Effect of Single Housing on Innate Immune Activation in Immunodeficiency Virus-Infected Pigtail Macaques ( Macaca nemestrina ) as a Model of Psychosocial Stress in Acute HIV Infection.

OBJECTIVE: Simian immunodeficiency virus (SIV) infection of macaques recapitulates many aspects of HIV pathogenesis and is similarly affected by both genetic and environmental factors. Psychosocial stress is associated with immune system dysregulation and worse clinical outcomes in people with HIV. This study assessed the impact of single housing, as a model of psychosocial stress, on innate immune responses of pigtailed macaques ( Macaca nemestrina ) during acute SIV infection. METHODS: A retrospective analysis of acute SIV infection of 2- to si6-year-old male pigtailed macaques was performed to compare the innate immune responses of socially ( n = 41) and singly ( n = 35) housed animals. Measures included absolute monocyte count and subsets, and in a subset ( n ≤ 18) platelet counts and activation data. RESULTS: SIV infection resulted in the expected innate immune parameter changes with a modulating effect from housing condition. Monocyte number increased after infection for both groups, driven by classical monocytes (CD14 + CD16 - ), with a greater increase in socially housed animals (227%, p < .001, by day 14 compared with preinoculation time points). Platelet numbers recovered more quickly in the socially housed animals. Platelet activation (P-selectin) increased by 65% ( p = .004) and major histocompatibility complex class I surface expression by 40% ( p = .009) from preinoculation only in socially housed animals, whereas no change in these measures occurred in singly housed animals. CONCLUSIONS: Chronic psychosocial stress produced by single housing may play an immunomodulatory role in the innate immune response to acute retroviral infection. Dysregulated innate immunity could be one of the pathways by which psychosocial stress contributes to immune suppression and increased disease severity in people with HIV.

Psychosocial Stress Alters the Immune Response and Results in Higher Viral Load During Acute Simian Immunodeficiency Virus Infection in a Pigtailed Macaque Model of Human Immunodeficiency Virus.

BACKGROUND: Although social distancing is a key public health response during viral pandemics, psychosocial stressors, such as social isolation, have been implicated in adverse health outcomes in general [1] and in the context of infectious disease, such as human immunodeficiency virus (HIV) [2, 3]. A comprehensive understanding of the direct pathophysiologic effects of psychosocial stress on viral pathogenesis is needed to provide strategic and comprehensive care to patients with viral infection. METHODS: To determine the effect of psychosocial stress on HIV pathogenesis during acute viral infection without sociobehavioral confounders inherent in human cohorts, we compared commonly measured parameters of HIV progression between singly (n = 35) and socially (n = 41) housed simian immunodeficiency virus (SIV)-infected pigtailed macaques (Macaca nemestrina). RESULTS: Singly housed macaques had a higher viral load in the plasma and cerebrospinal fluid and demonstrated greater CD4 T-cell declines and more CD4 and CD8 T-cell activation compared with socially housed macaques throughout acute SIV infection. CONCLUSIONS: These data demonstrate that psychosocial stress directly impacts the pathogenesis of acute SIV infection and imply that it may act as an integral variable in the progression of HIV infection and potentially of other viral infections.

Second assessment of NeuroAIDS in Africa.

In July of 2006, the National Institute of Mental Health (NIMH) Center for Mental Health Research on AIDS (CMHRA) sponsored the second conference on the Assessment of NeuroAIDS in Africa, which was held in Arusha, Tanzania. The conference mission was to address the regional variations in epidemiology of HIV-related neurological disorders as well as the assessment and diagnosis of these disorders. Participants discussed and presented data regarding the relevance and translation of neuroAIDS assessment measures developed in resource intensive settings and the challenges of neuro-assessment in Africa, including the applicability of current tools, higher prevalence of confounding diseases, and the complexity of diverse cultural settings. The conference presentations summarized here highlight the need for further research on neuroAIDS in Africa and methods for assessing HIV-related neurological disorders.

Rate of return to agility competition for dogs with cranial cruciate ligament tears treated with tibial plateau leveling osteotomy.

OBJECTIVE To determine rate of and factors associated with return to agility competition for dogs with cranial cruciate ligament (CrCL) rupture treated with tibial plateau leveling osteotomy (TPLO). DESIGN Retrospective case series with nested case-control study. ANIMALS 31 dogs involved in agility competition with CrCL tears treated by TPLO at a private veterinary clinic from 2007 through 2013. PROCEDURES Medical records were reviewed to collect information on dog signalment, lesion characteristics, and surgical data. Owners completed a survey regarding whether and when their dog returned to agility competition after TPLO and, if so, how the dog performed. Performance data before and after TPLO were compared. RESULTS 20 of 31 (65%) dogs returned to agility competition after TPLO, 16 (80%) of which returned within 9 months after TPLO. The mean convalescent period for returning dogs was 7.5 months (range, 3 to 12 months). No dog that returned to competition sustained an injury to the affected limb during the follow-up period. No significant difference was identified between dogs that returned or did not return to agility competition regarding severity of osteoarthritis or proportions with meniscal injury or partial (vs complete) CrCL tears. CONCLUSIONS AND CLINICAL RELEVANCE These data suggested that the prognosis for returning to agility competition was good for dogs undergoing TPLO. None of the evaluated lesion characteristics were associated with return to competition. Rate of return to competition and duration of the convalescent period may be useful outcome variables for future investigations involving orthopedic procedures in dogs.

Regulation of tissue inhibitor of metalloproteinase-1 by astrocytes: links to HIV-1 dementia.

The neuropathogenesis of HIV-1-associated dementia (HAD) revolves around the secretion of toxic molecules from infected and immune-competent mononuclear phagocytes. Astrocyte activation occurs in parallel but limited insights are available for its role in neurotoxicity and cognitive dysfunction. One means in which astrocytes may affect disease is through their production of tissue inhibitors of metalloproteinases (TIMPs). TIMPs are regulators of matrix metalloproteinases, enzymes that affect blood-brain barrier integrity through altering the extracellular matrix. We hypothesized that in response to injury and inflammation in HAD, astrocytes regulate the production of TIMP-1, the inducible type of TIMP that is important in inflammation. To address astrocyte-mediated TIMP-1 regulation in HAD, we evaluated the responses of primary human to IL-1beta and HIV-1. TIMP-1 levels in plasma, CSF, and brain tissue of control, HIV-1 infected patients without cognitive impairment, and HAD patients were also studied. Our data show that an upregulation of TIMP-1 results from astrocytes acutely activated with IL-1beta. In contrast, CSF and brain tissue samples from HAD patients showed reduced TIMP-1 levels compared to seronegative controls. MMP-2 levels in brains showed the opposite. Consistent with this, prolonged activation of astrocytes led to a reduction in TIMP-1 and MMP-2, but a sustained elevation in MMP-1. Our data suggest that in diseased brain tissue, the ability of astrocytes to counteract the destructive effects of MMP through expression of TIMP-1 is diminished by chronic activation. Our studies reveal new opportunities for repair-based therapeutic strategies in HAD.