Comparison of predictors for terminal disease progression in simian immunodeficiency virus/simian-HIV-infected rhesus macaques.

OBJECTIVES: CD4+ T-cell decline and increasing virus levels are considered hallmarks of HIV/AIDS pathogenesis but we previously demonstrated in rhesus macaques that tissue macrophage destruction by simian immunodeficiency virus (SIV) infection associated with increased monocyte turnover also appear to impact pathogenesis. It remains unclear, however, which factors best predict onset of terminal disease progression and survival time. The objective of this study, therefore, was to directly compare these co-variates of infection for predicting survival times in retrospective studies of SIV/simian-HIV (SHIV)-infected adult rhesus macaques. METHODS: Rhesus macaques were infected with various strains of SIV/SHIV and evaluated longitudinally for monocyte turnover, CD4+ T-cell loss, plasma viral load, and SIV/SHIV strain. Correlation analyses and machine learning algorithm modeling were applied to compare relative contributions of each of the co-variates to survival time. RESULTS: All animals with AIDS-related clinical signs requiring euthanasia exhibited increased monocyte turnover regardless of CD4+ T-cell level, viral strain, or plasma viral load. Regression analyses and machine learning algorithms indicated a stronger correlation and contribution between increased monocyte turnover and reduced survival time than between CD4+ T-cell decline, plasma viral load, or virus strain and reduced survival time. Decision tree modeling categorized monocyte turnover of 13.2% as the initial significant threshold that best predicted decreased survival time. CONCLUSION: These results demonstrate that monocytes/macrophages significantly affect HIV/SIV pathogenesis outcomes. Monocyte turnover analyses are not currently feasible in humans, so there is a need to identify surrogate biomarkers reflecting tissue macrophage damage that predict HIV infection disease progression.

Proliferation of Perivascular Macrophages Contributes to the Development of Encephalitic Lesions in HIV-Infected Humans and in SIV-Infected Macaques.

The aim of the present study was to investigate if macrophage proliferation occurs in the brain during simian immunodeficiency virus (SIV) infection of adult macaques. We examined the expression of the Ki-67 proliferation marker in the brains of uninfected and SIV-infected macaques with or without encephalitis. Double-label immunohistochemistry using antibodies against the pan-macrophage marker CD68 and Ki-67 showed that there was a significant increase in CD68+Ki-67+ cells in macaques with SIV encephalitis (SIVE) compared to uninfected and SIV-infected animals without encephalitis, a trend that was also confirmed in brain samples from patients with HIV encephalitis. Multi-label immunofluorescence for CD163 and Ki-67 confirmed that the vast majority of Ki-67+ nuclei were localized to CD163+ macrophages in perivascular cuffs and lesions. The proliferative capacity of Ki-67+ perivascular macrophages (PVM) was confirmed by their nuclear incorporation of bromodeoxyuridine. Examining SIVE lesions, using double-label immunofluorescence with antibodies against SIV-Gag-p28 and Ki-67, showed that the population of Ki-67+ cells were productively infected and expanded proportionally with lesions. Altogether, this study shows that there are subpopulations of resident PVM that express Ki-67 and are SIV-infected, suggesting a mechanism of macrophage accumulation in the brain via PVM proliferation.

Sickness behavior induced by cisplatin chemotherapy and radiotherapy in a murine head and neck cancer model is associated with altered mitochondrial gene expression.

The present study was undertaken to explore the possible mechanisms of the behavioral alterations that develop in response to cancer and to cancer therapy. For this purpose we used a syngeneic heterotopic mouse model of human papilloma virus (HPV)-related head and neck cancer in which cancer therapy is curative. Mice implanted or not with HPV+ tumor cells were exposed to sham treatment or a regimen of cisplatin and radiotherapy (chemoradiation). Sickness was measured by body weight loss and reduced food intake. Motivation was measured by burrowing, a highly prevalent species specific behavior. Tumor-bearing mice showed a gradual decrease in burrowing over time and increased brain and liver inflammatory cytokine mRNA expression by 28 days post tumor implantation. Chemoradiation administered to healthy mice resulted in a mild decrease in burrowing, body weight, and food intake. Chemoradiation in tumor-bearing mice decreased tumor growth and abrogated liver and brain inflammation, but failed to attenuate burrowing deficits. PCR array analysis of selected hypoxia and mitochondrial genes revealed that both the tumor and chemoradiation altered the expression of genes involved in mitochondrial energy metabolism within the liver and brain and increased expression of genes related to HIF-1α signaling within the brain. The most prominent changes in brain mitochondrial genes were noted in tumor-bearing mice treated with chemoradiation. These findings indicate that targeting mitochondrial dysfunction following cancer and cancer therapy may be a strategy for prevention of cancer-related symptoms.

Increased Expression of CD169 on Blood Monocytes and Its Regulation by Virus and CD8 T Cells in Macaque Models of HIV Infection and AIDS.

Increased expression of CD169 on monocytes has been reported in HIV-1-infected humans. Using rhesus macaque models of HIV infection, we sought to investigate whether simian immunodeficiency virus (SIV) infection upregulates CD169 expression on monocytes/macrophages. We also sought to determine whether CD8 T cells and plasma viral load directly impact the expression of CD169 on monocytes during SIV infection. We longitudinally assessed monocyte expression of CD169 during the course of SIV infection by flow cytometry, and examined the expression of CD169 on macrophages by immunohistochemistry in the spleen and lymph nodes of uninfected and infected macaques. CD169 expression on monocytes was substantially upregulated as early as 4 days during the hyperacute phase and peaked by 5-15 days after infection. After a transient decrease following the peak, its expression continued to increase during progression to AIDS. Monocyte CD169 expression was directly associated with plasma viral loads. To determine the contribution of CD8(+) T lymphocytes and virus to the control of monocyte CD169 expression, we used experimental CD8(+) lymphocyte depletion and antiretroviral therapy (ART) in SIV-infected macaques. Rapid depletion of CD8 T cells during acute infection of rhesus macaques induced an abrupt increase in CD169 expression. Importantly, levels of CD169 expression plummeted following initiation of ART and rebounded upon cessation of therapy. Taken together, our data reveal independent roles for virus and CD8(+) T lymphocytes in controlling monocyte CD169 expression, which may be an important link in further investigating the host response to viral infection.

Psychosocial experiences in the context of life-threatening illness: the cardiac rehabilitation patient.

OBJECTIVE: One of the most prevalent life-threatening illnesses is heart disease. The initial trauma of being diagnosed with a life-threatening illness or having a cardiac event can begin a psychosocial chain reaction that results in a transformation of the lives of these patients. The goal of our study was to investigate the lived experiences of psychosocial healing in rehabilitation of cardiac patients using a qualitative written interview. METHOD: A purposive sample of 14 cardiac event survivors was recruited. Participants were interviewed after informed consent and screening. We used a qualitative analysis and model-revision approach similar to the procedure outlined by Charmaz (2006). RESULTS: Participants consistently mentioned that a heightened awareness of mortality was a motivating factor that led to participants focusing more on their family and relationships, having an enhanced outlook on life, and making healthy lifestyle changes. SIGNIFICANCE OF RESULTS: If clinicians are able to employ a measure to better understand the nature of a patient's progression from cardiac event to successful recovery, interventions such as cardiac rehabilitation can be implemented earlier and more effectively during the course of the illness and recovery phases of treatment. Theoretically, this early detection of a patient's progression could reduce the time spent recovering from a cardiac event, and it would allow treatments for these conditions to better alleviate the psychosocial concerns faced by patients.

Expression of the mannose receptor CD206 in HIV and SIV encephalitis: a phenotypic switch of brain perivascular macrophages with virus infection.

We examined the expression of the mannose receptor CD206 by perivascular macrophages (PVM) in normal human and monkey brains and in brains of HIV-infected humans and of monkeys infected with simian immunodeficiency virus (SIV). Depletion of brain PVM in SIV-infected monkeys by intrathecal injection of liposome-encapsulated bisphosphonates eliminated CD206-expressing cells in the brain, confirming their perivascular location and phagocytic capacity. In vivo labeling with bromodeoxyuridine in normal uninfected and SIV-infected macaques in combination with CD206 immunostaining revealed a CD206+-to-CD206- shift within pre-existing PVM during SIV brain infection and neuroinflammation. These findings identify CD206 as a unique marker of human and macaque PVM, and underscore the utility of this marker in studying the origin, turnover and functions of these cells in AIDS.