Pre-existing SIV infection increases expression of T cell markers associated with activation during earlyMycobacterium tuberculosisco-infection and impairs TNF responses in granulomas
Authors: Larson Erica C. , Ellis Amy L. , Rodgers Mark A. , Balgeman Alexis J. , Moriarty Ryan V. , Ameel Cassaundra , Baranowski Tonilynn , Tomko Jaime , Causgrove Chelsea , Maiello Pauline , O’Connor Shelby L. , Scanga Charles A. 
Published: December 2020

AbstractTuberculosis (TB) is the leading infectious cause of death among people living with HIV (PLHIV). PLHIV are more susceptible to contractingMycobacterium tuberculosis(Mtb) infection and often have worsened TB disease. Understanding the immunologic defects caused by HIV and the consequences it has onMtbco-infection is critical in combating this global health epidemic. We previously established a model of simian immunodeficiency virus (SIV) andMtbco-infection in Mauritian cynomolgus macaques (MCM), and showed that SIV/Mtbco-infected MCM had rapidly progressive TB. We hypothesized that pre-existing SIV infection impairs early T cell responses toMtbinfection. To test our hypothesis, we infected MCM with SIVmac239 intrarectally followed by co-infection with a low dose ofMtbErdman 6 months later. SIV-naïve MCM were infected withMtbalone as controls. Six weeks afterMtbinfection, animals were necropsied and immune responses were measured by multiparameter flow cytometry. While the two groups exhibited similar TB progression at time of necropsy (Nx), longitudinal sampling of the blood (PBMC) and airways (BAL) revealed a significant reduction in circulating CD4+ T cells and an influx of CD8+ T cells in airways followingMtbco-infection of SIV+ animals. Differences in the activation markers CD69, PD-1, and TIGIT were observed. At sites ofMtbinfection (i.e.granulomas), SIV/Mtbco-infected animals had a higher proportion of CD4+ and CD8+ T cells expressing PD-1 and TIGIT. In addition, there were fewer TNF-producing CD4+ and CD8+ T cells in granulomas and airways of SIV/Mtbco-infected animals. Taken together, we show that concurrent SIV infection alters T cell phenotypes in granulomas during the early stages of TB disease. As it is critical to establish control ofMtbreplication soon after infection, these phenotypic changes may distinguish the immune dysfunction that arises from pre-existing SIV infection which promotes TB progression.Author SummaryPeople living with HIV are incredibly susceptible to TB and, when co-infected withMtb, often develop serious TB disease. We do not yet understand precisely how HIV infection impairs the early stages of the adaptive immune response againstMtbbacilli. We employed a non-human primate model of HIV, using SIV as a surrogate for HIV, followed byMtbco-infection to investigate the immunologic defects associated with pre-existing SIV infection over the first six weeks ofMtbco-infection. Our study focused on CD4+ and CD8+ T cells as these cells are known to play an important role inMtbcontrol. We found more CD8+ T cells in granulomas, the sites ofMtbinfection, from SIV/Mtbco-infected animals, with little difference in CD4+ T cells. SIV/Mtbco-infected animals and animals infected with SIV alone had a higher proportion of both CD4+ and CD8+ T cells expressing activation markers compared to SIV-naïve animals, consistent with SIV-dependent immune activation. Notably, we observed a lower proportion of TNF-producing T cells, a cytokine critical forMtbcontrol, in granulomas and airways of SIV/Mtbco-infected animals. Taken together, these data show that pre-existing SIV alters T cell phenotypes and reduces TNF responses early inMtbinfection.