title: Simian immunodeficiency virus-induced changes in T cell cytokine responses in cynomolgus macaques with latent Mycobacterium tuberculosis infection are associated with timing of reactivation.
abstract: Understanding the early immunologic events accompanying reactivated tuberculosis (TB) in HIV-infected individuals may yield insight into causes of reactivation and improve treatment modalities. We used the cynomolgus macaque (Macaca fascicularis) model of HIV-Mycobacterium tuberculosis coinfection to investigate the dynamics of multifunctional T cell responses and granuloma T cell phenotypes in reactivated TB. CD4(+) and CD8(+) T cells expressing Th1 cytokines (IFN-γ, IL-2, TNF) and Th2 cytokines (IL-4 and IL-10) were followed from latent M. tuberculosis infection to reactivation after coinfection with a pathogenic SIV. Coinfected animals experienced increased Th1 cytokine responses to M. tuberculosis Ags above the latent-response baseline 3-5 wk post-SIV infection that corresponded with peak plasma viremia. Th2 cytokine expression was not Ag specific, but strong, transient IL-4 expression was noted 4-7 wk post-SIV infection. Animals reactivating <17 wk post-SIV infection had significantly more multifunctional CD4(+) T cells 3-5 wk post-SIV infection and more Th2-polarized and fewer Th0-, Th1-polarized CD8(+) T cells during weeks 1-10 post-SIV infection than animals reactivating >26 wk post-SIV infection. Granuloma T cells included Th0-, Th1-, and Th2-polarized phenotypes but were particularly rich in cytolytic (CD107(+)) T cells. When combined with the changes in peripheral blood T cells, these factors indicate that events during acute HIV infection are likely to include distortions in proinflammatory and anti-inflammatory T cell responses within the granuloma that have significant effects on reactivation of latent TB. Moreover, it appears that mycobacteria-specific multifunctional T cells are better correlates of Ag load (i.e., disease status) than of protection.
authors.affiliation: Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
authors.forename: Joshua T
authors.initials: JT
authors.lastname: Mattila
authors.forename: Collin R
authors.initials: CR
authors.lastname: Diedrich
authors.forename: Philana Ling
authors.initials: PL
authors.lastname: Lin
authors.forename: Jiayao
authors.initials: J
authors.lastname: Phuah
authors.forename: JoAnne L
authors.initials: JL
authors.lastname: Flynn
mesh_terms: D000208:Acute Disease; D000818:Animals; D015897:Comorbidity; D016207:Cytokines / Q000096:biosynthesis* / Q000145:classification / Q000502:physiology; D006099:Granuloma / Q000150:complications / Q000276:immunology / Q000378:metabolism; D055985:Latent Tuberculosis / Q000150:complications / Q000276:immunology* / Q000378:metabolism; D008252:Macaca fascicularis; D009169:Mycobacterium tuberculosis / Q000276:immunology; D012008:Recurrence; D016097:Simian Acquired Immunodeficiency Syndrome / Q000150:complications / Q000276:immunology* / Q000378:metabolism*; D015302:Simian Immunodeficiency Virus / Q000276:immunology*; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D013997:Time Factors; D014397:Tuberculosis, Pulmonary / Q000150:complications / Q000276:immunology* / Q000378:metabolism
chemical_list: D016207:Cytokines