The prevalence of HAD has not changed in the era of HAART, nor has the rate of HIV-1 encephalitis. HAART has provided suboptimal improvement in HIV-1-related cognitive deficits. Monocyte/macrophage (M/Mphi) activation products may underlie this incomplete recovery. A reduction in M/Mphi activation markers has never been demonstrated in a longitudinal cohort and the extent to which incomplete resolution of M/Mcp activation post-HAART contributes to incomplete cognitive recovery is not known. We hypothesize that while M/M/phi activation is decreased with HAART, a degree of activation persists in some individuals and the degree of attenuation in M/M/phi activation relates to the degree of improvement on neuropsychological testing. We believe that one of the underlying mechanisms responsible for the residual macrophage activation involves continued HIV-1 infection in sequestered reservoirs, particularly within macrophages themselves. To test our hypotheses, we plan to quantify intracellular HIV-1 DNA copy number and measure M/M/phi activation markers at baseline and 6, 12, and 24 months after initiation of HAART in a cohort of HAD patients in Bangkok, Thailand as they initiate their first HAART regimen and compare these to non-HAD patients and HIV-negative controls. If our hypotheses are correct, we expect to see residual infection in M/M/phi's, particularly within CD14+/CD16+ cells, indicating a relationship between M/M/phi activation and intracellular infection. We further expect to see a time-relationship between treatment duration and percent activation. Finally, we expect to see a direct relationship between the decrease in activation and the improvement on neuropsychological testing. Given this unique cohort, we further intend to use proteomics to generate important molecular markers that predict M/M/phi response to HAART and that distinguish HAD in HAART-treated compared to HAART-naive individuals.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21MH072388-02
Application #
7099504
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Bao, Jing
Project Start
2005-08-01
Project End
2008-07-31
Budget Start
2006-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2006
Total Cost
$215,842
Indirect Cost
Name
University of Hawaii
Department
Type
Organized Research Units
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822
Hellmuth, Joanna; Valcour, Victor; Spudich, Serena (2015) CNS reservoirs for HIV: implications for eradication. J Virus Erad 1:67-71
Sithinamsuwan, Pasiri; Hutchings, Nicholas; Ananworanich, Jintanat et al. (2014) Practice effect and normative data of an HIV-specific neuropsychological testing battery among healthy Thais. J Med Assoc Thai 97 Suppl 2:S222-33
Valcour, Victor G; Ananworanich, Jintanat; Agsalda, Melissa et al. (2013) HIV DNA reservoir increases risk for cognitive disorders in cART-naïve patients. PLoS One 8:e70164
Shiramizu, B; Ananworanich, J; Chalermchai, T et al. (2012) Failure to clear intra-monocyte HIV infection linked to persistent neuropsychological testing impairment after first-line combined antiretroviral therapy. J Neurovirol 18:69-73
Valcour, Victor G; Shiramizu, Bruce T; Shikuma, Cecilia M (2010) HIV DNA in circulating monocytes as a mechanism to dementia and other HIV complications. J Leukoc Biol 87:621-6
Valcour, V G; Shiramizu, B T; Sithinamsuwan, P et al. (2009) HIV DNA and cognition in a Thai longitudinal HAART initiation cohort: the SEARCH 001 Cohort Study. Neurology 72:992-8
Ratto-Kim, Silvia; Chuenchitra, Thippawan; Pulliam, Lynn et al. (2008) Expression of monocyte markers in HIV-1 infected individuals with or without HIV associated dementia and normal controls in Bangkok Thailand. J Neuroimmunol 195:100-7
Sithinamsuwan, Pasiri; Punthanamongkol, Sirichai; Valcour, Victor et al. (2008) Frequency and characteristics of HIV-associated sensory neuropathy among HIV patients in Bangkok, Thailand. J Acquir Immune Defic Syndr 49:456-8
Shiramizu, Bruce; Ratto-Kim, Silvia; Sithinamsuwan, Pasiri et al. (2007) HIV DNA and dementia in treatment-naive HIV-1-infected individuals in Bangkok, Thailand. Int J Med Sci 4:13-8
Valcour, V G; Sithinamsuwan, P; Nidhinandana, S et al. (2007) Neuropsychological abnormalities in patients with dementia in CRF 01_AE HIV-1 infection. Neurology 68:525-7