Anti-retroviral therapy reduces TB disease in SIV-co-infected cynomolgus macaques
Collin R Diedrich1,2, Tara Rutledge1,2, Janelle Gleim1,2, Pauline Maiello2,3, Tonilynn M Baranowski1,2,3, Alexander G White2,3, H. Jacob Borish2,3, Jessica Brown4, Forrest Hopkins4, , Sarah M Fortune4, JoAnne L Flynn2,3, Zandrea Ambrose3, Philana Ling Lin1,2#
1Department of Pediatrics, Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center, Pittsburgh,Pennsylvania, USA; 2Center for Vaccine Research, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA; 3Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, Pittsburgh,Pennsylvania, USA
4Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts, USA
Human immunodeficiency virus infection is the most common risk factor for severe forms of tuberculosis (TB) regardless of CD4 T cell count. While the majority of HIV infected people are on anti-retroviral therapy (ART), they still remain more susceptible to TB than HIV-uninfected persons on a population level. We sought to determine how HIV viral replication influences progression of primary M. tuberculosis (Mtb) infection using a well-characterized cynomolgus macaque (NHP) model of HIV/Mtb co-infection. NHPs were infected with SIVdeltaB670 for 16 weeks without ART (SIV/Mtb, n = 10), SIV with immediate ART (SIV/ART/Mtb, n = 10) or Mtb only (n=10). The duration of Mtb infection was 12 weeks with baseline and serial immunologic, microbiologic, and PET CT imaging for disease progression. ART resulted in non-detectable plasma SIV RNA copies and prevented the SIV-induced reduction of CD4 T cell loss in PBMC and BAL. ART reduced SIV-induced spikes in various cytokines from SIV-specific and Mtb-specific CD4 and CD8 T cells within BAL and PBMC. SIV/Mtb NHP developed clinical signs of active TB often requiring early necropsy (median necropsy time was 8.8wks) compared to SIV/ART/Mtb and Mtb NHPs. SIV/Mtb animals had greater gross, pathology, bacterial burden, and extrapulmonary disease compared to SIV/ART/Mtb and Mtb only controls. Lung granulomas with SIV/Mtb NHP contained lower CD4 T cell frequencies compared to Mtb-only NHP and SIV/ART/Mtb NHP. Despite minimal differences in cytokine production by CD4 and CD8 T cells within lung granulomas among these cohorts, ART did increase the expression of HLA-DR and IL-10 on CD4 T cells compared to SIV/Mtb NHP and no difference in Mtb only NHP. In this highly controlled experiment, these data suggest that well controlled SIV replication with ART is associated with similar TB progression than no-SIV controls. The discordance with human epidemiologic data could be attributed to multiple factors such as ART compliance, duration of HIV prior to ART, etc.