Project #3. Approximately 10% of patients who successfully suppress HIV-1 in the blood with antiretroviral therapy have persistently higher levels of virus In the CSF. This likely represents ongoing replication in the CNS which has the potential to contribute to or worsen HIV-associated neurocognitive impairment. In Project 3 we will examine factors associated with the failure to suppress viral replication in the CNS. We will examine the virus present in the CSF to determine if it is T cell-tropic or macrophage-tropic. We will determine the drug levels in the CSF to determine if persistent replication could be the result of inadequate drug exposure in the CNS. A contributor to low drug levels that we will examine may be polymorphisms in drug transporter genes, which encode proteins that play a critical role In protecting the CNS from xenobiotics. We will also determine if persistent replication is associated with the development of drug resistance. Collectively, these studies will bring important insights to the significance and risks of persistent replication in the CNS in the face of otherwise successful therapeutic intervention.

Public Health Relevance

HIV can replicate In the CNS even in the face of successful antiretroviral therapy to suppress virus in the blood. The factors that allow continued replication in the CNS are not understood and this replication represents a potential risk for ongoing damage to the CNS. We will examine different parameters to determine which are associated with persistent HIV replication in the CNS.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01MH094177-04
Application #
8681212
Study Section
Special Emphasis Panel (ZMH1)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Joseph, Sarah B; Arrildt, Kathryn T; Sturdevant, Christa B et al. (2015) HIV-1 target cells in the CNS. J Neurovirol 21:276-89
Price, Richard W; Spudich, Serena S; Peterson, Julia et al. (2014) Evolving character of chronic central nervous system HIV infection. Semin Neurol 34:7-13
Jessen Krut, Jan; Mellberg, Tomas; Price, Richard W et al. (2014) Biomarker evidence of axonal injury in neuroasymptomatic HIV-1 patients. PLoS One 9:e88591
Joseph, Sarah B; Arrildt, Kathryn T; Swanstrom, Adrienne E et al. (2014) Quantification of entry phenotypes of macrophage-tropic HIV-1 across a wide range of CD4 densities. J Virol 88:1858-69