The proposed research focuses upon events in the central nervous system (CNS) during the earliest weeks and months after initial acquisition of HIV infection, collectively defined as primary HIV infection (PHI). HIV enters the CNS in the earliest stages of infection, and the CNS is a site of persistent viral infection throughout the chronic stages of disease. The underlying hypothesis of this proposal is that initial viral neuroinvasion is important in the neuropathogenesis of HIV, leading to the foundation of persistent and compartmentalized CNS infection, and initiating the process of brain injury. The investigators will longitudinally study 75 subjects presenting during PHI to study the course of host immune and neurological responses and features of cerebrospinal fluid (CSF) HIV quasispecies beginning during this period.
The first aim i s to understand the relationship between viral burden, early host inflammation, and tissue injury in the CNS, through measurement of CSF markers of inflammation, immune response, and neuronal injury, cerebral metabolites by high-field (4 Tesla) magnetic resonance spectroscopy, and neuropsychological testing.
The second aim i s to investigate the establishment of compartmentalized CNS infection through use of the heteroduplex tracking assay to detect HIV quasispecies sequence differences between and within CSF and plasma, and through measurement of viral replicative capacity and coreceptor utilization to define the character of early HIV species in each compartment.
The final aim i s to describe the effect of antiretroviral therapy initiated during PHI on the course of CNS inflammation and neurological responses. This study establishes a cohort for extended follow-up and a repository of banked longitudinal samples for future studies. Our proposed approach will provide crucial information about the clinical importance of early HIV in the nervous system;if immunoactivation-mediated brain injury or the establishment of compartmentalized CNS infection occurs during PHI, early treatment with immune- modulating or antiretroviral medications may provide previously unrecognized long-term neuroprotection. Similarly, detection of beneficial effects of treatment on the CNS during PHI has the potential to profoundly influence treatment strategies in early HIV. The overall goal of this proposal is to ameliorate or prevent HIV-related CNS damage through improved understanding of the early effects and treatment of HIV in the nervous system. Central nervous system (CNS) impairment remains a major complication of HIV-1 infection, and has the potential to affect at least 20% of the 40 million people worldwide who are living with HIV-1. Clarification of the time course of establishment of CNS infection and neurological injury will contribute to an understanding of the significance of the earliest stages of HIV-1 infection in the neuropathogenesis of AIDS. In addition, revealing the early effects of antiretroviral treatment in the CNS may provide a new rationale for initiating antiretroviral therapy in early HIV-1 infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH081772-06
Application #
8416999
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Joseph, Jeymohan
Project Start
2008-09-01
Project End
2015-01-31
Budget Start
2013-02-01
Budget End
2015-01-31
Support Year
6
Fiscal Year
2013
Total Cost
$510,565
Indirect Cost
$58,926
Name
Yale University
Department
Neurology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
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Gold, Jessica A; Grill, Marie; Peterson, Julia et al. (2014) Longitudinal characterization of depression and mood states beginning in primary HIV infection. AIDS Behav 18:1124-32
Young, Andrew C; Yiannoutsos, Constantin T; Hegde, Manu et al. (2014) Cerebral metabolite changes prior to and after antiretroviral therapy in primary HIV infection. Neurology 83:1592-600
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
Dahl, Viktor; Gisslen, Magnus; Hagberg, Lars et al. (2014) An example of genetically distinct HIV type 1 variants in cerebrospinal fluid and plasma during suppressive therapy. J Infect Dis 209:1618-22
Yilmaz, Aylin; Yiannoutsos, Constantin T; Fuchs, Dietmar et al. (2013) Cerebrospinal fluid neopterin decay characteristics after initiation of antiretroviral therapy. J Neuroinflammation 10:62
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
Dahl, Viktor; Peterson, Julia; Spudich, Serena et al. (2013) Single-copy assay quantification of HIV-1 RNA in paired cerebrospinal fluid and plasma samples from elite controllers. AIDS 27:1145-9
Peluso, Michael J; Meyerhoff, Dieter J; Price, Richard W et al. (2013) Cerebrospinal fluid and neuroimaging biomarker abnormalities suggest early neurological injury in a subset of individuals during primary HIV infection. J Infect Dis 207:1703-12
Schnell, Gretja; Joseph, Sarah; Spudich, Serena et al. (2011) HIV-1 replication in the central nervous system occurs in two distinct cell types. PLoS Pathog 7:e1002286

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