AIDS pathogenesis, HIV/SIV reservoirs
Immunology of aging
Regardless of highly active anti-retroviral therapy (HAART), chronic immune activation, particularly in the gut, is one of the single greatest causes of ongoing morbidities. However, despite intensive study, the mechanisms remain unknown. We have already shown that innate T cells, such as NKT cells are depleted in pathogenic SIV infection of rhesus macaques and the residual NKT cells are pro-inflammatory but not in the non-pathogenic SIV infection of sooty mangabeys (an AIDS-resistant NHP species). This is in line with several reports of depletion/dysregulation of other innate T cell subsets including γδ T cells and MAIT cells in HIV/SIV infections, suggesting that HIV and SIV target specific antiviral/immunomodulatory subsets of innate T cells. Considering their important anti- bacterial functions, the functional impairment of innate T cell subsets in HIV infection is critical in host-susceptibility to co-morbidities. We have also shown MAIT cell and γδ T cells are enriched in lung and gut mucosal tissues of macaques and have significant type-17 functions, which are critical for healthy mucosal barrier functions. Current and future studies focus on additional mechanisms of MAIT cell and gamma-delta T cell dysregulation in the gastrointestinal tract. We are specifically investigating role of innate T cells in the maintenance/disruption of gut mucosal homeostasis and chronic immune activation.
My laboratory is working toward a better understanding of how innate T cells can inhibit pathogens, both directly and indirectly, at the pathogen-mucosa interface. This can involve killing of virus-infected cells, cytokine-mediated inhibition, or cooperatively with adaptive cellular and humoral responses via immune crosstalk. Furthermore, we are interested in how we can modulate these functions in the context of vaccines and immunotherapeutics. To date, these mechanisms are poorly understood in these critical tissue sites due to the difficulty of accessing mucosal tissues in patient populations. To this end we are working on ways to modulate the cytotoxic killing or cytokine effector functions of gamma delta T cells in tissues with genetic modification and ligand-specific stimulation.
Chronic inflammation in biological aging (inflammaging) is linked to an increased risk of cardiovascular disease, impaired mobility, cancer, cognitive decline, and immunosenescence. Similarities between inflammaging and the course of treated HIV infections, including chronic inflammation and gut epithelial barrier damage with microbial translocation, suggest that HIV infection compresses the aging process, accelerating the development of comorbidities and frailty. We are focused on defining the inflammaging phenotype in aging macaques in the context of gut mucosal immunity and microbiome and investigating the contribution of long-term ART towards promoting this inflammaging phenotype in young adult macaques. Understanding the coordinated role of gut mucosal immunity and microbiome in the local and systemic inflammation of aging and ART will open new avenues to explore the development of applications aimed at modulating mucosal immune cells to reduce inflammaging and the risk of frailty syndrome in individuals aging with or without HIV.
Tuberculosis (TB) is a highly contagious infection that leads to chronic disease, causing 10.4 million new infections and 1.8 million deaths every year globally. Current tuberculosis (TB) vaccine strategies are targeted mainly towards conventional T cell responses to mycobacterial protein antigens. However, there is growing evidence for the role of mycobacterial lipid specific CD1-restricted T cell responses in anti-mycobacterial immunity. Understanding how the CD1-restricted T cells contribute to TB may provide critical insights into innate mechanisms of resistance to TB and aid the development of new therapies against TB. We are currently investigating mycobacterial lipid-antigen reactive CD1-restricted T cells and MAIT cells in macaques to evaluate their anti-mycobacterial functions and examine the impact of SIV infection on these functions. Through the NHP model of Mtb infection, we are addressing several primary barriers to understanding the pathogenesis of TB including: (i) limited understanding of non-peptide antigen-specific T cell responses to Mtb, (ii) limited access to samples in very early stages of infection, particularly from the lungs, and (iii) unknown impacts of HIV co-infection on immune control of Mtb.
View Dr. Rout's publications on PubMed here.
