The Role of Innate Immunity In HIV-1 Transmission and Pathogenesis: A Study of NK cells and Monocytes
Gasper, Melanie Ann
MetadataShow full item record
This dissertation investigates two key innate immune cell subsets, monocytes and NK cells, with regard to their ability to influence HIV transmission and disease progression, including their role in defense against opportunistic pathogens. Evaluation of HIV transmission focused on mother-to-child transmission (MTCT). We performed a case-control study to evaluate cord blood cells from HIV-1 exposed infants who acquired infection by one month (cases) to those who remained uninfected for 1 year (controls). Compared to controls, cord blood from cases displayed altered proportions of NK cell subsets, fewer activated non-HIV-target NK and CD8+ T cells and a higher proportion of HIV target effector memory CD4+ T cells. Subsequent studies were then performed to determine the role of BCG vaccine administration as a potential source of immune activation (which correlates with the risk of HIV acquisition) in HIV-exposed infants. BCG vaccination induced an increase in activated CD4+ T cells, which have potential to serve as a pool of HIV-1 targets, and this occurred independently of innate cell activation. Together, these studies identify altered cellular phenotypes that are associated with increased target cell activation and subsequent HIV-1 acquisition, providing insights into immune factors associated with MTCT. In the majority of patients that progress to AIDS, disease is accompanied by opportunistic infections (like Mycobacteria). To better understand HIV pathogenesis and increased susceptibility to opportunistic pathogens, we exposed peripheral blood cells from SIV+ sooty mangabey monkeys (that do not develop AIDS) and HIV-infected humans to Mycobacteria species and evaluated NK cell and monocyte responses. This study demonstrated that HIV+ patients have significantly altered NK cell gene expression profiles and deficient monocyte IL-12 production in response to the opportunistic pathogen BCG compared to HIV-negative donors. In contrast, SIV+ mangabeys maintain similar NK cell gene expression profiles and an increase in the production of monocyte-derived TNF-alpha and IL-12 (compared to uninfected controls). As these cytokines serve key roles in mycobacteria defense and are critical for activating NK cells, these studies provide tangible targets for immunotherapy designed to augment monocyte and NK cell function during pathogenic HIV infection to prevent acquisition of opportunistic infections.
- Pathobiology