Impact of sleep deprivation on neurocognition and inflammation in rhesus macaques.

Sleep deprivation in humans is associated with both cognitive impairment and immune dysregulation. An animal model of neuropathogenesis may provide insight to understand the effects of sleep deprivation on the brain. Human neurocognition is more closely mirrored by nonhuman primates (NHP) than other animals. As such, we developed an NHP model to assess the impact of sleep deprivation on neurocognition and markers of systemic immune activation. Six male rhesus macaques underwent three rounds of sleep deprivation (48 h without sleep) at days 0, 14, and 28. We performed domain specific cognitive assessments using the Cambridge Neuropsychological Test Automated Battery (CANTAB) via a touch screen before and after 24 and 48 h of sleep deprivation. Immune activation markers were measured in the blood by multiplex assay and flow cytometry. Although we observed variability in cognitive performance between the three rounds of sleep deprivation, cognitive impairments were identified in all six animals. We noted more cognitive impairments after 48 h than after 24 h of sleep deprivation. Following 48 h of sleep deprivation, elevations in markers of immune activation in the blood were observed in most animals. The observed impairments largely normalized after sleep. The co-occurrence of systemic immune alterations and cognitive impairment establishes this model as useful for studying the impact of sleep deprivation on neurobehavior and immune perturbations in rhesus macaques.

Neurocognitive impact of Zika virus infection in adult rhesus macaques.

BACKGROUND: Zika virus (ZIKV) is a mosquito-transmitted flavivirus that affects many regions of the world. Infection, in utero, causes microcephaly and later developmental and neurologic impairments. The impact of ZIKV infection on neurocognition in adults has not been well described. The objective of the study was to assess the neurocognitive impact of ZIKV infection in adult rhesus macaques. METHODS: Neurocognitive assessments were performed using the Cambridge Neuropsychological Test Automated Battery (CANTAB) via a touch screen and modified Brinkman Board before and after subcutaneous ZIKV inoculation. Immune activation markers were measured in the blood and cerebral spinal fluid (CSF) by multiplex assay and flow cytometry. RESULTS: All animals (N = 8) had detectable ZIKV RNA in plasma at day 1 post-inoculation (PI) that peaked at day 2 PI (median 5.9, IQR 5.6-6.2 log10 genome equivalents/mL). In all eight animals, ZIKV RNA became undetectable in plasma by day 14 PI, but persisted in lymphoid tissues. ZIKV RNA was not detected in the CSF supernatant at days 4, 8, 14 and 28 PI but was detected in the brain of 2 animals at days 8 and 28 PI. Elevations in markers of immune activation in the blood and CSF were accompanied by a reduction in accuracy and reaction speed on the CANTAB in the majority of animals. CONCLUSIONS: The co-occurrence of systemic and CSF immune perturbations and neurocognitive impairment establishes this model as useful for studying the impact of neuroinflammation on neurobehavior in rhesus macaques, as it pertains to ZIKV infection and potentially other pathogens.

Virological and Immunological Outcomes in Rhesus Monkeys after Exposure to Dengue Virus-Infected Aedes aegypti Mosquitoes.

This study describes the natural history of dengue virus (DENV) infection in rhesus monkeys exposed to the bites of DENV-infected Aedes aegypti mosquitoes. Dengue virus-infected mosquitoes were generated by either intrathoracic inoculation or by oral feeding on viremic blood meals. Each of the six rhesus monkeys that were fed upon by intrathoracically infected mosquitoes developed non-structural protein 1 (NS1) antigenemia and an IgM response; viremia was detected in 4/6 individuals. No virological or immunological evidence of DENV infection was detected in the three monkeys exposed to mosquitoes that had been orally infected with DENV. These results demonstrate the utility of mosquito-borne challenge of rhesus monkeys with DENV.

Impact of analytical treatment interruption on the central nervous system in a simian-HIV model.

OBJECTIVE(S): Analytical treatment interruption (ATI) studies are often used to evaluate potential HIV cure strategies. This study was conducted to determine the impact of ATI on simian-HIV (SHIV) infection in the central nervous system. DESIGN: Animal study. METHODS: Nine rhesus macaques were inoculated with SHIV-1157ipd3N4. Antiretroviral therapy (ART) was administered from week 2 to 18. At week 18, four animals were euthanized (no-ATI-group) and five underwent ATI (ATI-group) and were euthanized at 12 weeks post viral rebound. Plasma and cerebrospinal fluid (CSF) SHIV-RNA, markers of inflammation and brain CD3+, CD68+/CD163+ and RNA+ cells were measured. RESULTS: All nine animals were SHIV-infected, with median pre-ART plasma and CSF SHIV-RNA of 6.2 and 3.6 log10copies/ml. Plasma and CSF IL-15, monocyte chemoattractant protein-1, IFN-γ-induced protein-10 and neopterin increased postinfection. ART initiation was associated with rapid and complete suppression of plasma viremia and reductions in plasma and CSF IL-15, IFN-γ-induced protein-10, neopterin and CSF monocyte chemoattractant protein-1. Median time to plasma viral rebound was 21 days post-ATI. At 12 weeks postrebound, CSF SHIV-RNA was undetectable and no increases in plasma and CSF markers of inflammation were found. Higher numbers of CD3+ and CD68+/CD163+ cells were seen in the brains of 3/5 and 1/5 animals, respectively, in the ATI-group when compared with no-ATI-group. SHIV-RNA+ cells were not identified in the brain in either group post-ATI. CONCLUSION: ATI in macaques that initiated ART during early SHIV-1157ipd3N4 infection was associated with mild, localized T-cell infiltrate in the brain without detectable SHIV-RNA in the brain or CSF, or elevation in CSF soluble markers of inflammation.

Mammary carcinoma in a male rhesus macaque (Macaca mulatta): histopathology and immunohistochemistry of ductal carcinoma in situ.

BACKGROUND: A mammary nodule was noted in a male rhesus macaque during physical examination. METHODS AND RESULTS: Histopathological and immunohistochemical analysis was performed. Ductal carcinoma in situ was confirmed. CONCLUSIONS: To date, there are two reports of mammary carcinoma in male non-human primates, and none in the rhesus macaque.