CD4+ T-cell-independent mechanisms suppress reactivation of latent tuberculosis in a macaque model of HIV coinfection

Taylor W. Foreman, Smriti Mehra, Denae N. LoBato, Adel Malek, Xavier Alvarez, Nadia A. Golden, Allison N. Bucşan, Peter J. Didier, Lara A. Doyle-Meyers, Kasi E. Russell-Lodrigue, Chad J. Roy, James Blanchard, Marcelo J. Kuroda, Andrew A. Lackner, John Chan, Shabaana A. Khader, William R. Jacobs, Deepak Kaushal

Research output: Contribution to journalArticle

48 Scopus citations

Abstract

The synergy between Mycobacterium tuberculosis (Mtb) and HIV in coinfected patients has profoundly impacted global mortality because of tuberculosis (TB) and AIDS. HIV significantly increases rates of reactivation of latent TB infection (LTBI) to active disease, with the decline in CD4+ T cells believed to be the major causality. In this study, nonhuman primates were coinfected with Mtb and simian immunodeficiency virus (SIV), recapitulating human coinfection. A majority of animals exhibited rapid reactivation of Mtb replication, progressing to disseminated TB and increased SIV-associated pathology. Although a severe loss of pulmonary CD4+ T cells was observed in all coinfected macaques, a subpopulation of the animals was still able to prevent reactivation and maintain LTBI. Investigation of pulmonary immune responses and pathology in this cohort demonstrated that increased CD8+ memory T-cell proliferation, higher granzyme B production, and expanded B-cell follicles correlated with protection from reactivation. Our findings reveal mechanisms that control SIV- and TB-associated pathology. These CD4-independent protective immune responses warrant further studies in HIV coinfected humans able to control their TB infection. Moreover, these findings will provide insight into natural immunity to Mtb and will guide development of novel vaccine strategies and immunotherapies.

Original languageEnglish (US)
Pages (from-to)E5636-E5644
JournalProceedings of the National Academy of Sciences of the United States of America
Volume113
Issue number38
DOIs
StatePublished - Sep 20 2016

Keywords

  • B cells
  • CD4 T cells
  • CD8 T cells
  • Nonhuman primate
  • Tuberculosis

ASJC Scopus subject areas

  • General

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