Project #2: This project focuses on the effects of combination antiretroviral treatment (cART) on the central nervous system (CNS) infection and its consequences. It extends the findings of Project 1 related to cerebrospinal fluid (CSF) compartmentalization and T-lymphocyte and macrophage- tropism by examining their pathobiological consequences and influence on treatment responses. On the basis of previous studies, we postulate three types of CNS infection that differ in their location and tropism of the virus. Using CSF immune and neural biomarkers, neuropsychological test performance, this project proposes a series of studies to further characterize these three of CSF infection types. The project proposes three specific aims that examine, in turn, the effect of compartmentalization and tropism on: the pretreatment state, the treatment response kinetics and the longer term outcomes. Thus, the Aim 1 assesses the effect of pretreatment CSF viral compartmentalization and tropism on the other major baseline variables of interest that include: CSF immune activation and chemokine biomarkers, CSF neural injury biomarkers, and neuropsychological performance.
Aim 2 examines the effect of pre-treatment compartmentalization and tropism on the rate and magnitude of CSF HIV response to treatment compared to that of plasma, as well as the rate and magnitude of the reduction of intrathecal immune and chemokine responses, 'normalization'of CSF neural biomarkers, and improvement in neuropsychological performance.
Aim 3 assesses the effects of baseline compartmentalization and tropism on subsequent CSF viral suppression and 'CSF viral 'escape'(or 'discordant CSF response') after >1 year of treatment, and characterizes the CSF immune/Inflammatory and neural biomarker profiles and neuropsychological test performance in subjects with CSF viral escape compared to those with CSF suppression.
The pretreatment character of CNS HIV infection has critical implications for the integrity of the CNS, both before treatment is started and in response to treatment. These studies use CSF biomarkers, neuropsychological testing and treatment kinetics to characterize the biological consequences of CNS viral tropism. This characterization should inform prevention and treatment efforts to protect the CNS from the neuropathogenic effects of HIV.
|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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