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Dual Role of Activated and HIV-Specific CD8 T Cells in CSF During Acute HIV Infection
Lydie Trautmann1; Cari Kessing2; Eugène Kroon3; Donn Colby3; Shelly Krebs4; Napapon Sailasuta5; Jintana Intana3; Victor Valcour6; Jintanat Ananworanich4; Serena S. Spudich7; for the SEARCH 010/011/013 Study Groups
1Military HIV Rsr Prog, Silver Spring, MD, USA;2The Scripps Rsr Inst, Jupiter, FL, USA;3SEARCH, Bangkok, Thailand;4Military HIV Rsr Prog, Bethesda, MD, USA;5Univ of Hawaii, Honolulu, HI, USA;6Univ of California San Francisco, San Francisco, CA, USA;7Yale Univ Sch of Med, New Haven, CT, USA
HIV enters the CNS compartment as early 8 days post estimated exposure in humans. Infiltration of CD8 T cells into the CNS is a recognized feature of many neurodegenerative diseases and is seen in HIV-associated dementia. The number of CD8 T cells present in the cerebrospinal fluid (CSF) during HIV infection is elevated compared to other CNS diseases; however, the role of these CD8 T cells and whether they are serving a detrimental or protective effect during acute HIV infection is unknown.
We analyzed CD8 T cells from CSF in a unique cohort enrolled during the earliest stages of acute HIV infection (RV254/SEARCH010 cohort, n=26) compared to chronic HIV patients (SEARCH011, n=9, cART naïve) and uninfected controls (RV304/SEARCH013, n=8). We analyzed the absolute number and phenotype of CD8 T cells from the CSF and blood by flow cytometry. Phenotypic analyses were completed; we then correlated these with CSF HIV RNA and inflammatory markers from CSF. After in vitro expansion of the CSF CD8 T cells, we examined Vbeta repertoire usage by flow cytometry; HIV-specificity was determined by intracellular cytokine staining using peptide pools covering Env, Pol, Gag and Nef.
The total numbers and frequency of activated CSF CD8 T cells were elevated in chronic and acute HIV-infected participants compared to controls (P=0.04 and P<0.0001, respectively). Activated CD8 T cells correlated with CSF HIV RNA (P=0.001), and with markers of CNS inflammation [neopterine (P=0.0005), IP-10 (P=0.004), CD163 (P<0.0001), and sCD14 (P=0.02)]. CD8 T cells in the CSF harbored a more restricted Vbeta repertoire compared to total and activated CD8 T cells from peripheral blood. During acute infection, different Vbeta families were expanded in the CSF and peripheral blood, suggesting local specific expansions. Finally, HIV-specific CD8 T cells were detected during acute infection in CSF and activated CD8 T cells in blood. These CD8 T cells were found to target different HIV proteins in the CSF compared to peripheral blood.
These results highlight the dual role of activated CD8 T cells in CSF during HIV infection. Their increase in the CSF early in HIV infection and their correlation to neuro-inflammatory markers suggest that they could play a role in the development of HIV-associated neuroinflammatory disorders. Their unique T cell repertoire and HIV-specificity in the CSF in acute infection suggest that they could also play a role in controlling viral replication in the CNS compartment.