Enhancement of Human Immunodeficiency Virus (HIV)-Specific CD8⁺T Cells in Cerebrospinal Fluid Compared to Those in Blood among Antiretroviral Therapy-Naïve HIV-Positive Subjects

Abstract

During untreated human immunodeficiency virus type 1 (HIV-1) infection, virus-specific CD8؉ T cells partially control HIV replication in peripheral lymphoid tissues, but host mechanisms of HIV control in the central nervous system (CNS) are incompletely understood. We characterized HIV-specific CD8 ؉ T cells in cerebrospinal fluid (CSF) and peripheral blood among seven HIV-positive antiretroviral therapy-naïve subjects. All had grossly normal brain magnetic resonance imaging and spectroscopy and normal neuropsychometric testing. Frequencies of epitope-specific CD8 ؉ T cells by direct tetramer staining were on average 2.4-fold higher in CSF than in blood (P ‫؍‬ 0.0004), while HIV RNA concentrations were lower. Cells from CSF were readily expanded ex vivo and responded to a broader range of HIV-specific human leukocyte antigen class I restricted optimal peptides than did expanded cells from blood. HIV-specific CD8 ؉ T cells, in contrast to total CD8 ؉ T cells, in CSF and blood were at comparable maturation states, as assessed by CD45RO and CCR7 staining. The strong relationship between higher T-cell frequencies and lower levels of viral antigen in CSF could be the result of increased migration to and/or preferential expansion of HIV-specific T cells within the CNS. This suggests an important role for HIV-specific CD8 ؉ T cells in control of intrathecal viral replication.

Enhanced PD-1 Expression by T Cells in Cerebrospinal Fluid Does Not Reflect Functional Exhaustion during Chronic Human Immunodeficiency Virus Type 1 Infection

“…We hypothesized that T-cell PD1 expression would be lower in CSF than in blood, since HIV-1 RNA concentrations are lower in CSF than in plasma and the magnitude and breadth of IFN-␥-secreting HIV-specific T cells are greater in CSF than in blood (40). We show that, in CSF, HIV-1 RNA correlates directly with PD-1 expression on CD4 ϩ , CD8 ϩ , and HIVspecific CD8 ϩ T cells.…”

“…Individuals with chronic HIV-1 infection were recruited for study participation from the Vanderbilt University-affiliated Comprehensive Care Center (Nashville, TN). Of the 15 participants in the present study, 4 were included in a previous report (40). Participants were antiretroviral naïve.…”

“…Immune responses cause neuropathogenesis during other viral infections, and cytotoxic T lymphocytes can worsen the disease through direct cytotoxicity or release of inflammatory cytokines such as gamma interferon (IFN-␥) (14). However, we recently described higher frequencies of functional HIV-specific CD8 ϩ T cells in cerebrospinal fluid (CSF) than in blood among asymptomatic HIV-positive individuals with little or no HIV-1 RNA in CSF, suggesting that HIV-1-specific CD8 ϩ T cells help to control intrathecal viral replication (40).…”

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

“…Memory CD8 + T cells (both EM and CM) were more abundant in CSF than in blood regardless of subject group, consistent with previous reports. 4,6 EM CD8 + T cells were the most abundant subset in CSF, followed by CM cells (Fig. 2A).…”

“…1,2 The brain and CNS are generally considered as immune privileged; nevertheless, the presence of HIV-specific T cells in brain and cerebrospinal fluid (CSF) has been documented, both in HIV-infected humans [3][4][5][6] and in rhesus macaques infected with simian immunodeficiency virus (SIVmac). 7,8 Sampling of CSF from HIV-infected subjects can provide a window into host-virus interactions in the CNS.…”