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.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZMH1-ERB-M (02))
Program Officer
Joseph, Jeymohan
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California San Diego
Internal Medicine/Medicine
Schools of Medicine
La Jolla
United States
Zip Code
Dubé, Karine; Gianella, Sara; Concha-Garcia, Susan et al. (2018) Ethical considerations for HIV cure-related research at the end of life. BMC Med Ethics 19:83
Chaillon, Antoine; Gianella, Sara; Lada, Steven M et al. (2018) Size, Composition, and Evolution of HIV DNA Populations during Early Antiretroviral Therapy and Intensification with Maraviroc. J Virol 92:
Oliveira, Michelli F; Chaillon, Antoine; Nakazawa, Masato et al. (2017) Early Antiretroviral Therapy Is Associated with Lower HIV DNA Molecular Diversity and Lower Inflammation in Cerebrospinal Fluid but Does Not Prevent the Establishment of Compartmentalized HIV DNA Populations. PLoS Pathog 13:e1006112
Morris, Sheldon R; Zhao, Mitchell; Smith, Davey M et al. (2017) Longitudinal Viral Dynamics in Semen During Early HIV Infection. Clin Infect Dis 64:428-434
Chaillon, Antoine; Essat, Asma; Frange, Pierre et al. (2017) Spatiotemporal dynamics of HIV-1 transmission in France (1999-2014) and impact of targeted prevention strategies. Retrovirology 14:15
Gianella, Sara; Chaillon, Antoine; Mutlu, Ece A et al. (2017) Effect of cytomegalovirus and Epstein-Barr virus replication on intestinal mucosal gene expression and microbiome composition of HIV-infected and uninfected individuals. AIDS 31:2059-2067
Gianella, Sara; Taylor, Jeff; Brown, Timothy R et al. (2017) Can research at the end of life be a useful tool to advance HIV cure? AIDS 31:1-4
Chaillon, Antoine; Nakazawa, Masato; Wertheim, Joel O et al. (2017) No Substantial Evidence for Sexual Transmission of Minority HIV Drug Resistance Mutations in Men Who Have Sex with Men. J Virol 91:
Chaillon, Antoine; Smith, Davey M; Vanpouille, Christophe et al. (2017) HIV Trafficking Between Blood and Semen During Early Untreated HIV Infection. J Acquir Immune Defic Syndr 74:95-102
Gianella, Sara; Anderson, Christy M; Var, Susanna R et al. (2016) Replication of Human Herpesviruses Is Associated with Higher HIV DNA Levels during Antiretroviral Therapy Started at Early Phases of HIV Infection. J Virol 90:3944-3952

Showing the most recent 10 out of 53 publications