RELATIONSHIP BETWEEN SYSTEMIC AND CENTRAL NERVOUS SYSTEM MONOCYTE/MACROPHAGE INFECTION IN SIMIAN IMMUNODEFICIENCY VIRUS ENCEPHALITIS

Approximately ¼ of AIDS patients develop HIVE, the pathologic entity associated with cognitive, motor, and behavioral deficits attributed to synaptic damage and neuronal loss. It still remains unclear why only a subset of HIV-infected individuals develops abundant central nervous system (CNS) macrophage/microglia infection that characterizes HIVE. The overarching hypothesis of this body of work is that simian immunodeficiency virus (SIV) encephalitis (SIVE) is the CNS manifestation of a systemic increase in SIV infection and activation of monocyte/macrophage elements. Specifically, we examined the relationship of infected and activated monocyte/macrophage elements outside of the CNS during the evolution of lentiviral encephalitis to the presence of infected macrophages in the CNS. We studied three models of SIV infection: SIV-infection of rhesus and pigtailed macaques and SIV-infection of CD8+ T cell depleted macaques. Antibody-mediated CD8+ T cell depletion did not increase the incidence of SIVE in infected rhesus macaques. In SIV-infected rhesus macaques, we examined whether presence of activated macrophages or SIV-infected macrophages is associated with the presence of neuronal damage. The presence of abundant infected macrophages in the CNS is related to postsynaptic neuronal damage in macaques with SIVE. At the same time cerebrospinal fluid viral load increased in SIV-infected CD8-depleted rhesus and non-depleted pigtailed macaques that developed encephalitis, monocyte-derived macrophages produced more virus ex vivo than macaques that did not develop encephalitis. Compared to pigtailed macaques that did not develop SIVE, the monocyte associated SIV-DNA load of monocytes was elevated in macaques that developed SIVE. Pigtailed macaques with SIVE had more infected macrophages in peripheral organs, with the exception of lymph nodes, than macaques without SIVE. Longitudinal analysis of phenotypic markers of monocyte activation show that increases in proportion of CD14+/CD16+ monocytes is associated with chronic disease. Brains with SIVE have greater numbers of T cells with cytotoxic potential. In conclusion, these findings suggest that inherent differences in host macrophage viral production or immune response to macrophage infection are associated with development of encephalitis. Further understanding of the differential role monocyte/macrophages have in the development of lentiviral encephalitis will identify therapeutic targets to halt this public health epidemic

Age-Related Pathology Associated with H1N1 A/California/07/2009 Influenza Virus Infection

Influenza virus infection causes a spectrum of diseases, ranging from mild upper respiratory tract infection to severe lower respiratory tract infection, that can lead to diffuse alveolar damage, interstitial and airspace inflammation, or acute respiratory failure. Mechanisms instructing disease severity are not completely understood, but host, viral, and bacterial factors influence disease outcome. With age being one host factor associated with a higher risk of severe influenza, we investigated regional pulmonary distribution and severity of pneumonia after 2009 H1N1 influenza virus infection in newly weaned, adult, and aged ferrets to better understand age-dependent susceptibility and pathology. Aged ferrets exhibited greater weight loss and higher rates of mortality than adult ferrets, whereas most newly weaned ferrets did not lose weight but had a lack of weight gain. Newly weaned ferrets exhibited minimal pneumonia, whereas adult and aged ferrets had a spectrum of pneumonia severity. Influenza virus-induced pneumonia peaked earliest in adult ferrets, whereas aged ferrets had delayed presentation. Bronchial severity differed among groups, but bronchial pathology was comparable among all cohorts. Alveolar infection was strikingly different among groups. Newly weaned ferrets had little alveolar cell infection. Adult and aged ferrets had alveolar infection, but aged ferrets were unable to clear infection. These different age-related pneumonia and infection patterns suggest therapeutic strategies to treat influenza should be tailored contingent on age

Aged Chinese-origin rhesus macaques infected with SIV develop marked viremia in absence of clinical disease, inflammation or cognitive impairment

Abstract Background Damage to the central nervous system during HIV infection can lead to variable neurobehavioral dysfunction termed HIV-associated neurocognitive disorders (HAND). There is no clear consensus regarding the neuropathological or cellular basis of HAND. We sought to study the potential contribution of aging to the pathogenesis of HAND. Aged (range = 14.7–24.8 year) rhesus macaques of Chinese origin (RM-Ch) (n = 23) were trained to perform cognitive tasks. Macaques were then divided into four groups to assess the impact of SIVmac251 infection (n = 12) and combined antiretroviral therapy (CART) (5 infected; 5 mock-infected) on the execution of these tasks. Results Aged SIV-infected RM-Ch demonstrated significant plasma viremia and modest CSF viral loads but showed few clinical signs, no elevations of systemic temperature, and no changes in activity levels, platelet counts or weight. Concentrations of biomarkers of acute and chronic inflammation such as soluble CD14, CXCL10, IL-6 and TNF-α are known to be elevated following SIV infection of young adult macaques of several species, but concentrations of these biomarkers did not shift after SIV infection in aged RM-Ch and remained similar to mock-infected macaques. Neither acute nor chronic SIV infection or CART had a significant impact on accuracy, speed or percent completion in a sensorimotor test. Conclusions Viremia in the absence of a chronic elevated inflammatory response seen in some aged RM-Ch is reminiscent of SIV infection in natural disease resistant hosts. The absence of cognitive impairment during SIV infection in aged RM-Ch might be in part attributed to diminishment of some facets of the immunological response. Additional study encompassing species and age differences is necessary to substantiate this hypothesis

Systemic and Brain Macrophage Infections in Relation to the Development of Simian Immunodeficiency Virus Encephalitis▿

The brains of individuals with lentiviral-associated encephalitis contain an abundance of infected and activated macrophages. It has been hypothesized that encephalitis develops when increased numbers of infected monocytes traffic into the central nervous system (CNS) during the end stages of immunosuppression. The relationships between the infection of brain and systemic macrophages and circulating monocytes and the development of lentiviral encephalitis are unknown. We longitudinally examined the extent of monocyte/macrophage infection in blood and lymph nodes of pigtailed macaques that did or did not develop simian immunodeficiency virus encephalitis (SIVE). Compared to levels in macaques that did not develop SIVE, more ex vivo virus production was detected from monocyte-derived macrophages and nonadherent peripheral blood mononuclear cells (PBMCs) from macaques that did develop SIVE. Prior to death, there was an increase in the number of circulating PBMCs following a rise in cerebrospinal fluid viral load in macaques that did develop SIVE but not in nonencephalitic macaques. At necropsy, macaques with SIVE had more infected macrophages in peripheral organs, with the exception of lymph nodes. T cells and NK cells with cytotoxic potential were more abundant in brains with encephalitis; however, T-cell and NK-cell infiltration in SIVE and human immunodeficiency virus encephalitis was more modest than that observed in classical acute herpes simplex virus encephalitis. These findings support the hypothesis that inherent differences in host systemic and CNS monocyte/macrophage viral production are associated with the development of encephalitis

Experimental Mycobacterium tuberculosis Infection of Cynomolgus Macaques Closely Resembles the Various Manifestations of Human M. tuberculosis Infection

Nonhuman primates were used to develop an animal model that closely mimics human Mycobacterium tuberculosis infection. Cynomolgus macaques were infected with low doses of virulent M. tuberculosis via bronchoscopic instillation into the lung. All monkeys were successfully infected, based on tuberculin skin test conversion and peripheral immune responses to M. tuberculosis antigens. Progression of infection in the 17 monkeys studied was variable. Active-chronic infection, observed in 50 to 60% of monkeys, was characterized by clear signs of infection or disease on serial thoracic radiographs and in other tests and was typified by eventual progression to advanced disease. Approximately 40% of monkeys did not progress to disease in the 15 to 20 months of study, although they were clearly infected initially. These monkeys had clinical characteristics of latent tuberculosis in humans. Low-dose infection of cynomolgus macaques appears to represent the full spectrum of human M. tuberculosis infection and will be an excellent model for the study of pathogenesis and immunology of this infection. In addition, this model will provide an opportunity to study the latent M. tuberculosis infection observed in ∼90% of all infected humans

MOESM1 of Aged Chinese-origin rhesus macaques infected with SIV develop marked viremia in absence of clinical disease, inflammation or cognitive impairment

Additional file 1: Figure S1. Effect of age and SIV-infection on weight. In comparison to mock-infected macaques, SIV-infection of aged Chinese rhesus macaques does not impact weight. Animals were weighed on a weekly basis. Median longitudinal weight (kg) over the course of infection for each group (A). Change in median weight (kg) from baseline in SIV-infected (red) and mock-infected (blue) macaques during the acute phase of infection (B). Both SIV-infected and mock infected macaques lost weight at 2 and 3 wpi. At 4 wpi, SIV-infected macaques lost a small amount of mass while mock-infected macaques slightly gained mass. Change in median weight (kg) from baseline in SIV-infected (red) and mock-infected (blue) macaques at time of necropsy (C). Mock-infected macaques gained over 1 kg by the end of the study whereas SIV-infected macaques were similar to their starting weight. Figure S2. Effect of age, SIV-infection and cART on body temperature. There were no changes in body temperature after SIV-infection in aged Chinese rhesus macaques. Body temperature was recorded at least once a day and the median temperature determined in two week intervals. Baseline temperature (week 0 post-infection) was the average of 12 weeks of preinoculation measurements. Time course of body temperature in SIV-infected macaques and controls (A). Lines represent median values. Time course of change in temperature (Δ °C) from baseline (B). Change in temperature from baseline during the first 4 weeks post-infection (C). Change in temperature from baseline at necropsy (D). Figure S3. Effect of age, SIV-infection and cART on platelet counts. Platelet counts are not significantly altered during acute SIV infection in aged rhesus macaques of Chinese origin. Time course of median platelet counts during the duration of infection (A). Lines represent median values. Platelet counts of SIV-infected and mock-infected macaques during the first 4 weeks post-infection (B). Figure S4. Total cell counts during the course of SIV infection. Total CD4+ T-cell counts decrease during SIV infection in aged rhesus macaques of Chinese origin. Total CD8+ T-cell and NK-cell counts shown an elevation during acute infection then fall to similar levels as mock-infected macaques. Time course change in CD4+ T-cell (A), CD8+ T-cell (B), NK-cell (C), and B-cell counts (D) during SIV and mock infection. Lines represent median values. Figure S5. Total monocyte subset counts during the course of SIV infection. CD14+CD16- (A), CD14+CD16+ (B), CD14-CD16+ (C) monocyte subset counts during SIV infection in aged rhesus macaques of Chinese origin. Lines represent median values. Figure S6. Plasma and CSF viral load versus temperature in individual SIV-infected macaques. Each graph shows the time course of plasma SIV loads, CSF SIV loads and temperature in an individual aged Chinese rhesus macaque during SIV infection. Graphs of SIV-infected macaques that did not receive treatment (Group 1) are shown in (a) and graphs of SIV-infected macaques that were treated with CART (Group 4) are shown in (b). The green shaded area represents the period macaques received CART or saline. Figure S7. Plasma and CSF viral load versus CD4+ and CD8+ T-cell count in SIV-infected macaques. Each graph shows the time course of plasma SIV loads, CSF SIV loads, CD4+ T-cell counts, and CD8+ T-cell counts in an individual aged Chinese rhesus macaque during SIV infection. Graphs of SIV-infected macaques that did not receive treatment (Group 1) are shown in (a) and graphs of SIV-infected macaques that were treated with CART (Group 4) are shown in (b). The green shaded area represents the period macaques received CART or saline. Figure S8. Plasma and CSF viral load versus reaction time and accuracy in SIV-infected macaques. Each graph shows the time course of plasma SIV loads, CSF SIV loads, reaction time (RT), and percent accuracy (Acc) in an individual aged Chinese rhesus macaque during SIV infection. Graphs of SIV-infected macaques that did not receive treatment (Group 1) are shown in (a) and graphs of SIV-infected macaques that were treated with CART (Group 4) are shown in (b). The green shaded area represents the period macaques received CART or saline. Figure S9. Time and accuracy in mock-infected macaques. Each graph shows the reaction time (RT) and percent accuracy (Acc) in a speeded motor task for an individual aged Chinese rhesus macaque over the study period. Graphs of mock-infected macaques that did not receive treatment (Group 2) are shown in (a) and graphs of mock-infected macaques that were treated with CART (Group 3) are shown in (b). The green shaded area represents the period macaques received CART or saline