VIRAL AND CELLULAR DETERMINANTS OF HIV DEMENTIA

HIV 痴呆的病毒和细胞决定因素

• 批准号: 6338940
• 负责人: SUZANNE GARTNER
• 金额: $ 14.29万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6338940
• 关键词: AIDS /HIV neuropathy; AIDS dementia complex; CD16 molecule; HIV envelope protein gp120; HIV infections; blood chemistry; brain; cellular immunity; circular DNA; clinical research; human immunodeficiency virus 1; human subject; leukocyte activation /transformation; longitudinal human study; monocyte; proliferating cell nuclear antigen; site directed mutagenesis; virus DNA

Still unresolved is the paradox of why AIDS dementia does not generally develop until the onset of frank immunosuppression, if, indeed, as the evidence indicates, HIV-1 enters the brain early in infection. Although the trafficking of infected monocytes into brain has frequently been heralded a the mode in HIV entry into the central nervous system (CNS), few studies have examined HIV infection of circulating monocytes within the context of neurological disease, including AIDS dementia. Similarly, in spite of the fact that monocytes, including, presumably, HIV-infected ones, enter the blood from the bone marrow, little is known about HIV-host cell interactions in this tissue. The interrelationships of these cellular compartments--blood, brain and bone marrow--with respect to HIV infection and the development of AIDS dementia, is a major focus of this proposal. Both cellular and viral aspects of these interactions will be investigated. Blood monocytes from patients with and without dementia, followed longitudinally, will be examined for CD16 cell surface expression, proliferating cell nuclear antigen (PCNA) expression. the ability to proliferate in clonal assays and the presence of circular forms of HIV-1 DNA. Brain and bone marrow tissues from patients with and without dementia will be examined for the presence of PCNA-positive macrophages and the presence of circular HIV DNA. While cellular determinants of AIDS dementia might be related primarily to events that take place outside of the CNS, prior to entry into brain, it is likely that many of the viral determinants of this disease related to post-entry events. Therefore, towards identification of viral determinants of dementia, complementary studies of HIV phenotype of viruses from brain and blood monocytes are proposed. These viruses, from patients with and without dementia, will be evaluated for replication potential, level of expression, ability to spread, ability to elicit cytokine and chemokine production, and ability to kill human neurons in vitro. The phenotypes of these viruses will be compared with those recovered from T-cells from the same patients. Chimeric viruses will be constructed to identify the genetic determinants associated with the biological properties. Site-directed mutagenesis will be used to pinpoint the critical nucleotide and activation of intracellular signaling pathways in infected macrophages will be examined. We believe an understanding of the dynamics of trafficking of monocytes, both infected and uninfected, is critical for the development of successful treatment modalities for HIV neurological disease.

仍然没有解决的悖论是为什么艾滋病痴呆没有普遍