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 #
5R01MH095613-03
Application #
8472533
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
2013-06-01
Budget End
2014-05-31
Support Year
3
Fiscal Year
2013
Total Cost
$590,811
Indirect Cost
$28,342
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
Spudich, Serena S (2016) Immune activation in the central nervous system throughout the course of HIV infection. Curr Opin HIV AIDS 11:226-33
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
Kore, Idil; Ananworanich, Jintanat; Valcour, Victor et al. (2015) Neuropsychological Impairment in Acute HIV and the Effect of Immediate Antiretroviral Therapy. J Acquir Immune Defic Syndr 70:393-9
Hellmuth, Joanna; Valcour, Victor; Spudich, Serena (2015) CNS reservoirs for HIV: implications for eradication. J Virus Erad 1:67-71
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
Zayyad, Zaina; Spudich, Serena (2015) Neuropathogenesis of HIV: from initial neuroinvasion to HIV-associated neurocognitive disorder (HAND). Curr HIV/AIDS Rep 12:16-24
Sailasuta, Napapon; Ross, William; Ananworanich, Jintanat et al. (2012) Change in brain magnetic resonance spectroscopy after treatment during acute HIV infection. PLoS One 7:e49272
Valcour, Victor; Chalermchai, Thep; Sailasuta, Napapon et al. (2012) Central nervous system viral invasion and inflammation during acute HIV infection. J Infect Dis 206:275-82