High Number of Activated CD8+ T Cells Targeting HIV Antigens Are Present in Cerebrospinal Fluid in Acute HIV Infection

Abstract

Background Central nervous system (CNS) infiltration by CD8+ T cells is associated with neuroinflammation in many neurodegenerative diseases, including HIV-associated dementia. However, the role of CD8+ T cells in the CNS during acute HIV infection is unknown. Methods We analyzed the phenotype, gene expression, TCR repertoire and HIV-specificity of CD8+ T cells in cerebrospinal fluid (CSF) of a unique cohort captured during the earliest stages of acute HIV infection (AHI) (n=26), chronic (n=23), and uninfected (n=8). Results CSF CD8+ T cells were elevated in AHI compared to uninfected controls. The frequency of activated CSF CD8+ T cells positively correlated to CSF HIV RNA and to markers of CNS inflammation. In contrast, activated CSF CD8+ T cells during chronic infection (CHI) were associated with markers of neurological injury and microglial activation. CSF CD8+ T cells in AHI exhibited increased functional gene expression profiles associated with CD8+ T cells effector function, proliferation and TCR signaling, a unique restricted TCR Vbeta repertoire and contained HIV-specific CD8+ T cells directed to unique HIV epitopes compared to the periphery. Conclusions These results suggest that CSF CD8+ T cells in AHI expanding in the CNS are functional and directed against HIV antigens. These cells could thus play a beneficial role protective of injury seen in CHI if cART is initiated early.

In Vivo Suppression of HIV Rebound by Didehydro-Cortistatin A, a “Block-and-Lock” Strategy for HIV-1 Treatment

“…In cell models of latency, virus can be reactivated either upon ART removal or upon cellular stimulation with HIV LRAs. To study the ability of dCA to limit viral transcription in these contexts, we used a previously established protocol to maintain primary CD4 + T cells from infected individuals for up to 10 weeks in culture, while preserving their characteristic representation of the HIV reservoir (Kessing et al, 2017; Mousseau et al, 2015a). …”

“…Even if not significant, we observed GATA3 and CCR7 genes to be the most altered between ART and ART+dCA samples at day 14. It has been reported that GATA3 and CCR7 expression is inversely correlated with HIV expression (Kessing et al, 2017; Ramirez et al, 2014; Rueda et al, 2012). As such, in future work we will further investigate these genes during the expansion of the cells in vitro .…”

Persistent HIV-infected cells in cerebrospinal fluid are associated with poorer neurocognitive performance

“…CSF mononuclear cells are primarily composed of T lymphocytes in HIVindividuals and individuals with HIV pre-and post-ART (14). The CD4 + T cell percentage ranges from approximately 40% in participants who started ART during acute HIV infection to 25% in those who start ART in chronic infection (38), and CD4/CD8 ratio measured in blood by clinical labs highly correlates with the percentage of CD4 + T lymphocytes in CSF (13,14).…”

Longitudinal Trajectories of Brain Volume and Cortical Thickness in Treated and Untreated Primary Human Immunodeficiency Virus Infection

“…It has been hypothesized that structural brain alterations may occur in primary HIV infection (PHI; defined as <1 year after exposure), possibly before cART initiation [3]. Several studies have demonstrated that prominent inflammation [5][6][7], immune activation [8][9][10] and blood-brain barrier (BBB) disruption [11] were evident during the first year of infection, and progressively worsened in the absence of cART [5,9,11]. All of these factors have been linked to neuronal injury during this period [12], and could contribute, in part, to brain volume reductions previously reported in PHI individuals [13][14][15].…”