Enrichment and Persistence of Virus-Specific CTL in the Brain of Simian Immunodeficiency Virus-Infected Monkeys Is Associated with a Unique Cytokine Environment

Abstract

The host reaction to infection of the brain contributes to a number of CNS pathologies including neuro-AIDS. In this study, we have identified the accumulation of SIV-specific CTL in the brains of SIV-infected animals who have neurophysiological abnormalities but are otherwise asymptomatic. SIV-specific CTL enter the brain early after viral infection and are maintained in the brain even when those reactive with an immunodominant epitope in Tat are lost from the rest of the body. The specialized CNS environment contributes to this unique outcome. Following SIV infection, brain levels of IL-15 were significantly elevated whereas IL-2 was absent, creating an environment that favors CTL persistence. Furthermore, in response to IL-15, brain-derived CD8+ T cells could expand in greater numbers than those from spleen. The accumulation, persistence, and maintenance of CTL in the brain are closely linked to the increased levels of IL-15 in the absence of IL-2 in the CNS following SIV infection.

IL-15 Treatment during Acute Simian Immunodeficiency Virus (SIV) Infection Increases Viral Set Point and Accelerates Disease Progression despite the Induction of Stronger SIV-Specific CD8+ T Cell Responses

“…It should be noted that previous studies to date have failed to establish a relationship between neuropathological findings, numbers of SIV-replicating cells, T cell infiltration, and repertoires of proinflammatory cytokines (42). However, a recent study suggests that IL-15 mRNA levels in the brain are increased in SIV infection and that this may indeed lead to maintenance of SIV-specific CD8 ϩ T cells in the CNS (67). Our results could therefore be interpreted in different ways.…”

Effects of simian immunodeficiency virus on the circadian rhythms of body temperature and gross locomotor activity

“…1 B, D, and F). However, in the SIV-infected group, the group mean cosinor analysis indicated a progressive decrease in the temperature amplitude in SIVE monkeys compared with baseline, reaching a significant reduction of 28%, 33%, and 62% [F (5,35) ϭ 36.73, P Ͻ 0.0001] during the progressing stages 1, 2, and 3, respectively (Fig. 1C), whereas a significant difference in the MESOR occurred in the progressing stage 3 [F (5,35) ϭ 9.73, P Ͻ 0.01] (Fig.…”

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

“…Various cytokines, including IL-2, IL-12, IL-23, IFN-␥, and TNF-␣, are produced in the CNS by different neural cells under pathological as well as physiological conditions (5). SIV infection in rhesus macaques leads to enhanced brain levels of IL-15, which has been implicated in enrichment and persistence of SIV-specific T cells in the CNS (28). In the HIV-positive individuals in the present study, IL-2 and IL-7 were undetectable in CSF, and culturing PBMCs ex vivo in autologous CSF did not enhance PD-1 expression on these cells.…”