Activated CD8+ T cells infiltrate the central nervous system (CNS) early in acute HIV infection (AHI). Whether CD8+ T cells in cerebral spinal fluid (CSF) are CNS specific or recirculate from the peripheral blood is not yet known. We characterized the CD8+ T cells in CSF and blood in different HIV infection stages by sequencing their T cell receptor (TCR) and measuring frequencies of HIV-specific CD8+ T cells.
Participants enrolled in the Thai RV254/RV304 cohorts who consented to optional lumbar puncture were studied. Blood and CSF samples were collected at the time of ART initiation during AHI (n=15) or chronic HIV infection (CHI; n=6), as well as after 24 and 96 weeks of ART in both groups. Genomic DNA was purified from polyclonally expanded CD8+ T cells for sequencing of the TCR? chain. Repertoire clonality was measured by Simpson clonality index and diversity by Morisita index. HIV-specificity was measured in polyclonally expanded CD8+ T cells by cytokine staining after stimulation with CRF01_AE HIV peptide pools.
Comparison of the CD8+ TCR? repertoires between CSF and blood revealed differences prior to ART intiation in AHI (p=0.07), but not in CHI or after ART, suggesting CNS compartmentalization of CD8+ T cells in AHI. CD8+ TCR? repertoires were significantly more clonal in AHI than in CHI in CSF (Fig. 1A, p<0.001), but not in blood. CD8+ T cell turnover in CSF, measured as change in TCR? diversity between pre-ART and 24 weeks post-ART, was higher in participants who initiated ART in AHI compared to CHI (p=0.06). HIV-specific CD8+ T cells were detectable in the CSF in all stages of AHI and were still detected at similar frequencies on ART in contrast to blood where they declined after ART. Interestingly, the level of TCR? clonality in CSF during AHI was associated with the frequencies of Env-specific (r=0.62, p<0.05), Nef-specific (r=0.71, p<0.01), Pol-specific (r=0.63, p<0.05), and Rev/Tat-specific (r=0.59, p<0.05) CD8+ T cells in the CSF detected after 24 weeks of ART (Fig. 1B). There were no correlations between TCR? clonality and HIV-specific CD8+ T cell responses in the peripheral blood.
These data suggest that there is compartmentalization of CD8+ T cells in the CSF during AHI that is not seen after ART intiation or in CHI. Further, increased clonal expansion of CD8+ T cells in AHI, probably driven by local expansion of HIV-specific CD8+ T cell responses, were associated with persistence of HIV-specific CD8+ T cell responses in the CNS after ART.