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.
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.
|GisslÃ©n, Magnus; Price, Richard W; Andreasson, Ulf et al. (2016) Plasma Concentration of the Neurofilament Light Protein (NFL) is a Biomarker of CNS Injury in HIV Infection: A Cross-Sectional Study. EBioMedicine 3:135-40|
|Sturdevant, Christa Buckheit; Joseph, Sarah B; Schnell, Gretja et al. (2015) Compartmentalized replication of R5 T cell-tropic HIV-1 in the central nervous system early in the course of infection. PLoS Pathog 11:e1004720|
|Dumond, Julie B; Yang, Kuo H; Kendrick, Racheal et al. (2015) Pharmacokinetic Modeling of Lamivudine and Zidovudine Triphosphates Predicts Differential Pharmacokinetics in Seminal Mononuclear Cells and Peripheral Blood Mononuclear Cells. Antimicrob Agents Chemother 59:6395-401|
|Joseph, Sarah B; Arrildt, Kathryn T; Sturdevant, Christa B et al. (2015) HIV-1 target cells in the CNS. J Neurovirol 21:276-89|
|Bednar, Maria M; Sturdevant, Christa Buckheit; Tompkins, Lauren A et al. (2015) Compartmentalization, Viral Evolution, and Viral Latency of HIV in the CNS. Curr HIV/AIDS Rep 12:262-71|
|Arrildt, Kathryn T; LaBranche, Celia C; Joseph, Sarah B et al. (2015) Phenotypic Correlates of HIV-1 Macrophage Tropism. J Virol 89:11294-311|
|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|
|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|
|Peterson, Julia; Gisslen, Magnus; Zetterberg, Henrik et al. (2014) Cerebrospinal fluid (CSF) neuronal biomarkers across the spectrum of HIV infection: hierarchy of injury and detection. PLoS One 9:e116081|
|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|
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