The interactions of HIV-1 with T cells and macrophages in the central nervous system (CMS) are critical to chronic CMS infection and the development of HIV encephalitis and the AIDS dementia complex (ADC). The CMS is exposed to HIV during primary infection, leading to persistent infection accompanied in many individuals by a chronic increase in cerebrospinal fluid (CSF) T cells. These interactions have been modified by antiretroviral therapy. This modified competing renewal application describes a series of studies to characterize functional populations of CSF white blood cells in HIV infection using multiparameter flow cytometry. The proposed studies are grounded in the overall hypothesis that traffic and character of T cells and monocyte/macrophages importantly determine CNS HIV infection and disease, and that clear definition of these cells will advance understanding of pathogenesis, treatment and diagnosis. This revised competing renewal application proposes to continue studies that use CSF as a model of CNS HIV infection and virus-immune cell interactions within a non-lymphoid organ. It uses state-of-the-art Multiparameter Flow Cytometry to characterize CSF T cells and monocyte functional phenotypes with respect to their maturational/developmental state, activation, expression of receptors involved in tissue homing and migration, and HIV antigen specificity. This will be accomplished through an ordered sequence of studies. First we will develop flow cytometry 'panels'that define these complex cell phenotypes and the inter-relations of their expression. Our next aim is to explore the distribution of these phenotypes cross-sectionally to examine differences between CSF and blood and HIV-infected and uninfected subjects, variation with stage of systemic HIV infection and immunological dysregulation, and their changes in response to antiretroviral treatment.
The third aim i s to further test relationships of selected phenotypic characteristics in selected longitudinal studies of immunomodulatory and antiviral treatment. In parallel studies, our final aim will examine HIV-specific T cells using tetramer/pentamer technology to characterize CSF T cells and their relationship to treatment responses cross-sectionally and longitudinally. This proposal presents a unique set of studies addressing a central facet of CNS HIV infection. Beyond its immediate implications for prevention, diagnosis and treatment of Neuro-AIDS, it bears on the understanding other immune, inflammatory and degenerative neurological diseases.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
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NeuroAIDS and other End-Organ Diseases Study Section (NAED)
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Joseph, Jeymohan
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University of California San Francisco
Schools of Medicine
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United States
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Gisslén, Magnus; Price, Richard W; Andreasson, Ulf et al. (2016) Plasma Concentration of the Neurofilament Light Protein (NFL) is a Biomarker of CNS Injury in HIV Infection: A Cross-Sectional Study. EBioMedicine 3:135-140
Price, Richard W; Spudich, Serena S; Peterson, Julia et al. (2014) Evolving character of chronic central nervous system HIV infection. Semin Neurol 34:7-13
Peterson, Julia; Gisslen, Magnus; Zetterberg, Henrik et al. (2014) Cerebrospinal fluid (CSF) neuronal biomarkers across the spectrum of HIV infection: hierarchy of injury and detection. PLoS One 9:e116081
Jessen Krut, Jan; Mellberg, Tomas; Price, Richard W et al. (2014) Biomarker evidence of axonal injury in neuroasymptomatic HIV-1 patients. PLoS One 9:e88591
Price, Richard W; Peterson, Julia; Fuchs, Dietmar et al. (2013) Approach to cerebrospinal fluid (CSF) biomarker discovery and evaluation in HIV infection. J Neuroimmune Pharmacol 8:1147-58
Grund, Birgit; Wright, Edwina J; Brew, Bruce J et al. (2013) Improved neurocognitive test performance in both arms of the SMART study: impact of practice effect. J Neurovirol 19:383-92
Peluso, Michael J; Ferretti, Francesca; Peterson, Julia et al. (2012) Cerebrospinal fluid HIV escape associated with progressive neurologic dysfunction in patients on antiretroviral therapy with well controlled plasma viral load. AIDS 26:1765-74
Spudich, Serena; Gisslen, Magnus; Hagberg, Lars et al. (2011) Central nervous system immune activation characterizes primary human immunodeficiency virus 1 infection even in participants with minimal cerebrospinal fluid viral burden. J Infect Dis 204:753-60
Price, Richard W (2011) Impact of antiretroviral therapy on HIV-related brain injury. Clin Infect Dis 52:244-7
Probasco, John C; Deeks, Steven G; Lee, Evelyn et al. (2010) Cerebrospinal fluid in HIV-1 systemic viral controllers: absence of HIV-1 RNA and intrathecal inflammation. AIDS 24:1001-5

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