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Simian immunodeficiency virus (SIV) infection of pigtailed macaques is a highly representative and well-characterized animal model for HIV neuropathogenesis studies that provides an excellent opportunity to study and develop prognostic markers of HIV-associated neurocognitive disorders (HAND) for HIV-infected individuals. SIV studies can be performed in a controlled setting that enhances reproducibility and offers high-translational value. Similar to observations in HIV-infected patients receiving antiretroviral therapy (ART), ongoing neurodegeneration and inflammation are present in SIV-infected pigtailed macaques treated with suppressive ART. By developing quantitative viral outgrowth assays that measure both CD4+ T cells and macrophages harboring replication competent SIV as well as a highly sensitive mouse-based viral outgrowth assay, we have positioned the SIV/pigtailed macaque model to advance our understanding of latent cellular reservoirs, including potential CNS reservoirs, to promote HIV cure. In addition to contributing to our understanding of the pathogenesis of HAND, the SIV/pigtailed macaque model also provides an excellent opportunity to test innovative approaches to eliminate the latent HIV reservoir in the brain. [ABSTRACT FROM AUTHOR]

As the prevalence of human immunodeficiency virus (HIV)-induced central nervous system (CNS) disease has increased with antiretroviral treatment, there is a critical need for identifying biomarkers that predict HIV CNS disease. To identify novel hematologic markers that precede and predict CNS disease, the authors examined longitudinal hematology data from 47 simian immunodeficiency virus (SIV)-infected macaques. This study demonstrated that the magnitude of decline in circulating platelet counts beginning at day 28 post infection, during asymptomatic SIV infection, predicted the eventual development of SIV encephalitis. Univariate analysis performed on platelet values obtained day 56 post inoculation demonstrated that SIV-infected macaques with the greatest decline in platelet numbers were 18 times more likely to develop SIV CNS disease than SIV-infected animals with minimal to no decline in circulating platelet counts. Decline in platelet number was a more robust marker than decline in hemoglobin levels, a previously identified marker of HIV CNS disease. The identification of an association between decline in platelets and the development of encephalitis demonstrates that monitoring platelet decline in HIV-infected individuals may serve as a predictive marker for clinical progression to HIV-induced CNS disease. Identifying those HIV-infected individuals at risk for CNS disease during asymptomatic stages of infection would promote early interventive, neuroprotective therapy to prevent neuronal damage and loss. [ABSTRACT FROM AUTHOR]

Despite the high incidence of cognitive and motor impairment in acquired immunodeficiency syndrome (AIDS) patients, the mechanisms of AIDS-related central nervous system (CNS) pathology are not completely understood. Infection with simian immunodeficiency virus (SIV) in macaques provides an excellent model of AIDS, including human immunodeficiency virus (HIV)-induced CNS pathology and cognitive/behavioral impairment. Co-inoculation with two SIV strains, SIV/17E-Fr and SIV/DeltaB670, accelerates SIV CNS disease, producing SIV encephalitis in over 90% of pig-tailed macaques within 3 months. In the present study, this SIV model was employed to identify cellular and viral correlates of behavioral impairment following SIV infection. Measures of psychomotor speed (simple reaction time), fine motor control (bimanual motor task), and general motor activity (home cage movement) were all adversely affected by SIV disease. Prior to euthanasia, performance was significantly impaired in both a simple reaction time task in 6 of 12 monkeys and a bimanual motor task in 5 of 6 monkeys. All monkeys evaluated (11 of 11) showed significant reductions in spontaneous motor activity. Significant correlations were found between impaired performance on the bimanual motor test and axonal damage (accumulation of β-amyloid precursor protein in the corpus callosum) as well as increased microglial activation and macrophage infiltration (levels of CD68 and Ham56 immunostaining). These results suggest that axonal damage is related to the behavioral impairment induced by infection with SIV. The axonal damage may result from neuroimmune responses, including microglial and macrophage activation. Therefore, axonal damage may be a morphologic manifestation of neuronal dysfunction that underlies development of behavioral impairment in HIV/SIV CNS infection. [ABSTRACT FROM AUTHOR]