Project 1 is focused on the virology of CNS infection as sampled in the CSF. We have recently identified macrophage-tropic virus in the CSF of a subset of subjects diagnosed with HIV-associated dementia. In another subset of HAD subjects we identified CSF-compartmentalized HIV that had an entry phenotype that required high concentrations of CD4 indicative of infection of activated T cells, and this was associated with pleocytosis. Thus, CNS infection can occur through two distinct pathways, infection of T cells presumably drawn into the CNS by concurrent inflammation, or infection of long-lived macrophage/microglia cells. We have also detected both types of viruses as compartmentalized variants in non-demented subjects. We propose to analyze the extent of compartmentalization and tropism in subjects entering therapy. This will be part of a comprehensive analysis of Inflammation, neuronal damage, and neuropsychiatric evaluation at entry and during the first year of therapy (Project 2). In addition, this information will be used in the context of persistent CNS infection in the face of successful treatment (Project 3). We hypothesize that knowledge about the nature of CNS infection will be important to understanding the complex of symptoms known as HAND, and that this knowledge will ultimately contribute to a mechanism-based intervention that will reverse and alleviate its effects.

Public Health Relevance

HIV Infection can include infection of cells in the central nervous system. We propose to examine virus present in the CSF to determine the extent and nature of HIV infection in the brain. These studies are designed to develop a more mechanistic understand of the neurocognitive impact of HIV infection.

Agency
National Institute of Health (NIH)
Type
Research Program Projects (P01)
Project #
5P01MH094177-04
Application #
8681210
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
Gisslén, 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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