Immune Activation and HIV-Specific CD8⁺T Cells in Cerebrospinal Fluid of HIV Controllers and Noncontrollers

Abstract

The central nervous system (CNS) is an important target of HIV, and cerebrospinal fluid (CSF) can provide a window into host-virus interactions within the CNS. The goal of this study was to determine whether HIVspecific CD8+ T cells are present in CSF of HIV controllers (HC), who maintain low to undetectable plasma viremia without antiretroviral therapy (ART). CSF and blood were sampled from 11 HC, defined based on plasma viral load (VL) consistently below 2,000 copies/ml without ART. These included nine elite controllers (EC, plasma VL <40 copies/ml) and two viremic controllers (VC, VL 40-2,000 copies/ml). All controllers had CSF VL <40 copies/ml. Three comparison groups were also sampled: six HIV noncontrollers (NC, VL >10,000 copies/ml, no ART); seven individuals with viremia suppressed due to ART (Tx, VL <40 copies/ml); and nine HIV-negative controls. CD4+ and CD8 + T cells in CSF and blood were analyzed by flow cytometry to assess expression of CCR5, activation markers CD38 and HLA-DR, and memory/effector markers CD45RA and CCR7. HIV-specific CD8 + T cells were quantified by major histocompatibility complex class I multimer staining. HIV-specific CD8 + T cells were detected ex vivo at similar frequencies in CSF of HC and noncontrollers; the highest frequencies were in individuals with CD4 counts below 500 cells/ll. The majority of HIV-specific CD8 + T cells in CSF were effector memory cells expressing CCR5. Detection of these cells in CSF suggests active surveillance of the CNS compartment by HIV-specific T cells, including in individuals with long-term control of HIV infection in the absence of therapy.

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

“…However, there is still a possibility that CD8+ T cells may contribute to inflammation and damage in the CNS, as a recent study found an association with the presence of HIV-specific CD8+T cells in the CSF to disease progression. 16 Little is known about the frequency of CD8+ T cells recognizing HIV antigens over the course of HIV infection especially in the CNS. A recent study suggested that inflammatory cytokines present during untreated chronic HIV infection triggers proliferation and expression of activation markers in CD8+ T cells in the periphery independent of antigen specificity.…”

“…13–15 A recent study found HIV-specific CD8+ T cells were most frequent in the CSF of individuals with a CD4 count below 500 cells/μL, suggesting a possible association between HIV-specific CD8+ T cells in the CSF and disease progression. 16 High frequencies of SIV-specific CD8+ T cells have also been detected in CSF of macaques chronically infected with SIV. 17,18 Recent studies suggested that early ART initiation would preserve these effective responses in the periphery.…”

T-cell activation state differentially contributes to neuropsychiatric complications in women with HIV

“…These aberrant CD8 + T-cell immune responses are not restricted to the periphery, and their presence in the CNS may also directly contribute to neurologic decline. CD8 + T-cells may enter the brain parenchyma and cerebrospinal fluid of PWH ( Ganesh et al, 2016 ; Ho et al, 2013 ; Kessing et al, 2017 ). This may not be beneficial, as interferon-gamma expressing CD8 + T-cells in the cerebrospinal fluid was strongly correlated with cognitive status ( Schrier et al, 2015 ).…”

Shock and kill within the CNS: A promising HIV eradication approach?

“…The most prominent immune cells in the CNS are the resident perivascular macrophages and microglia, but other peripheral immune subsets such as macrophages, dendritic cells, and T cells are also present 182 . The number of HIV‐specific CD4 + and CD8 + T cells is limited in the CNS as compared with the periphery but they can be detected in the CSF of PWH 183 . This indicates that immune‐mediated clearance of HIV can occur in the CNS and is suggested to be one of the mechanisms that may be involved in killing reactivated cells following latency reversal.…”