Increased trafficking of HIV-infected monocytes into the brain plays a critical role in the development of HIV-associated dementia (HAD). Increased numbers of circulating CD16+ monocytes are associated with HAD. Furthermore, perivascular CD14+CD16+ monocytes/macrophages are a major reservoir of virus in the CNS of patients with HAD. Preliminary studies suggest that CD16+ monocytes sustain a long-lived reservoir of infectious virus that upon migration can perpetuate infection in the brain by activation of viral gene expression. Moreover, we show that CD16+ monocytes are likely to traffic into the CNS through interactions between fractalkine (FKN) and its receptor, CX3CR1. The goal of this proposal is to investigate the role of CD16+ monocytes in sustaining the long-lived reservoir of viral infection in the CNS in patients with HAD. Approximately 85% of the patients in the study cohort acquired HIV infection through intravenous drug use and many have relatively high viral RNA levels in plasma due to lack of medication adherence. We will quantify the different forms of HIV DNA and mRNA present in CD16+ and CD16- monocytes to define the viral variables associated with the persistent reservoir. We will also investigate the regulation of CD16+ monocyte trafficking by CX3CR1/FKN and other chemokine receptors, and the role of these cells and their associated HIV strains in mechanisms that may contribute to neurologic injury in HAD.
The specific aims are: 1) To determine whether levels of HIV DNA and RNA are higher in CD16+ monocytes compared to CD16- monocytes in AIDS patients, and whether increased levels of viral DNA and RNA in CD16+ monocytes are associated with clinical dementia; 2) To determine whether viruses with specific genetic or functional characteristics that directly impact neurotropism or neurovirulence are more frequent in CD16+ monocytes in AIDS patients with HAD compared to non-demented AIDS patients; and 3) To determine the role of CX3CR1/FKN and other chemokine receptors in regulation of CD16+ monocyte trafficking. These studies will help to elucidate the role of CD16+ monocytes in the establishment of HIV infection in the CNS and its associated neurologic sequelae and will provide information that is important for understanding the pathogenesis and optimal treatment of HAD. These studies will also elucidate mechanisms that are relevant for the pathogenesis and treatment of other infectious, inflammatory, or degenerative neurologic diseases. ? ?
