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

Megan A. O'Connor, Paul V. Munson, Hillary C. Tunggal, Nika Hajari, Thomas B. Lewis, Debra Bratt, Cassie Moats, Jeremy Smedley, Kenneth C. Bagley, James I. Mullins, Deborah H. Fuller

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)295-305
Number of pages11
JournalAIDS Research and Human Retroviruses
Volume35
Issue number3
DOIs
StatePublished - Mar 1 2019
Externally publishedYes

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Keywords

  • antiretroviral therapy
  • mucosal immune responses
  • rhesus macaque
  • simian immunodeficiency virus
  • Th17
  • Treg

ASJC Scopus subject areas

  • Immunology
  • Virology
  • Infectious Diseases

Cite this

O'Connor, M. A., Munson, P. V., Tunggal, H. C., Hajari, N., Lewis, T. B., Bratt, D., Moats, C., Smedley, J., Bagley, K. C., Mullins, J. I., & Fuller, D. H. (2019). Mucosal T Helper 17 and T Regulatory Cell Homeostasis Correlate with Acute Simian Immunodeficiency Virus Viremia and Responsiveness to Antiretroviral Therapy in Macaques. AIDS Research and Human Retroviruses, 35(3), 295-305. https://doi.org/10.1089/aid.2018.0184