Highly Activated CD8+ T Cells in the Brain Correlate with Early Central Nervous System Dysfunction in Simian Immunodeficiency Virus Infection

Abstract

One of the consequences of HIV infection is damage to the CNS. To characterize the virologic, immunologic, and functional factors involved in HIV-induced CNS disease, we analyzed the viral loads and T cell infiltrates in the brains of SIV-infected rhesus monkeys whose CNS function (sensory evoked potential) was impaired. Following infection, CNS evoked potentials were abnormal, indicating early CNS disease. Upon autopsy at 11 wk post-SIV inoculation, the brains of infected animals contained over 5-fold more CD8+ T cells than did uninfected controls. In both infected and uninfected groups, these CD8+ T cells presented distinct levels of activation markers (CD11a and CD95) at different sites: brain > CSF > spleen = blood > lymph nodes. The CD8+ cells obtained from the brains of infected monkeys expressed mRNA for cytolytic and proinflammatory molecules, such as granzymes A and B, perforin, and IFN-γ. Therefore, the neurological dysfunctions correlated with increased numbers of CD8+ T cells of an activated phenotype in the brain, suggesting that virus-host interactions contributed to the related CNS functional defects.

CD8+ Lymphocyte-Mediated Injury of Dorsal Root Ganglion Neurons during Lentivirus Infection: CD154-Dependent Cell Contact Neurotoxicity

“…Nonetheless, both FIV-infected and uninfected CD8ϩ T cells, rather than CD4ϩ T cells and CD22ϩ B cells, exhibited cytotoxicity to DRG neurons in the current study. This finding may reflect that activated CD8ϩ T cells exhibiting a distinct clonal repertoire with the capacity to cause neurological damage (Marcondes et al, 2001;Shacklett et al, 2004), although HIV-specific CD8ϩ T cells play a central role in immune response against viruses.…”

“…However, activated CD8ϩ T cells represent the major T cell subset in the HIV-or SIV-infected CNS (Marcondes et al, 2001;Shacklett et al, 2004). In the PNS, T cell subsets have not been identified in peripheral nerves and DRG of HIV-infected patients and of FIV-infected animals because of limited speciesspecific tools (e.g., antibodies).…”

High Frequency of Virus-Specific CD8+T Cells in the Central Nervous System of Macaques Chronically Infected with Simian Immunodeficiency Virus SIVmac251

“…The presence of memory CD8 ϩ T cells in the brain has been correlated with functional and histopathological abnormalities (27). Despite a high frequency of virus-specific CD8…”

“…For HIV-1 or SIV infection, the finding in CSF of large numbers of HIV-1-specific CTLs that recognize epitopes different from those recognized by blood CTLs (20,46) (3,27,44). Our data for SIVmac251-infected macaques support the notion that virus-specific CD8 ϩ T cells may be either induced in, or recruited to, the brain.…”

“…CSF cells were collected by centrifugation at 200 ϫ g for 7 min and, after removal of supernatant, were resuspended in Hanks balanced salt solution. Brain lymphocytes were collected as previously described (27 ϩ CD8 ϩ T lymphocytes were also isolated from the brain.…”