SIV and Mycobacterium tuberculosis synergy within the granuloma accelerates the reactivation pattern of latent tuberculosis

Abstract

Human immunodeficiency virus infection is the most common risk factor for severe forms of tuberculosis (TB), regardless of CD4 T cell count. Using a well-characterized cynomolgus macaque model of human TB, we compared radiographic, immunologic and microbiologic characteristics of early (subclinical) reactivation of latent M. tuberculosis (Mtb) infection among animals subsequently infected with simian immunodeficiency virus (SIV) or who underwent anti-CD4 depletion by a depletion antibody. CD4 depleted animals had significantly fewer CD4 T cells within granulomas compared to Mtb/SIV co-infected and Mtb-only control animals. After 2 months of treatment, subclinical reactivation occurred at similar rates among CD4 depleted (5 of 7 animals) and SIV infected animals (4 of 8 animals). However, SIV-induced reactivation was associated with more dissemination of lung granulomas that were permissive to Mtb growth resulting in greater bacterial burden within granulomas compared to CD4 depleted reactivators. Granulomas from Mtb/SIV animals displayed a more robust T cell activation profile (IFN-, IFN-{gamma}, TNF, IL-17, IL-2, IL-10, IL-4 and granzyme B) compared to Mtb/CD4 animals and controls though these effectors did not protect against reactivation or dissemination, but instead may be related to increased viral and/or Mtb antigens. SIV replication within the granuloma was associated with reactivation, greater overall Mtb growth and Mtb killing resulting in greater overall Mtb burden. These data support that SIV disrupts protective immune responses against latent Mtb infection beyond the loss of CD4 T cells, and that synergy between SIV and Mtb occurs within granulomas. Author SummaryMost humans are able to control infection with Mycobacterium tuberculosis (Mtb), the bacteria that causes tuberculosis (TB). Controlled, asymptomatic infection (latent infection) can develop into symptomatic, severe TB (reactivation TB) when the immune system is impaired, and HIV is the most common risk factor. Chronic HIV infection is associated with low CD4 T cells but there are likely other factors involved. Using macaques with latent Mtb infection, we could induce reactivation from either CD4 T cell depletion or SIV infection. We found that SIV induced reactivation was more dramatic with more bacterial dissemination and bacterial growth compared to those with CD4 depletion. While SIV-infected animals had more activated immune responses in the lung granulomas (a collection of immune cells that functions to combat Mtb), they could not prevent bacterial spread of Mtb resulting in more TB pathology, higher bacterial burden and disease throughout the body. These data suggest that the HIV-induced reactivation TB is not solely from the loss of CD4 T cells. Furthermore, our data suggest that SIV and Mtb have a synergistic relationship within granulomas that impairs the ability to kill Mtb and that this relationship exacerbates TB disease.