Molecular basis for neuronal nicotinic receptor upregulation: potential implications in HIV associated dementia (SNRP project)
(SNRP grant http://snrp.rcm.upr.edu/index.html . Collaboration with Dr. Valerie Wojna and Dr. Loyda Melendez, UPR-Medical Sciences Campus, San Juan, PR)
The association between tobacco use and HIV/AIDS epidemics represents an area of growing clinical and public health importance. A study from our longitudinal cohort of HIV-seropositive women showed that active smokers had improved neuropsychological performance; however, smoking induced a higher plasma viral load and lower CD4 cell counts (Wojna et al., 2007). More recently, we found a potential mechanistic link between nicotine and HIV pathogenesis. We demonstrated that the HIV-1 envelope neurotoxin, gp120, induces a functional upregulation of the α7 neuronal nicotinic receptor in human macrophages, lymphocytes, and neuronal cell lines ex vivo. We confirmed the upregulation of α7 AChR in HIV-seropositive women. Flow cytometry analysis of macrophages and lymphocytes from HIV-seropositive women demonstrated α7 nAChR upregulation as compared with HIV-seronegative women (Santiago et al., in review). We also found that HIV-1 gp-120-induced upregulation of the α7 nAChR in neuronal cell lines in culture (Ballester et al., 2009, in review). Furthermore, we found that a gp120-transgenic mouse model displays upregulation of the α7 AChR in peritoneal and lung macrophages.
This consistent gp120-induced upregulation of the neuronal α7 AChR reveals a fundamental link between tobacco use, upregulation of the α7 AChR, and HIV/AIDS pathogenesis. Our working hypothesis is that the gp120-induced upregulation of the α7 AChR plays a fundamental role in the deterioration of the immune system in HIV/AIDS patients via activation of apoptotic pathways in macrophages and lymphocytes. The main goal of this project is to define the functional link between smoking, the upregulation of the α7 AChR, and HIV/AIDS disease progression.