• Main Authors: O'Connor, Megan A, Munson, Paul V, Tunggal, Hillary C, Hajari, Nika, Lewis, Thomas B, Bratt, Debra, Moats, Cassie, Smedley, Jeremy, Bagley, Kenneth C, Mullins, James I, Fuller, Deborah H
• Format: Journal Article
• Language: English
• Published: United States 01-03-2019
• Subjects: Animals; Anti-Retroviral Agents - administration & dosage; Anti-Retroviral Agents - therapeutic use; Colon - pathology; Disease Models, Animal; HIV Infections - immunology; Homeostasis - immunology; Intestinal Mucosa - immunology; Lymph Nodes - immunology; Macaca mulatta; Male; Mesentery; Monkey Diseases - drug therapy; Simian Acquired Immunodeficiency Syndrome - drug therapy; Simian Acquired Immunodeficiency Syndrome - virology; Simian Immunodeficiency Virus - pathogenicity; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Th17 Cells - immunology; Treatment Outcome; Viral Load - genetics; Viremia - virology; simian immunodeficiency virus; mucosal immune responses; rhesus macaque; Th17; antiretroviral therapy; Treg
• ISSN: 1931-8405
• DOI: 10.1089/aid.2018.0184

Depletion of gut T helper 17 (Th17) cells during HIV infection leads to decreased mucosal integrity and increased disease progression. Conversely, T regulatory (Treg) cells may inhibit antiviral responses or immune activation. In HIV elite controllers, a balanced Th17/Treg ratio is maintained in the blood, suggesting a role for these responses in controlling inflammation and viral replication. HIV-infected individuals exhibit a range in responsiveness to combination antiretroviral therapy (cART). Given the link between the Th17/Treg ratio and HIV disease, we reasoned these responses may play a role in cART responsiveness. In this study, we investigated the relationship between the mucosal Th17/Treg ratio to acute simian immunodeficiency virus (SIV) viremia and the response to cART. Nineteen rhesus macaques were infected with highly pathogenic SIVΔB670 virus and cART was initiated 6 weeks postinfection. Mucosal CD4 T cell subsets were assessed by intracellular cytokine staining in the colon and mesenteric lymph nodes. Higher baseline Th17/Treg ratios corresponded with increased acute SIV viremia. Th17/Treg ratios decreased during acute SIV infection and were not restored during cART, and this corresponded to increased gut immune activation (Ki67
), markers of microbial translocation (sCD14), and T cell exhaustion (TIGIT
). Animals that maintained a more balanced mucosal Th17/Treg ratio at the time of cART initiation exhibited a better virological response to cART and maintained higher peripheral CD4 counts. These results suggest mucosal Th17 and Treg homeostasis influences acute viremia and the response to cART, a result that suggests therapeutic interventions that improve the Th17/Treg ratio before or during cART may improve treatment of HIV.