HIV-associated neurocognitive disorder (HAND) continues to be a debilitating disorder affecting the aging HIV patient population. This is despite the fact that currently available highly active antiretroviral therapy (HAART) is capable of suppressing HIV RNA to undetectable levels in both blood and cerebrospinal fluid (CSF). The persistence of HAND is likely due to a complex interplay between poorly understood virologic factors and natural aging processes. Understanding the biological determinants at the core of this complex interplay, and how they lead to the development of HAND even in the presence of suppressive HAART, will require a more detailed investigation of virologic factors and how they compound various human aging pathways. To better understand the biological correlates of HAND, we propose to use an analysis that combines clinical, neuromedical, and laboratory data with ultradeep sequencing (UDS) technology. We have identified a group of 56 individuals from the CNS HIV Antiretroviral Therapy Effects Research (CHARTER) cohort who are older than 50 years in age, have been followed longitudinally for at least four years, and have been suppressed with HAART throughout this time. Using UDS, we propose to sequence the env, gag, pro and reverse transcriptase coding regions of HIV-1 DNA populations in peripheral blood mononuclear cells (PBMCs) and CSF cell pellets (approximately 400 samples and 6.5 million sequences in total). These data will then be co-analyzed with clinical, antiretroviral, host geneti, and bio-marker data currently available in CHARTER. Specifically, we will investigate how the age of a subject and the presence or absence of HAND are associated with HIV-1 DNA levels in PBMCs and CSF cell pellets (Aim 1), the frequency of viral populations with differing co-receptor usage and drug resistance (Aim 2), anatomic compartmentalization and viral diversity between blood and CSF (Aim 3), and the rate of viral evolution during HAART (Aim 4). These analyses will be accomplished using a combination of phylogenetic, computational, and statistical techniques we developed and employ as part of our research at UCSD to better understand aspects of viral dynamics within human hosts. Collectively, this study will yield a more complete understanding of how various virologic factors impact natural aging processes and thereby lead to HAND within the context of HAART.

Public Health Relevance

There is a growing body of literature into how viral dynamics and aging influence neurologic disease during HIV infection, but these studies are often limited by small numbers of participants, lack of standardized neurologic and clinical assessments, and practical restrictions of the virologic assays. Using data and samples collected from a large cohort designed to investigate neurologic dysfunction during HIV infection, this project aims to use novel next- generation ultradeep sequencing methods to better evaluate how human aging and HIV dynamics influence neurologic disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH097520-03
Application #
8600730
Study Section
Special Emphasis Panel (ZMH1-ERB-M (02))
Program Officer
Joseph, Jeymohan
Project Start
2012-03-05
Project End
2016-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
3
Fiscal Year
2014
Total Cost
$325,435
Indirect Cost
$111,685
Name
University of California San Diego
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Heaton, Robert K; Franklin Jr, Donald R; Deutsch, Reena et al. (2015) Neurocognitive change in the era of HIV combination antiretroviral therapy: the longitudinal CHARTER study. Clin Infect Dis 60:473-80
Okulicz, Jason F; Le, Tuan D; Agan, Brian K et al. (2015) Influence of the timing of antiretroviral therapy on the potential for normalization of immune status in human immunodeficiency virus 1-infected individuals. JAMA Intern Med 175:88-99
Little, Susan J; Kosakovsky Pond, Sergei L; Anderson, Christy M et al. (2014) Using HIV networks to inform real time prevention interventions. PLoS One 9:e98443
Wagner, Gabriel A; Pacold, Mary E; Kosakovsky Pond, Sergei L et al. (2014) Incidence and prevalence of intrasubtype HIV-1 dual infection in at-risk men in the United States. J Infect Dis 209:1032-8
Tatro, Erick T; Purnajo, Intan; Richman, Douglas D et al. (2014) Antibody response to Achromobacter xylosoxidans during HIV infection is associated with lower CD4 levels and increased lymphocyte activation. Clin Vaccine Immunol 21:46-50
Chaillon, A; Gianella, S; Massanella Luna, M et al. (2014) A case cluster demonstrating the relationship between HLA concordance and virologic and disease outcomes in human immunodeficiency virus infection. Virology 449:104-8
Chaillon, Antoine; Gianella, Sara; Wertheim, Joel O et al. (2014) HIV migration between blood and cerebrospinal fluid or semen over time. J Infect Dis 209:1642-52
Grant, Igor; Franklin Jr, Donald R; Deutsch, Reena et al. (2014) Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline. Neurology 82:2055-62
Ku, N S; Lee, Y; Ahn, J Y et al. (2014) HIV-associated neurocognitive disorder in HIV-infected Koreans: the Korean NeuroAIDS Project. HIV Med 15:470-7
Tilghman, Myres W; Bhattacharya, Jayanta; Deshpande, Suprit et al. (2014) Genetic attributes of blood-derived subtype-C HIV-1 tat and env in India and neurocognitive function. J Med Virol 86:88-96

Showing the most recent 10 out of 14 publications