The systemic immune response and central nervous system (CNS) events occurring during acute HIV likely set the stage for chronic HIV-related CNS injury and the establishment of CNS-relevant HIV reservoirs. Just as the earliest systemic features such as peak plasma HIV RNA, level of T-cell activation, and early loss of CD4 cells are crucial determinants of HIV disease trajectory, CNS processes initiated during the earliest stages may critically inform the establishment of a CNS-relevant viral reservoirs, CNS compartmentalized virus, the hosts'ability to control CNS virus, and the long-term CNS consequences of infection. Logistical challenges have lead to heavy reliance on animal data to define the likely CNS events during acute HIV. In this application, we extend existing partnerships with US Army studies underway in Thailand to define these earliest events in humans and determine factors that influence long-term CNS outcomes. This application proposes to provide intensive CNS characterization for 60 Thai subjects enrolled during acute HIV (<1 month after exposure). In our schema, one-half of subjects will begin HAART immediately after initial assessments for a fixed 18-month course. We will longitudinally characterize CNS clinical events, neurological, neuropsychological, and psychiatric factors, multimodal magnetic resonance imaging, CSF immunology and compartment specific full-genome HIV sequencing to determine how the events that occur in acute HIV impact chronic HIV CNS disorders. We will also determine CNS founder and established viruses and determine if early HAART intervention impacts these relationships. The parent studies include extensive systemic immunological and virological characterization allowing us to determine if the earliest systemic events impact long-term CNS outcomes.

Public Health Relevance

This project will aid in clarifying how the earliest events during HIV infection may affect brain injury during chronic HIV. Defining these events could direct interventions aimed at reducing cognitive disorders for people living with HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH095613-01
Application #
8209926
Study Section
Special Emphasis Panel (ZMH1-ERB-M (03))
Program Officer
Joseph, Jeymohan
Project Start
2011-07-26
Project End
2016-05-31
Budget Start
2011-07-26
Budget End
2012-05-31
Support Year
1
Fiscal Year
2011
Total Cost
$636,382
Indirect Cost
Name
University of California San Francisco
Department
Neurology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Hellmuth, Joanna; Colby, Donn; Valcour, Victor et al. (2017) Depression and Anxiety are Common in Acute HIV Infection and Associate with Plasma Immune Activation. AIDS Behav 21:3238-3246
Sereti, Irini; Krebs, Shelly J; Phanuphak, Nittaya et al. (2017) Persistent, Albeit Reduced, Chronic Inflammation in Persons Starting Antiretroviral Therapy in Acute HIV Infection. Clin Infect Dis 64:124-131
Peluso, Michael J; Valcour, Victor; Phanuphak, Nittaya et al. (2017) Immediate initiation of cART is associated with lower levels of cerebrospinal fluid YKL-40, a marker of microglial activation, in HIV-1 infection. AIDS 31:247-252
Kessing, Cari F; Spudich, Serena; Valcour, Victor et al. (2017) High Number of Activated CD8+ T Cells Targeting HIV Antigens Are Present in Cerebrospinal Fluid in Acute HIV Infection. J Acquir Immune Defic Syndr 75:108-117
Spudich, Serena S (2016) Immune activation in the central nervous system throughout the course of HIV infection. Curr Opin HIV AIDS 11:226-33
Hellmuth, Joanna; Fletcher, James L K; Valcour, Victor et al. (2016) Neurologic signs and symptoms frequently manifest in acute HIV infection. Neurology 87:148-54
Ananworanich, Jintanat; Sacdalan, Carlo P; Pinyakorn, Suteeraporn et al. (2016) Virological and immunological characteristics of HIV-infected individuals at the earliest stage of infection. J Virus Erad 2:43-48
Chan, Phillip; Hellmuth, Joanna; Spudich, Serena et al. (2016) Cognitive Impairment and Persistent CNS Injury in Treated HIV. Curr HIV/AIDS Rep 13:209-17
Valcour, Victor G; Spudich, Serena S; Sailasuta, Napapon et al. (2015) Neurological Response to cART vs. cART plus Integrase Inhibitor and CCR5 Antagonist Initiated during Acute HIV. PLoS One 10:e0142600
Peluso, Michael J; Valcour, Victor; Ananworanich, Jintanat et al. (2015) Absence of Cerebrospinal Fluid Signs of Neuronal Injury Before and After Immediate Antiretroviral Therapy in Acute HIV Infection. J Infect Dis 212:1759-67

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