HIV-1 -associated dementia (HAD) continues to be a clinically important issue in the era of highly active antiretroviral therapy (HAART). Because the etiology of HAD remains unclear, further research into its pathogenesis is warranted. We recently reported that HIV-1 DMAlevels (HIV DNA) are elevated in peripheral blood mononuclear cells (PBMC) in subjects diagnosed with HAD. Our preliminary investigation also suggests that the high PBMC HIV DNA is specifically within CD14*VCD16+ monocytes/macrophages (M/MO) rather than CD14+/CD16"""""""" M/Mct>or lymphocytes (CD14""""""""). The central hypothesis to be addressed in this proposal is that peripheral HIV DNA in M/MO outside the central nervous system plays a pivotal role in the development of HAD. Utilizing 167 viably banked PBMC specimens from neurologically well-characterized individuals followed longitudinally within the HawaiiAging with HIV Cohort study, our grant submission proposes to: 1) further define the direct relationship between PBMC HIV DNA and HIV-1-associated neurocognitive impairment (NCI) particularly among those diagnosed to have Minor Cognitive Motor Disorder (MCMD);2) clearly demonstrate that the high HIV DNA in PBMC in individuals with HAD is predominantly within CD14*/CD16+ M/MO and not lymphocytes;and 3) assess the mechanistic link between HIV DNA in M/MO and CD14VCD16"""""""" phenotype in an in vitro model. This in vitro model will determine the relative infectiviity of CD14VCD16* M/MO compared to CD14VCD16""""""""M/MO, assess for a possible difference in HIV- 1 binding capacity of these 2 M/MO subsets, and also determine whether HIV-1-infection of the CD14+/CD16+ M/MO alters its cytokine secretory pattern. This project is innovative in its use of a pre- existing neurologically well-characterized cohort and the translational approach proposed to address this critically important issue. The significance lies in the knowledge to be gained on how HIV DNA in M/MO leads to HAD;why HAD and MCMD continue to be seen in the era of HAART;and in the potential that new therapeutic targets for prevention or treatment of HAD might be identified through this research. The proposal brings together a unique investigative team with multi-disciplinary expertise and established successful working relationships. This resource-rich team is well-positioned to conduct this investigation into the pathogenesis of HAD.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS053345-05
Application #
7806603
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Wong, May
Project Start
2006-05-01
Project End
2013-04-30
Budget Start
2010-05-01
Budget End
2013-04-30
Support Year
5
Fiscal Year
2010
Total Cost
$228,084
Indirect Cost
Name
University of Hawaii
Department
Other Clinical Sciences
Type
Schools of Medicine
DUNS #
965088057
City
Honolulu
State
HI
Country
United States
Zip Code
96822
Agsalda-Garcia, Melissa A; Sithinamsuwan, Pasiri; Valcour, Victor G et al. (2017) Brief Report: CD14+ Enriched Peripheral Cells Secrete Cytokines Unique to HIV-Associated Neurocognitive Disorders. J Acquir Immune Defic Syndr 74:454-458
Shikuma, Cecilia M; Gangcuangco, Louie Mar A; Killebrew, Deirdre A et al. (2014) The role of HIV and monocytes/macrophages in adipose tissue biology. J Acquir Immune Defic Syndr 65:151-9
Ndhlovu, Lishomwa C; Umaki, Tracie; Chew, Glen M et al. (2014) Treatment intensification with maraviroc (CCR5 antagonist) leads to declines in CD16-expressing monocytes in cART-suppressed chronic HIV-infected subjects and is associated with improvements in neurocognitive test performance: implications for HIV-associa J Neurovirol 20:571-82
Kallianpur, Kalpana J; Valcour, Victor G; Lerdlum, Sukalaya et al. (2014) HIV DNA in CD14+ reservoirs is associated with regional brain atrophy in patients naive to combination antiretroviral therapy. AIDS 28:1619-24
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
Nakamoto, Beau K; Shikuma, Cecilia M; Ogata-Arakaki, Debra et al. (2013) Feasibility and potential role of ferumoxytol-enhanced neuroimaging in HIV-associated neurocognitive disorder. J Neurovirol 19:601-5
Agsalda-Garcia, Melissa; Shiramizu, Bruce; Melendez, Loyda et al. (2013) Different levels of HIV DNA copy numbers in cerebrospinal fluid cellular subsets. J Health Care Poor Underserved 24:8-16
Kusao, Ian; Shiramizu, Bruce; Liang, Chin-Yuan et al. (2012) Cognitive performance related to HIV-1-infected monocytes. J Neuropsychiatry Clin Neurosci 24:71-80
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
Shikuma, Cecilia M; Nakamoto, Beau; Shiramizu, Bruce et al. (2012) Antiretroviral monocyte efficacy score linked to cognitive impairment in HIV. Antivir Ther 17:1233-42

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