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 (AHI) is unknown.

Methods:

We analyzed the phenotype, gene expression, T cell receptor (TCR) repertoire, and HIV specificity of CD8+ T cells in cerebrospinal fluid (CSF) of a unique cohort captured during the earliest stages of AHI (n= 26), chronic (n= 23), and uninfected (n= 8).

Results:

CSF CD8+ T cells were elevated in AHI compared with 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 HIV infection 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 with 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 chronic HIV infection if combination antiretroviral therapy is initiated early.

BACKGROUND

HIV infects the central nervous system (CNS) within days of initial exposure and induces neuroinflammation that includes invasion of infected mononuclear cells and subsequent activation of localized inflammatory cells. These activated CNS resident cells release an array of neurotoxins that can be measured in the cerebrospinal fluid (CSF), 1 and additional neuronal injury can occur directly from HIV proteins, such as tat and gp120. 2 Tissue damage persists despite combination antiretroviral therapy (cART) because of incomplete eradication of HIV reservoirs and sustained CNS inflammation, in part as a result of limitations in CNS drug penetration. 3–5 This ongoing injury likely plays a role in a pervasive low-level encephalopathy presenting as continued mild cognitive impairment. 6–8 These inflammatory mechanisms need to be elucidated to develop therapeutic strategies to limit CNS damage and preserve or restore cognitive function in HIV-infected individuals.