Host Immunity toMycobacterium tuberculosisInfection is Similar in Simian Immunodeficiency Virus (SIV)-infected, Antiretroviral Therapy-treated and SIV-naïve Juvenile Macaques

Abstract

Pre-existing HIV infection increases tuberculosis (TB) risk in children. Antiretroviral therapy (ART) reduces, but does not abolish, this risk in children with HIV. The immunologic mechanisms involved in TB progression in both HIV-naïve and HIV-infected children have not been explored. Much of our current understanding is based on human studies in adults and adult animal models. In this study, we sought to model childhood HIV/Mycobacterium tuberculosis(Mtb) coinfection in the setting of ART and characterize T cells during TB progression. Macaques equivalent to 4-8 year-old children were intravenously infected with SIVmac239M, treated with ART three months later, and coinfected with Mtb three months after initiating ART. SIV-naïve macaques were similarly infected with Mtb alone. TB pathology and total Mtb burden did not differ between SIV-infected, ART-treated and SIV-naïve macaques, although lung Mtb burden was lower in SIV-infected, ART-treated macaques. No major differences in frequencies of CD4+ and CD8+ T cells and unconventional T cell subsets (Vγ9+ γδ T cells, MAIT cells, and NKT cells) in airways were observed between SIV-infected, ART-treated and SIV-naïve macaques over the course of Mtb infection, with the exception of CCR5+ CD4+ and CD8+ T cells which were slightly lower. CD4+ and CD8+ T cell frequencies did not differ in the lung granulomas obtained at necropsy, nor did they differ in the frequency of immune checkpoint and proliferative markers. Thus, ART treatment of juvenile macaques, three months after SIV infection, resulted in similar progression of Mtb and T cell responses compared to Mtb in SIV-naïve macaques.

Transiently boosting Vγ9+Vδ2+ γδ T cells early in Mtb coinfection of SIV-infected juvenile macaques does not improve Mtb host resistance

“…In this study, we sought to boost V9+V2+  T cells, a  T cell subset associated with anti-Mtb activity (14-16), using our nonhuman primate model of pediatric HIV/Mtb coinfection (26) to determine whether augmenting V9+V2+  T cells could reduce Mtb burden and overall TB disease in the presence of a pre-existing SIV infection. Several groups have shown that inducing V9+V2+  T cells by various approaches is moderately efficacious against Mtb infection in SIV-naïve, adult rhesus macaques (16)(17)(18).…”

“…We have shown previously that MCM chronically infected with SIV had defective adaptive immune responses to Mtb coinfection (47). Treating SIV-infected juvenile macaques with ART appeared to ameliorate these defects (26). Zhou and colleagues have also shown that SIV infection impairs mycobacterial-specific responses in V2+  T cells (48).…”

“…MHC haplotype was determined by MiSeq sequencing and animals with the presence of at least one copy of the M1 MHC haplotype were selected for this study (51), for consistency with our previous SIV/Mtb coinfection studies (26,31,47,52,53).…”

“…Animal welfare was monitored as described previously (26). In brief, all animals were checked at least twice daily to assess appetite, attitude, activity level, hydration status, etc.…”

“…Using our juvenile nonhuman primate (NHP) model of pediatric HIV/Mtb coinfection (26), we evaluated whether boosting V9+V2+  T cells reduces TB disease. Zoledronate (ZOL; brand name, Reclast®), is an FDA-approved drug used for treating osteoporosis, Paget's disease of bone, and high levels of calcium in the blood caused by certain types of cancer (27).…”