UCSF

Plasmacytoid dendritic cell function in pathogenic vs. non-pathogenic HIV and SIV infection

by

Rebecca A. Botelho

ABSTRACT

The role of plasmacytoid dendritic cells (pDC) in HIV disease has been studied extensively but a clear consensus on the impact of pDC function on disease progression has not been reached. This thesis studied cases of pathogenic and non-pathogenic lentiviral infection in humans and non-human primates. Pathogenic HIV infection in humans and SIV infection in non-natural hosts is associated with a generalized, nonspecific immune activation and inflammation which persists during chronic infection and is associated with a progressive decline in CD4+ T cells, leading to immune deficiency and eventually development of AIDS. By contrast, nonpathogenic HIV and SIV infections are characterized by limited bystander immune activation and non-specific inflammation.

Plasmacytoid dendritic cells (pDCs) are an essential component of the innate immune response to viral infection and help to shape the innate and adaptive immune antiviral response. Multiple studies point to the possibility that pDC number and/or function may be different in the setting of pathogenic vs. non-pathogenic HIV and SIV infections. pDC functionality consists of maturation into antigen-presenting cells (APCs), secretion of type-I IFNs (most notably IFNα), and, as more recently characterized, production of the immunosuppressive enzyme, indoleamine-2,3-deoxygenase (IDO). All of these functions have discreet effects on the development of the antiviral immune response, and all can be induced through stimulation across various receptors expressed by pDCs.

Because of the wide array of pDC functionality that exists, the potential for important differences in pDC function in pathogenic vs. nonpathogenic infections in humans and non-human primates are considerable. This thesis work examined whether intrinsic differences in pDC function (possibly influenced by genetics) might be associated with differences in HIV disease status. This work also examined whether intrinsic differences existed in pDC function between natural and non-natural hosts of SIV infection, who undergo non-pathogenic and pathogenic infection courses, respectively, and are thought to be a good model for pathogenic vs. non-pathogenic HIV infection in humans. Overall, this work concludes that while significant differences exist in pDC function between natural and non-natural SIV hosts, few, if any, significant differences exist in pDC function between HIV+ human patients with different disease outcomes.