| Platelet decline commonly occurs in human immunodeficiency virus (HIV)-infected individuals and has been linked to adverse sequelae of infection, including central nervous system (CNS) disease. A role for platelets in the pathogenesis of HIV infection has yet to be demonstrated, and existing literature on both causes and consequences of platelet decline has yet to illuminate a clear consensus. As platelets may play different roles in acute, asymptomatic and terminal stages of HIV infection, we used the simian immunodeficiency virus (SIV)/macaque model to examine whether causes of platelet decline differed throughout infection. We found that platelet decline was biphasic, with an acute transient drop in numbers of circulating platelets preceding a decline that persisted from mid-asymptomatic to terminal infection. We therefore examined decreased production, increased destruction, and increased platelet activation and use as possible causes of platelet decline during acute and asymptomatic infection. We demonstrated that platelet activation and sequestration of platelets in CD16+ plateletmonocyte aggregates drove platelet decline during acute infection, and herein discuss the implications of the association of platelets with greater than 90% of pro-migratory CD16+ monocytes for the development of CNS disease. During asymptomatic infection, we identified decreased production, increased destruction, and increased activation, with decreased platelet production dominating. Thrombopoietin (THPO) stimulates platelet production by promoting maturation of platelet producing megakaryocytes within bone marrow, and THPO is transcriptionally downregulated by cytokines such as transforming growth factor beta (TGFbeta). We found that elevated plasma TGFbeta during asymptomatic infection correlated inversely with a 10,000-fold downregulation of THPO transcription, and that THPO mRNA correlated positively with megakaryocyte numbers. As platelet decline during asymptomatic infection does not generally occur in patients using combined antiretroviral therapy (cART), we evaluated whether cART increased platelet production, and demonstrated that cART corrected plasma TGFbeta levels and platelet count. Finally, we identified an association between frontal cortex transcription of THPO, which is pro-apoptotic to neurons in culture, and the presence of CNS disease during asymptomatic and terminal SIV infection. In summary, this dissertation establishes that the cause of platelet decline differs depending upon the stage of lentiviral infection, and presents candidate mechanisms that may link platelet decline to the pathogenesis of HIV-associated CNS disease. |
