Deep analysis of CD4 T cells in the rhesus CNS during SIV infection

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  • Elizaldi S.R.
    • Other Affiliation: UC Davis
  • Verma A.
    • Other Affiliation: University of Pittsburgh School of Public Health
  • Ma Z.-M.
    • Other Affiliation: UC Davis
  • Ott S.
    • Other Affiliation: UC Davis
  • Rajasundaram D.
    • Other Affiliation: University of Pittsburgh School of Public Health
  • Hawes C.E.
    • Other Affiliation: UC Davis
  • Lakshmanappa Y.S.
    • Other Affiliation: UC Davis
  • Cottrell M.L.
    • Affiliation: Eshelman School of Pharmacy
  • Kashuba A.D.M.
    • Affiliation: Eshelman School of Pharmacy
  • Ambrose Z.
    • Other Affiliation: University of Pittsburgh School of Public Health
  • Lifson J.D.
    • Other Affiliation: Frederick National Laboratory
  • Morrison J.H.
    • Other Affiliation: UC Davis
  • Iyer S.S.
    • Other Affiliation: University of Pittsburgh School of Public Health
Abstract
  • Virologic suppression with antiretroviral therapy (ART) has significantly improved health outcomes for people living with HIV, yet challenges related to chronic inflammation in the central nervous system (CNS)—known as Neuro-HIV- persist. As primary targets for HIV-1 with the ability to survey and populate the CNS and interact with myeloid cells to co-ordinate neuroinflammation, CD4 T cells are pivotal in Neuro-HIV. Despite their importance, our understanding of CD4 T cell distribution in virus-targeted CNS tissues, their response to infection, and potential recovery following initiation of ART remain limited. To address these gaps, we studied ten SIVmac251-infected rhesus macaques using an ART regimen simulating suboptimal adherence. We evaluated four macaques during the acute phase pre-ART and six during the chronic phase. Our data revealed that HIV target CCR5+ CD4 T cells inhabit both the brain parenchyma and adjacent CNS tissues, encompassing choroid plexus stroma, dura mater, and the skull bone marrow. Aligning with the known susceptibility of CCR5+ CD4 T cells to viral infection and their presence within the CNS, high levels of viral RNA were detected in the brain parenchyma and its border tissues during acute SIV infection. Single-cell RNA sequencing of CD45+ cells from the brain revealed colocalization of viral transcripts within CD4 clusters and significant activation of antiviral molecules and specific effector programs within T cells, indicating CNS CD4 T cell engagement during infection. Acute infection led to marked imbalance in the CNS CD4/CD8 ratio which persisted into the chronic phase. These observations underscore the functional involvement of CD4 T cells within the CNS during SIV infection, enhancing our understanding of their role in establishing CNS viral presence. Our findings offer insights for potential T cell-focused interventions while underscoring the challenges in eradicating HIV from the CNS, particularly in the context of sub-optimal ART.
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  • Article
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  • In Copyright
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  • Attribution 4.0 International
Journal title
  • PLoS Pathogens
Journal volume
  • 19
Journal issue
  • 12
Language
  • English
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  • 1553-7366
Publisher
  • Public Library of Science

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