HIV creates complex genetic populations within a host, and remains latent in a variety of cell types and tissues under antiretroviral therapy, representing a barrier to therapeutic cure. Yet little is known about the relative sizes of latent viral reservoirs in different tissues such as the central nervous system (CNS), and even less about exchange between viral subpopulations in different tissues over time. Deep sequencing technologies allow extensive sampling of these populations. Previous studies have been hampered by limited sampling of viral diversity in the CNS and because they studied only single or occasionally multiple, sparse time points. Designing workable viral eradication strategies will require a characterizing the CNS viral reservoir and its population dynamics with higher resolution. To address these gaps in knowledge, we will apply recently developed techniques, digital PCR (dPCR) and ultra deep sequencing (UDS), to quantify tissue reservoir size and the dynamics of viral subpopulations in archived, longitudinal samples of cerebrospinal fluid cells and supernatant and peripheral blood mononuclear cells and plasma. Here we will evaluate viral subpopulation interactions occurring after antiretroviral treatment interruption, which provides a substantial perturbation of steady state viral and cellular dynamics to anchor the observations. We will apply phylogenetic methods to viral population sequences from CNS and blood over time to assess population dynamics. The study sample comprises a unique, densely serially sampled group of 10 HIV+ subjects undergoing antiretroviral (ART) treatment interruption or viral rebound in the face of continued ART. The project will generate approximately 1.2 million viral sequences. These will be analyzed to delineate how the CNS viral reservoir interacts dynamically with other viral subpopulations and contributes to viral diversification and pathogenicity. The project also will measure the size of CNS viral reservoirs. After de-identification of human subjects, viral sequences will be posted as appropriate on public scientific data resource utilities and software generated for this project will be made publicly available.

Public Health Relevance

Despite the development of combination antiretroviral therapies, HIV infection remains a major cause of illness and death in adults. Infection is suppressed, but not cured by antiretroviral therapy. By delineating how and why HIV persists in the central nervous system and other tissues, this project will provide the groundwork for developing future strategies to eradicate infection

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH101012-02
Application #
8655911
Study Section
Special Emphasis Panel (ZMH1)
Program Officer
Joseph, Jeymohan
Project Start
2013-05-01
Project End
2016-01-31
Budget Start
2014-02-01
Budget End
2015-01-31
Support Year
2
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Neurosciences
Type
Schools of Medicine
DUNS #
City
La Jolla
State
CA
Country
United States
Zip Code
92093
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
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
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:
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; 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; 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
de Almeida, Sergio M; Rotta, Indianara; Ribeiro, Clea E et al. (2017) Dynamic of CSF and serum biomarkers in HIV-1 subtype C encephalitis with CNS genetic compartmentalization-case study. J Neurovirol 23:460-473
Gianella, Sara; Kosakovsky Pond, Sergei L; Oliveira, Michelli F et al. (2016) Compartmentalized HIV rebound in the central nervous system after interruption of antiretroviral therapy. Virus Evol 2:vew020
Pérez-Santiago, Josué; Schrier, Rachel D; de Oliveira, Michelli F et al. (2016) Cell-free mitochondrial DNA in CSF is associated with early viral rebound, inflammation, and severity of neurocognitive deficits in HIV infection. J Neurovirol 22:191-200
Smith, Davey M; Nakazawa, Masato; Freeman, Michael L et al. (2016) Asymptomatic CMV Replication During Early Human Immunodeficiency Virus (HIV) Infection Is Associated With Lower CD4/CD8 Ratio During HIV Treatment. Clin Infect Dis 63:1517-1524

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