Cerebrospinal Fluid (CSF) CD8+ T-Cells That Express Interferon-Gamma Contribute to HIV Associated Neurocognitive Disorders (HAND)
Year: 2015
Type: article
Study design: Observational Study
Abstract: BACKGROUND: HIV associated neurocognitive disorders (HAND) continue to affect cognition and everyday functioning despite anti-retroviral treatment (ART). Previous studies focused on mechanisms related to monocyte/macrophage mediated inflammation. However, in the ART era, there is increasing evidence for the involvement of CD8+ T-cells in CNS pathogenesis. METHODS: To investigate the relationship between T-cell responses and neurocognitive impairment (NCI), cerebrospinal fluid (CSF) and peripheral blood CD4+ and CD8+ T-cell intracellular cytokine (IFNγ, IL-2, TNFα) and lytic marker (CD107a) expression were assessed in HIV infected subjects who underwent comprehensive neurocognitive (NC) evaluation and either initiated or changed ART. RESULTS: Data were collected from 31 participants at 70 visits. The frequency of cytokine expressing T-cells in CSF was significantly higher than in peripheral blood for CD4+T-cells: TNFα, IL-2, IFNγ and CD8+T-cells: IL-2 and IFNγ. Analysis of T-cell activity and NCI as a function of CSF HIV RNA levels suggested a general association between NCI, high CSF CD8+ (but not CD4+T-cell) cytokine expression and CSF HIV RNA <103 copies/ml (p<0.0001). Specifically, CSF CD8+ T-cell IFNγ expression correlated with severity of NCI (r = 0.57, p = 0.004). Multivariable analyses indicated that CSF CD8+T-cell IFNγ and myeloid activation (CD163) contributed equally and independently to cognitive status and a composite variable produced the strongest correlation with NCI (r = 0.83, p = 0.0001). In contrast, CD8+ cytolytic activity (CD107a expression) was negatively correlated with NCI (p = 0.05) but was dependent on CD4 levels >400/μl and low CSF HIV RNA levels (<103 copies/ml). In our longitudinal analysis of 16 subjects, higher CSF CD8+IFNγ expression at baseline predicted NC decline at follow-up (p = 0.02). Severity of NCI at follow-up correlated with level of residual HIV RNA in CSF. CONCLUSIONS: Presence of IFNγ expressing CD8+ T-cells, absence of cytolytic CD8+ T-cells, high myeloid activation, and failure of ART to suppress HIV replication in CSF contribute to increased risk of HAND.
Source: PLoS ONE
Authors: Rachel D. Schrier, Suzi Hong, Melanie Crescini, Ronald Ellis, Josué Pérez-Santiago, Celsa Spina, Scott Letendre, for the HNRP Group
Institution: University of California San Diego
Language: English
Topic: HIV Research and Treatment
Subfield: Virology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,382
Funders: U.S. Department of Veterans Affairs, National Institutes of Health, University of California, San Diego, Veterans Affairs San Diego Healthcare System, National Heart, Lung, and Blood Institute, National Institute of Mental Health, National Institute on Drug Abuse, National Institute of Allergy and Infectious Diseases
Awards: G128245230, G1349047428, G1766461084, HIV Neurocognitive Disorders: A Randomized Clinical Trial of CNS-Targeted HAART, Translational Methamphetamine AIDS Research Center (TMARC), G3715862790, G3789320706, G495691247, G5248170545, G5269898105, G5377080265, G645235059, G7987025476, Midcareer Investigator Award in Patient-Oriented NeuroAIDS Research, G8662205033, G9000042209, G9000070645, G9000124410, G9000350240, San Diego Center for AIDS Research (SD CFAR), HIV Neurobehavioral Research Center, HOPE Training Grant, G991514021
OpenAlex ID: W2060413782