This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Towards identification of the relative contributions of inadequate virologic suppression, immune activation and cell trafficking to the development of HIV-associated dementia (HAD), this proposal focuses on critical questions relating to HIV reservoirs, including the Central Nervous System (CNS) as a reservoir, as well as virologic and immunologic relationships between the lymphoid and CNS compartments. We seek to (1) determine if the CNS can serve as a reservoir for reseeding the periphery with HIV, and (2) identify cell and tissue reservoirs for antiretroviral drug-sensitive, versus drug-resistant, HIV species. For these studies, HIV genotyping will be performed using contemporaneously-collected, ante-mortem bone marrow and excisional cervical lymph node biopsy specimens, in conjunction with patient-matched plasma, cerebrospinal fluid (CSF), and separated blood monocyte and T-lymphocyte specimens collected concomitantly, as well as prior to, and following biopsy. Two regions of the HIV genome will be examined, the V1-V4 region of the envelope gene, and a 1.2kb fragment which includes the protease gene and that portion of the reverse transcriptase gene which codes for most of the antiretroviral resistance mutations of significance. To optimally address the question of whether the brain can seed the periphery with HIV, we will evaluate the HIV species present not only within the lymph node (LN) CD4+ T-cell population, but also those associated with LN germinal center follicular dendritic cells (FDC). These investigations will be complemented with studies of post-mortem tissues. In addition, we seek to identify events in bone marrow associated with the development of cognitive impairment and systemic virologic failure. Ante-mortem marrow and blood cell specimens collected from AIDS patients with and without cognitive impairment, will be evaluated using flow cytometry and immunohistochemistry. These studies will provide new insight into mechanisms underlying the development of HAD, particularly the role of immune activation in the disease process. Also, an accurate understanding of HIV reservoirs and the trafficking of HIV particles and infected cells throughout the body, is critical to successful patient treatment.
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