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Despite effective antiretroviral therapy, HIV co-morbidities remain where central nervous system (CNS) neurocognitive disorders and cardiovascular disease (CVD)-pathology that are linked with myeloid activation are most prevalent. Comorbidities such as neurocogntive dysfunction and cardiovascular disease (CVD) remain prevalent among people living with HIV. We sought to investigate if cardiac pathology (inflammation, fibrosis, cardiomyocyte damage) and CNS pathology (encephalitis) develop together during simian immunodeficiency virus (SIV) infection and if their co-development is linked with monocyte/ macrophage activation. We used a cohort of SIV-infected rhesus macaques with rapid AIDS and demonstrated that SIV encephalitis (SIVE) and CVD pathology occur together more frequently than SIVE or CVD pathology alone. Their co-development correlated more strongly with activated myeloid cells, increased numbers of CD14+CD16+ monocytes, plasma CD163 and interleukin18 (IL-18) than did SIVE or CVD pathology alone, or no pathology. Animals with both SIVE and CVD pathology had greater numbers of cardiac macrophages and increased collagen and monocyte/macrophage accumulation, which were better correlates of CVD-pathology than SIV-RNA. Animals with SIVE alone had higher levels of activated macrophage biomarkers and cardiac macrophage accumulation than SIVnoE animals. These observations were confirmed in HIV infected individuals with HIV encephalitis (HIVE) that had greater numbers of cardiac macrophages and fibrosis than HIV-infected controls without HIVE. These results underscore the notion that CNS and CVD pathologies frequently occur together in HIV and SIV infection, and demonstrate an unmet need for adjunctive therapies targeting macrophages. [ABSTRACT FROM AUTHOR]

Background: Persistent immune activation is thought to contribute to heightened atherosclerotic cardiovascular disease (ASCVD) risk among people with human immunodeficiency virus (PWH).Methods: Participants (≥18 years) with or without human immunodeficiency virus (HIV) and without history of clinical ASCVD were enrolled. We hypothesized that increased macrophage-specific arterial infiltration would relate to plaque composition and systemic immune activation among PWH. We applied a novel targeted molecular imaging approach (technetium-99m [99mTc]-tilmanocept single photon emission computed tomography [SPECT]/CT) and comprehensive immune phenotyping.Results: Aortic 99mTc-tilmanocept uptake was significantly higher among PWH (n = 20) than participants without HIV (n = 10) with similar 10-year ASCVD risk (P = .02). Among PWH, but not among participants without HIV, noncalcified aortic plaque volume related directly to aortic 99mTc-tilmanocept uptake at different uptake thresholds. An interaction (P = .001) was seen between HIV status and noncalcified plaque volume, but not calcified plaque (P = .83). Systemic levels of caspase-1 (P = .004), CD14-CD16+ (nonclassical/patrolling/homing) monocytes (P = .0004) and CD8+ T cells (P = .005) related positively and CD4+/CD8+ T-cell ratio (P = .02) inversely to aortic 99mTc-tilmanocept uptake volume.Conclusions: Macrophage-specific arterial infiltration was higher among PWH and related to noncalcified aortic plaque volume only among PWH. Key systemic markers of immune activation relating to macrophage-specific arterial infiltration may contribute to heightened ASCVD risk among PWH.Clinical Trials Registration: NCT02542371. [ABSTRACT FROM AUTHOR]

The dynamic nature of the SIV population during disease progression in the SIV/macaque model of AIDS and the factors responsible for its behavior have not been documented, largely owing to the lack of sufficient spatial and temporal sampling of both viral and host data from SIV-infected animals. In this study, we detail Bayesian coalescent inference of the changing collective intra-host viral effective population size (Ne) from various tissues over the course of infection and its relationship with what we demonstrate is a continuously changing immune cell repertoire within the blood. Although the relative contribution of these factors varied among hosts and time points, the adaptive immune response best explained the overall periodic dynamic behavior of the effective virus population. Data exposing the nature of the relationship between the virus and immune cell populations revealed the plausibility of an eco-evolutionary mathematical model, which was able to mimic the large-scale oscillations in Ne through virus escape from relatively few, early immunodominant responses, followed by slower escape from several subdominant and weakened immune populations. The results of this study suggest that SIV diversity within the untreated host is governed by a predator-prey relationship, wherein differing phases of infection are the result of adaptation in response to varying immune responses. Previous investigations into viral population dynamics using sequence data have focused on single estimates of the effective viral population size (Ne) or point estimates over sparse sampling data to provide insight into the precise impact of immune selection on virus adaptive behavior. Herein, we describe the use of the coalescent phylogenetic frame- work to estimate the relative changes in Ne over time in order to quantify the relationship with empirical data on the dynamic immune composition of the host. This relationship has allowed us to expand on earlier simulations to build a predator-prey model that explains the deterministic behavior of the virus over the course of disease progression. We show that sequential viral adaptation can occur in response to phases of varying immune pressure, providing a broader picture of the viral response throughout the entire course of progression to AIDS. [ABSTRACT FROM AUTHOR]

Despite improvements in antiretroviral therapy, human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) remain prevalent in subjects undergoing therapy. HAND significantly affects individuals' quality of life, as well as adherence to therapy, and, despite the increasing understanding of neuropathogenesis, no definitive diagnostic or prognostic marker has been identified. We investigated transcriptomic profiles in frontal cortex tissues of Simian immunodeficiency virus (SIV)-infected Rhesus macaques sacrificed at different stages of infection. Gene expression was compared among SIV-infected animals (n = 11), with or without CD8+ lymphocyte depletion, based on detectable (n = 6) or non-detectable (n = 5) presence of the virus in frontal cortex tissues. Significant enrichment in activation of monocyte and macrophage cellular pathways was found in animals with detectable brain infection, independently from CD8+ lymphocyte depletion. In addition, transcripts of four poly (ADP-ribose) polymerases (PARPs) were up-regulated in the frontal cortex, which was confirmed by real-time polymerase chain reaction. Our results shed light on involvement of PARPs in SIV infection of the brain and their role in SIV-associated neurodegenerative processes. Inhibition of PARPs may provide an effective novel therapeutic target for HIV-related neuropathology. [ABSTRACT FROM AUTHOR]

Human immunodeficiency virus (HIV) is a rapidly evolving virus, allowing its genetic sequence to act as a fingerprint for epidemiological processes among, as well as within, individual infected hosts. Though primarily infecting the CD4+ T-cell population, HIV can also be found in monocytes, an immune cell population that differs in several aspects from the canonical T-cell viral target. Using single genome viral sequencing and statistical phylogenetic inference, we investigated the viral RNA diversity and relative contribution of each of these immune cell types to the viral population within the peripheral blood. Results provide evidence of an increased prevalence of circulating monocytes harboring virus in individuals with high viral load in the absence of suppressive antiretroviral therapy. Bayesian phyloanatomic analysis of three of these individuals demonstrated a measurable role for these cells, but not the circulating T-cell population, as a source of cell-free virus in the plasma, supporting the hypothesis that these cells can act as an additional conduit of virus spread. [ABSTRACT FROM AUTHOR]

Despite the advent of highly active anti-retroviral therapy HIV-associated neurocognitive disorders (HAND) continue to be a significant problem. Furthermore, the precise pathogenesis of this neurodegeneration is still unclear. The objective of this study was to examine the relationship between infection by the simian immunodeficiency virus (SIV) and neuronal injury in the rhesus macaque using in vivo and postmortem sampling techniques. The effect of SIV infection in 23 adult rhesus macaques was investigated using an accelerated NeuroAIDS model. Disease progression was modulated either with combination anti-retroviral therapy (cART, 4 animals) or minocycline (7 animals). Twelve animals remained untreated. Viral loads were monitored in the blood and cerebral spinal fluid, as were levels of activated monocytes in the blood. Neuronal injury was monitored in vivo using magnetic resonance spectroscopy. Viral RNA was quantified in brain tissue of each animal postmortem using reverse transcription polymerase chain reaction (RT-PCR), and neuronal injury was assessed by immunohistochemistry. Without treatment, viral RNA in plasma, cerebral spinal fluid, and brain tissue appears to reach a plateau. Neuronal injury was highly correlated both to plasma viral levels and a subset of infected/activated monocytes (CD14+CD16+), which are known to traffic the virus into the brain. Treatment with either cART or minocycline decreased brain viral levels and partially reversed alterations in in vivo and immunohistochemical markers for neuronal injury. These findings suggest there is significant turnover of replicating virus within the brain and the severity of neuronal injury is directly related to the brain viral load. [ABSTRACT FROM AUTHOR]

Abstract: The progression to AIDS is influenced by changes in the biology of heterogeneous monocyte subsets. Classical (CD14++CD16–), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++) monocytes may represent progressive stages of monocyte maturation or disparate myeloid lineages with different turnover rates and function. To investigate the relationship between monocyte subsets and the response to SIV infection, we performed microarray analysis of monocyte subsets in rhesus macaques at three time points: prior to SIV infection, 26 days postinfection, and necropsy with AIDS. Genes with a 2‐fold change between monocyte subsets (2023 genes) or infection time points (424 genes) were selected. We identify 172 genes differentially expressed among monocyte subsets in both uninfected and SIV‐infected animals. Classical monocytes express genes associated with inflammatory responses and cell proliferation. Nonclassical monocytes express genes associated with activation, immune effector functions, and cell cycle inhibition. The classical and intermediate subsets are most similar at all time points, and transcriptional similarity between intermediate and nonclassical monocytes increases with AIDS. Cytosolic sensors of nucleic acids, restriction factors, and IFN‐stimulated genes are induced in all three subsets with AIDS. We conclude that SIV infection alters the transcriptional relationship between monocyte subsets and that the innate immune response to SIV infection is conserved across monocyte subsets. [ABSTRACT FROM AUTHOR]

Particle dispersion in the vicinity of an agricultural fertilizer spreader is difficult to capture due to the rapid particle traveling motion. This paper introduced a granule impact indentation-based technique to simultaneously record the two-dimensional particle dispersion from a spinning concave disc type of spreader. A Nitrogen-Phosphorus-Potassium (NPK) type of fertilizer was utilized to induce indentations on aluminum foils placed on the wall panels confining an experimental spreader system. Subsequently, an image processing technique which is comprised of the multicolor edge detection, the curve closing, and the region merging techniques was purposely developed to automatically identify and locate the granule impacts on the sampled foil digital images. Overlapping impacts were characterized based on the granulometry of the fertilizer sample. The reconstructed particle dispersion pattern using the image processing method showed good agreement with the experimental observations. The outcome of this research enabled a fast and effective method for quantitatively assessing the particle distribution for a specific fertilizer spreader. [ABSTRACT FROM AUTHOR]

The plasma kynurenine/tryptophan (KT) ratio, a marker of adaptive immune defects, strongly predicts mortality during treated human immunodeficiency virus (HIV) disease in Ugandans as compared to US-based populations. Here, the KT ratio and T-cell and plasma biomarkers of immune activation were measured among 535 HIV-infected Ugandans prior to ART initiation and at month 6 of viral suppression. The month 6 KT ratio (adjusted hazard ratio [aHR], 2.74), soluble CD14 level (aHR, 2.32), interleukin 6 level (aHR, 2.34), and D-dimer level (aHR, 1.95) were associated with mortality occurring ≥6 months after ART initiation. The KT ratio remained significantly predictive of mortality even after adjustment for the additional biomarkers, suggesting an independent contribution to clinical outcomes in resource-limited settings. [ABSTRACT FROM AUTHOR]

Background: The ability to noninvasively assess arterial CD206+ macrophages may lead to improved understanding of human immunodeficiency virus (HIV)-associated cardiovascular disease.Methods: We trialed a novel macrophage-specific arterial imaging technique.Results: We demonstrated colocalization between technetium Tc 99m tilmanocept (99mTc-tilmanocept) and CD206+ macrophages ex vivo. In vivo application of 99mTc-tilmanocept single-photon emission computed tomography/computed tomography revealed high-level 99mTc-tilmanocept uptake across 20.4% of the aortic surface volume among HIV-infected subjects, compared with 4.3% among non-HIV-infected subjects (P = .009). Among all subjects, aortic high-level 99mTc-tilmanocept uptake was related to noncalcified aortic plaque volume (r = 0.87; P = .003) on computed tomographic angiography, and this relationship held when we controlled for HIV status.Conclusion: These first-in-human data introduce a novel macrophage-specific arterial imaging technique in HIV.Clinical Trials Registration: NCT02542371. [ABSTRACT FROM AUTHOR]

Background:  Human immunodeficiency virus (HIV)-infected patients demonstrate increased activation of the renin-angiotensin-aldosterone system (RAAS). We evaluated changes in immune markers with physiological RAAS activation.Methods:  Immune activation markers were assessed serially in 18 HIV-infected and 7 non-HIV-infected subjects consuming an ad libitum diet followed by a standardized low-sodium diet.Results:  Levels of CCL-2 (P = .0004) and soluble CD163 (P = .0001) significantly increased with sodium restriction and RAAS activation, compared with levels in individuals with ad libitum sodium intake, among chronically treated HIV-infected subjects (mean duration of ART [±SEM], 11 ± 1 years), but not among non-HIV-infected subjects of similar age and sex.Conclusions:  Dietary sodium restriction, which activates RAAS, uniquely stimulates critical indices of immune activation during HIV infection.Clinical Trials Registration:  NCT01407237. [ABSTRACT FROM AUTHOR]

The potential role of gender in the occurrence of HIV-related neurocognitive impairment (NCI) and associations with markers of HIV-related immune activity has not been previously examined. In this study 149 antiretroviral-naïve seropositive subjects in Nigeria (SP, 92 women and 57 men) and 58 seronegative (SN, 38 women and 20 men) were administered neuropsychological testing that assessed 7 ability domains. From the neuropsychological test scores was calculated a global deficit score (GDS), a measure of overall NCI. Percentages of circulating monocytes and plasma HIV RNA, soluble CD163 and soluble CD14 levels were also assessed. HIV SP women were found to be younger, more educated and had higher CD4+ T cell counts and borderline higher viral load measures than SP men. On the neuropsychological testing, SP women were more impaired in speed of information processing and verbal fluency and had a higher mean GDS than SN women. Compared to SP men, SP women were also more impaired in speed of information processing and verbal fluency as well as on tests of learning and memory. Numbers of circulating monocytes and plasma sCD14 and sCD163 levels were significantly higher for all SP versus all SN individuals and were also higher for SP women and for SP men versus their SN counterparts. Among SP women, soluble CD14 levels were slightly higher than for SP men, and SP women had higher viral load measurements and were more likely to have detectable virus than SP men. Higher sCD14 levels among SP women correlated with more severe global impairment, and higher viral load measurements correlated with higher monocyte numbers and sCD14 and sCD14 levels, associations that were not observed for SP men. These studies suggest that the risk of developing NCI differ for HIV infected women and men in Nigeria and, for women, may be linked to effects from higher plasma levels of HIV driving activation of circulating monocytes. [ABSTRACT FROM AUTHOR]

In order to reveal the unsteady features of gas–solid flow, the pressure fluctuations were measured at different locations along the length of the pipeline while conveying powders through the pipeline. Power spectral density (PSD) functions were obtained for the analysis of the pressure fluctuation. Two types of powders (fly ash and alumina) were used in this analysis. The PSD analysis was conducted by taking into account different aspects such as flow conditions (dilute or dense), location of transmitter (top and bottom transmitters), location of transmitter along the length of the pipeline (three different locations), material property (fly ash or alumina), etc. Analysis of signals from top and bottom transmitters shows that it is not possible to identify the flow mode at upper and lower portions of pipeline. The magnitude of power is found to be higher for alumina as compared to fly ash. PSD parametric analysis reveals that frequency bandwidth and average power decreases exponentially with increase in solid loading ratio. [ABSTRACT FROM AUTHOR]

Dendritic cells (DCs) modulate B-cell survival and differentiation, mainly through production of growth factors such as B lymphocyte stimulator (BLyS/BAFF). In recent longitudinal studies involving HIV-1-infected individuals with different rates of disease progression, we have shown that DCs were altered in number and phenotype in the context of HIV-1 disease progression and B-cell dysregulations were associated with increased BLyS/BAFF expression in plasma and by blood myeloid DCs (mDCs) in rapid and classic progressors but not in HIV-1-elite controllers (EC). Suggesting that the extent to which HIV-1 disease progression is controlled may be linked to BLyS/BAFF expression status and the capacity to orchestrate B-cell responses. Herein, longitudinal analyses of simian immunodeficiency virus (SIV)-infected rhesus macaques also revealed increased expression of BLyS/BAFF by blood mDCs as soon as day 8 and throughout infection. Strikingly, granulocytes presented the highest BLyS/BAFF expression profile in the blood of SIV-infected macaques. BLyS/BAFF levels were also increased in plasma and correlated with viral loads. Consequently, these SIV-infected animals had plasma hyperglobulinemia and reduced blood B-cell numbers with altered population frequencies. These data underscore that BLyS/BAFF is associated with immune dysregulation in SIV-infected rhesus macaques and suggest that BLyS/BAFF is a key regulator of immune activation that is highly conserved among primates. These findings emphasize the potential importance of this SIV-infected primate model to test whether blocking excess BLyS/BAFF has an effect on the overall inflammatory burden and immune restoration. [ABSTRACT FROM AUTHOR]

Loss of circulating CD123+ plasmacytoid dendritic cells (pDCs) during HIV infection is well established. However, changes of myeloid DCs (mDCs) are ambiguous since they are studied as a homogeneous CD11c+ population despite phenotypic and functional heterogeneity. Heterogeneity of CD11c+ mDCs in primates is poorly described in HIV and SIV infection. Using multiparametric flow cytometry, we monitored longitudinally cell number and cell-associated virus of CD123+ pDCs and non-overlapping subsets of CD1c+ and CD16+ mDCs in SIV-infected CD8-depleted rhesus macaques. The numbers of all three DC subsets were significantly decreased by 8 days post-infection. Whereas CD123+ pDCs were persistently depleted, numbers of CD1c+ and CD16+ mDCs rebounded. Numbers of CD1c+ mDCs significantly increased by 3 weeks post-infection while numbers of CD16+ mDCs remained closer to pre-infection levels. We found similar changes in the numbers of all three DC subsets in CD8 depleted animals as we found in animals that were SIV infected animals that were not CD8 lymphocyte depleted. CD16+ mDCs and CD123+ pDCs but not CD1c+ mDCs were significantly decreased terminally with AIDS. All DC subsets harbored SIV RNA as early as 8 days and then throughout infection. However, SIV DNA was only detected in CD123+ pDCs and only at 40 days post-infection consistent with SIV RNA, at least in mDCs, being surface-bound. Altogether our data demonstrate that SIV infection differently affects CD1c+ and CD16+ mDCs where CD16+ but not CD1c+ mDCs are depleted and might be differentially regulated in terminal AIDS. Finally, our data underline the importance of studying CD1c+ and CD16+ mDCs as discrete populations, and not as total CD11c+ mDCs. [ABSTRACT FROM AUTHOR]

Four SIV-infected monkeys with high plasma virus and CNS injury were treated with an anti-α4 blocking antibody (natalizumab) once a week for three weeks beginning on 28 days post-infection (late). Infection in the brain and gut were quantified, and neuronal injury in the CNS was assessed by MR spectroscopy, and compared to controls with AIDS and SIV encephalitis. Treatment resulted in stabilization of ongoing neuronal injury (NAA/Cr by 1H MRS), and decreased numbers of monocytes/macrophages and productive infection (SIV p28+, RNA+) in brain and gut. Antibody treatment of six SIV infected monkeys at the time of infection (early) for 3 weeks blocked monocyte/macrophage traffic and infection in the CNS, and significantly decreased leukocyte traffic and infection in the gut. SIV – RNA and p28 was absent in the CNS and the gut. SIV DNA was undetectable in brains of five of six early treated macaques, but proviral DNA in guts of treated and control animals was equivalent. Early treated animals had low-to-no plasma LPS and sCD163. These results support the notion that monocyte/macrophage traffic late in infection drives neuronal injury and maintains CNS viral reservoirs and lesions. Leukocyte traffic early in infection seeds the CNS with virus and contributes to productive infection in the gut. Leukocyte traffic early contributes to gut pathology, bacterial translocation, and activation of innate immunity. [ABSTRACT FROM AUTHOR]

This paper presents an experiment that evaluates the effect of financial incentives and complexity in political science voting experiments. To evaluate the effect of complexity we adopt a level-k reasoning model concept. This model by Nagel [1] postulates that players might be of different types, each corresponding to the level of reasoning in which they engage. Furthermore, to postulate the effect of financial incentives on subjects' choice, we used the Quantal Response Equilibrium (QRE) concept. In a QRE, players' decisions are noisy, with the probability of playing a given strategy increasing in its expected payoff. Hence, the choice probability is a function of the magnitude of the financial incentives. Our results show that low complexity promotes the highest degree of level-k strategic reasoning in every payment treatment. Standard financial incentives are enough to induce equilibrium behavior, and the marginal effect of extra incentives on equilibrium behavior seems to be negligible. High complexity, instead, decreases the rate of convergence to equilibrium play. With a sufficiently high complexity, increasing payoff amounts does promote more strategic behavior in a significant manner. Our results show with complex voting games, higher financial incentives are required for the subjects to exert the effort needed to complete the task. [ABSTRACT FROM AUTHOR]

Background. Little is known about coronary plaque in human immunodeficiency virus (HIV)–infected women.Methods. Sixty HIV-infected and 30 non–HIV-infected women without symptoms or history of cardiovascular disease were recruited to assess coronary plaque with coronary computed tomographic angiography and immune activation. Data from 102 HIV-infected men and 41 non–HIV-infected male controls were compared.Results. HIV-infected women demonstrated significantly higher percentages of segments with noncalcified plaque (mean ± SD, 74% ± 28% vs 23% ± 39% compared to female control subjects; median [interquartile range], 75% [63%–100%] vs 0% [0%–56%]; P = .007) and more segments with noncalcified plaque (mean ± SD, 0.92 ± 1.48 vs 0.40 ± 1.44; median [interquartile range], 0 [0–2] vs 0 [0–0]; P = .04). Immune activation parameters, including soluble CD163 (sCD163; P = .006), CXCL10 (P = .002), and percentages of CD14+CD16+ monocytes (P = .008), were higher in HIV-infected women than in female control subjects, but no differences were seen in general inflammatory markers. Among HIV-infected women with noncalcified coronary plaque, sCD163 levels were significantly higher than in HIV-infected women without noncalcified plaque (P = .04). In multivariate modeling for sCD163 levels among male and female subjects, significant effects of HIV (P < .0001), age (P = .002), and sex (P = .0002) were seen.Conclusions. Young, asymptomatic, HIV-infected women, demonstrate increased noncalcified coronary plaque and increased immune activation, particularly monocyte activation. Independent effects of sex, HIV status, and aging on immune activation may contribute to cardiovascular disease in this population.Clinical Trials Registration. NCT00455793. [ABSTRACT FROM AUTHOR]

Neurological sequelae of human immunodeficiency virus ( HIV) infection have been and remain a significant problem. Monocytes and macrophages in humans and monkeys are susceptible to infection by HIV and simian immunodeficiency virus ( SIV), and are considered to be a main mechanism by which the central nervous system ( CNS) is infected. Within the infected CNS, perivascular macrophages and, in some cases, parenchymal microglia are infected as are multinucleated giant cells when present. While neurons are not themselves directly infected, neuronal damage occurs within the infected CNS. Despite the success of antiretroviral therapy ( ART) in limiting virus in plasma to non-detectable levels, neurological deficits persist. This review discusses the continued neurological dysfunctions that persist in the era of ART, focusing on the roles of monocyte and macrophage as targets of continued viral infection and as agents of pathogenesis in what appears to be emergent macrophage-mediated disease resulting from long-term HIV infection of the host. Data discussed include the biology of monocyte/macrophage activation with HIV and SIV infection, traffic of cells into and out of the CNS with infection, macrophage-associated biomarkers of CNS and cardiac disease, the role of antiretroviral therapy on these cells and CNS disease, as well as the need for effective adjunctive therapies targeting monocytes and macrophages. [ABSTRACT FROM AUTHOR]

The article presents a study focusing on arterial inflammation in patients with human immunodeficiency virus (HIV). It showed that arterial inflammation was determined as the ratio of fluorine-2-deoxy-Dglucose (FDG) uptake in the arterial wall of the ascending aorta to venous background as the target-to-background ratio (TBR). The study concludes that participants with HIV vs noninfected control participants with similar cardiac risk factors suffered from signs of increased arterial inflammation, which was associated with a circulating marker of monocyte and macrophage activation.

Background. Pro-inflammatory monocytes/macrophages may contribute to increased atherosclerosis in human immunodeficiency virus (HIV)-infected patients. We investigatedto our knowledge, for the first timedsCD163 and other markers of monocyte activation in relationship to atherosclerotic plaque in HIV-infected patients. Methods. One hundred two HIV-infected and 41 HIV-seronegative men with equivalent cardiovascular risk factors and without history of coronary artery disease were prospectively recruited and underwent computed tomography coronary angiography. Results. sCD163 levels and presence of plaque were significantly higher among antiretroviral-treated subjects with undetectable HIV RNA levels, compared with seronegative controls (1172±646 vs. 883±561 ng/mL [P=.02] for sCD163 and 61% vs. 39% [P =.03] for presence of plaque). After adjusting for age, race, lipids, blood pressure, glucose, smoking, sCD14, and HIV infection, sCD163 remained independently associated with noncalcified plaque (P =.008). Among HIV-infected patients, sCD163 was associated with coronary segments with noncalcified plaque (r = 0.21; P = .04), but not with calcium score. In contrast, markers of generalized inflammation, including C-reactive protein level, and D-dimer were not associated with sCD163 or plaque among HIV-infected patients. Conclusions. sCD163, a monocyte/macrophage activation marker, is increased in association with noncalcified Conclusions. sCD163, a monocyte/macrophage activation marker, is increased in association with noncalcified coronary plaque in men with chronic HIV infection and low or undetectable viremia. These data suggest a potentially important role of chronic monocyte/macrophage activation in the development of noncalcified vulnerable plaque. [ABSTRACT FROM AUTHOR]

Proton magnetic resonance spectroscopy has emerged as one of the most informative neuroimaging modalities for studying the effect of HIV infection in the brain, providing surrogate markers by which to assess disease progression and monitor treatment. Reductions in the level of N-Acetylaspartate and N-Acetylaspartate/creatine are established markers of neuronal injury or loss. However, the biochemical basis of altered creatine levels in neuroAIDS is not well understood. This study used a rapid progression macaque model of neuroAIDS to elucidate the changes in creatine. As the disease progressed, proton magnetic resonance spectroscopy revealed a decrease in N-Acetylaspartate, indicative of neuronal injury, and an increase in creatine yet to be elucidated. Subsequently, immunohistochemistry and stereology measures of decreased synaptophysin, microtubule-associated protein 2, and neuronal density confirmed neuronal injury. Furthermore, increases in ionized calcium binding adaptor molecule 1 and glial fibrillary acidic protein indicated microglial and astroglial activation, respectively. Given these data, elevated creatine may reflect enhanced high-energy phosphate turnover in highly metabolizing activated astrocytes and microglia. Magn Reson Med, 2011. © 2011 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

CD163, a monocyte- and macrophage-specific scavenger receptor, is shed during activation as soluble CD163 (sCD163). We have previously demonstrated that monocyte expansion from bone marrow with simian immunodeficiency virus (SIV) infection correlated with plasma sCD163, the rate of AIDS progression, and the severity of macrophage-mediated pathogenesis. Here, we examined sCD163 in human immunodeficiency virus (HIV) infection. sCD163 was elevated in the plasma of individuals with chronic HIV infection (>1 year in duration), compared with HIV-seronegative individuals. With effective antiretroviral therapy (ART), sCD163 levels decreased in parallel with HIV RNA levels but did not return to HIV-seronegative levels, suggesting the presence of residual monocyte/macrophage activation even with plasma viral loads below the limit of detection. In individuals with early HIV infection (≤1 year in duration), effective ART resulted in decreased sCD163 levels that were comparable to levels in HIV-seronegative individuals. sCD163 levels in plasma were positively correlated with the percentage of CD14+CD16+ monocytes and activated CD8+HLA-DR+CD38+ T lymphocytes and were inversely correlated with CD163 expression on CD14+CD16+ monocytes. With ART interruption in subjects with early HIV infection, sCD163 and plasma virus levels spiked but rapidly returned to baseline with reinitiation of ART. This study points to the utility of monocyte- and macrophage-derived sCD163 as a marker of HIV activity that links viral replication with monocyte and macrophage activation. These observations underscore the significance of monocyte and macrophage immune responses with HIV pathogenesis. [ABSTRACT FROM PUBLISHER]

We report on majority voting experiments where subjects are randomly assigned identities in common with a candidate. However, subjects sometimes receive a financial incentive from voting contrary to their identity. We vary the size of the incentive as well as information voters have about the advantage of the incentive. We find that subjects are influenced by their assigned identities, and the effect is stronger when voters have less information. Nevertheless, financial incentives reduce this influence when voters have full information. Our results suggest that identity may have an important affect on voter choices in elections where incentives or information are low. [ABSTRACT FROM PUBLISHER]

Background: Minocycline is a tetracycline antibiotic that has been proposed as a potential conjunctive therapy for HIV-1 associated cognitive disorders. Precise mechanism(s) of minocycline's functions are not well defined. Methods: Fourteen rhesus macaques were SIV infected and neuronal metabolites measured by proton magnetic resonance spectroscopy (¹H MRS). Seven received minocycline (4 mg/kg) daily starting at day 28 post-infection (pi). Monocyte expansion and activation were assessed by flow cytometry, cell traffic to lymph nodes, CD16 regulation, viral replication, and cytokine production were studied. Results: Minocycline treatment decreased plasma virus and pro-inflammatory CD14+CD16+ and CD14loCD16+ monocytes, and reduced their expression of CD11b, CD163, CD64, CCR2 and HLA-DR. There was reduced recruitment of monocyte/ macrophages and productively infected cells in axillary lymph nodes. There was an inverse correlation between brain NAA/ Cr (neuronal injury) and circulating CD14+CD16+ and CD14loCD16+ monocytes. Minocycline treatment in vitro reduced SIV replication CD16 expression on activated CD14+CD16+ monocytes, and IL-6 production by monocytes following LPS stimulation. Conclusion: Neuroprotective effects of minocycline are due in part to reduction of activated monocytes, monocyte traffic. Mechanisms for these effects include CD16 regulation, reduced viral replication, and inhibited immune activation. [ABSTRACT FROM AUTHOR]

Background: Despite the advent of highly active anti-retroviral therapy (HAART), HIV-associated neurocognitive disorders continue to be a significant problem. In efforts to understand and alleviate neurocognitive deficits associated with HIV, we used an accelerated simian immunodeficiency virus (SIV) macaque model of NeuroAIDS to test whether minocycline is neuroprotective against lentiviral-induced neuronal injury. Methodology/Principal Findings: Eleven rhesus macaques were infected with SIV, depleted of CD8+ lymphocytes, and studied until eight weeks post inoculation (wpi). Seven animals received daily minocycline orally beginning at 4 wpi. Neuronal integrity was monitored in vivo by proton magnetic resonance spectroscopy and post-mortem by immunohistochemistry for synaptophysin (SYN), microtubule-associated protein 2 (MAP2), and neuronal counts. Astrogliosis and microglial activation were quantified by measuring glial fibrillary acidic protein (GFAP) and ionized calcium binding adaptor molecule 1 (IBA-1), respectively. SIV infection followed by CD8+ cell depletion induced a progressive decline in neuronal integrity evidenced by declining N-acetylaspartate/creatine (NAA/Cr), which was arrested with minocycline treatment. The recovery of this ratio was due to increases in NAA, indicating neuronal recovery, and decreases in Cr, likely reflecting downregulation of glial cell activation. SYN, MAP2, and neuronal counts were found to be higher in minocyclinetreated animals compared to untreated animals while GFAP and IBA-1 expression were decreased compared to controls. CSF and plasma viral loads were lower in MN-treated animals. Conclusions/Significance: In conclusion, oral minocycline alleviates neuronal damage induced by the AIDS virus. [ABSTRACT FROM AUTHOR]

Cells of the myeloid lineage are significant targets for human immunodeficiency virus (HIV) in humans and simian immunodeficiency virus (SIV) in monkeys. Monocytes play critical roles in innate and adaptive immunity during inflammation. We hypothesize that specific subsets of monocytes expand with AIDS and drive central nervous system (CNS) disease. Additionally, there may be expansion of cells from the bone marrow through blood with subsequent macrophage accumulation in tissues driving pathogenesis. To identify monocytes that recently emigrated from bone marrow, we used 5- bromo-29-deoxyuridine (BrdU) labeling in a longitudinal study of SIV-infected CD8+ T lymphocyte depleted macaques. Monocyte expansion and kinetics in blood was assessed and newly migrated monocyte/macrophages were identified within the CNS. Five animals developed rapid AIDS with differing severity of SIVE. The percentages of BrdU+ monocytes in these animals increased dramatically, early after infection, peaking at necropsy where the percentage of BrdU+ monocytes correlated with the severity of SIVE. Early analysis revealed changes in the percentages of BrdU+ monocytes between slow and rapid progressors as early as 8 days and consistently by 27 days post infection. Soluble CD163 (sCD163) in plasma correlated with the percentage of BrdU+ monocytes in blood, demonstrating a relationship between monocyte activation and expansion with disease. BrdU+ monocytes/macrophages were found within perivascular spaces and SIVE lesions. The majority (80-90%) of the BrdU+ cells were Mac387+ that were not productively infected. There was a minor population of CD68+BrdU+ cells (,10%), very few of which were infected (,1% of total BrdU+ cells). Our results suggest that an increased rate of monocyte recruitment from bone marrow into the blood correlates with rapid progression to AIDS, and the magnitude of BrdU+ monocytes correlates with the severity of SIVE. [ABSTRACT FROM AUTHOR]

The human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV) have a long biological history. Both viruses evolved from Africa and remnants of them can be found in the ‘fossil record’ of several species in which they are not endemic. SIV remains endemic in several species of monkeys in Africa where it does not cause immune deficiency. HIV and SIV actively replicate within humans and Asian non-human primates, despite cellular and genetic viral restriction factors and genes, and at times robust innate and adaptive immune responses. While Lentiviruses are considered ‘slow viruses’ it is clear in humans and susceptible Asian monkeys that virus production is rapid and highly active. This results in a massive loss of CD4+ memory effector T cells early after infection and a continued race between viral evolution, cytotoxic lymphocytes, and failed neutralizing antibody responses. Concurrently, HIV and SIV can infect monocyte/macrophage populations in blood and more importantly in tissues, including the central nervous system, where the virus can remain sequestered and not cleared by anti-retroviral therapy, and hide for years. This review will discuss species and cellular barriers to infection, and the role of innate and acquired immunity with infection and pathogenesis of HIV and SIV in select species. [ABSTRACT FROM AUTHOR]

Although the dynamics of human immunodeficiency virus and Simian immunodeficiency virus (SIV)-specific cytotoxic T cells (CTLs) have been well documented in the blood, little is known regarding CTL development in other tissues. In this study, seven Mamu-A*01+ macaques were inoculated with SIVmac. Two macaques were killed at 21 days of infection, and SIV gag p11C tetramer responses were measured in the blood, axillary and mesenteric lymph nodes, spleen, bone marrow, and thymus. Three with clinical signs of disease were killed and similarly examined. Four macaques were followed throughout disease progression, and intestinal biopsies and blood were examined at regular time points after inoculation. In animals followed prospectively, peak early tetramer responses were detected in the blood (3.9–19% of CD3+ CD8+ T cells) between day 14–21 post-inoculation (p.i.). After day 49, tetramer responses in the blood diminished and remained relatively stable through day 200, ranging from 0.7–6.5% of CD3+ CD8+ T cells. In contrast, tetramer-positive T cells increased in the intestine in later stages of infection (100–200 days p.i.) in all four infected animals (peak values from 5.3 to 28.8%). Percentages of tetramer-positive cells were consistently higher in the intestine than in the blood in all four animals after day 100. In animals with acquired immunodeficiency syndrome, percentages of CTL in tissues were variable, but were consistently higher in the intestine and spleen compared with blood. These data suggest that while high CTL responses develop at a similar rate, and magnitude in both peripheral and mucosal lymphoid tissues in primary SIV infection, mucosal CTL responses may predominate later in the course of the disease. [ABSTRACT FROM AUTHOR]

Examines the aggregation process of information, which is a prerequisite for the operation of a democratic system, within a principal-agent model of elections. Requirement needed in order for political office-holders to act responsively; Motive for conducting laboratory experiments; Activity undertaken by voters in a principal-agent theory of elections.

Focuses on the role of the extended macrophage/monocyte family in the central nervous system (CNS) during HIV or simian immunodeficiency virus infection (SIV). Lineage of monoyctes and macrophage cells in the CNS; Mechanisms of HIV and SIV infection of the CNS; Molecular basis of macrophage tropism of HIV and SIV.

Before the antiretroviral therapy (ART) era, people living with HIV (PLWH) experienced complications due to AIDS more so than aging. With ART and the extended lifespan of PLWH, HIV comorbidities also include aging—most likely due to accelerated aging—as well as a cardiovascular, neurocognitive disorders, lung and kidney disease, and malignancies. The broad evidence suggests that HIV with ART is associated with accentuated aging, and that the age-related comorbidities occur earlier, due in part to chronic immune activation, co-infections, and possibly the effects of ART alone. Normally the immune system undergoes alterations of lymphocyte and monocyte populations with aging, that include diminished naïve T- and B-lymphocyte numbers, a reliance on memory lymphocytes, and a skewed production of myeloid cells leading to age-related inflammation, termed "inflamm-aging". Specifically, absolute numbers and relative proportions of monocytes and monocyte subpopulations are skewed with age along with myeloid mitochondrial dysfunction, resulting in increased accumulation of reactive oxygen species (ROS). Additionally, an increase in biomarkers of myeloid activation (IL-6, sCD14, and sCD163) occurs with chronic HIV infection and with age, and may contribute to immunosenescence. Chronic HIV infection accelerates aging; meanwhile, ART treatment may slow age-related acceleration, but is not sufficient to stop aging or age-related comorbidities. Overall, a better understanding of the mechanisms behind accentuated aging with HIV and the effects of myeloid activation and turnover is needed for future therapies. [ABSTRACT FROM AUTHOR]

Retrospective considerations do influence vote choice. But the manner in which voters incorporate retrospective evaluations is still an empirical question. This essay compares two voting rules: a traditional retrospective rule and a retrospective-prospective rule. The rules are differentiated based on the information costs associated with each. It is assumed that the traditional retrospective rule is less costly since voters need only make evaluations about the incumbent, whereas using a retrospective-prospective rule, voters must acquire additional information about the challenger. This essay argues that a choice of voting rule is a function of whether voters perceive the electoral environment as being stable or unstable (in terms of the issue positions candidates adopt over time). Laboratory experiments are conducted to test this proposition. In general, the results show that voters show a greater tendency to rely on a traditional retrospective rule when they perceive a stable electoral environment. [ABSTRACT FROM AUTHOR]

Examines how resources and credit-claiming opportunities influence congressional decisions to delegate authority. Delegation, the two Congresses, and the problems of collective action; Credit claiming, constituency service, and private claims legislation; Expected relationship between increased staff resources and private claims.

Explores sequential voting in drawn-out primaries and simultaneous voting in front-loaded ones theoretically. Use of laboratory elections to examine the predictions empirically; Evidence that in sequential voting later voters can use early outcomes to infer information about candidates and make choice that better reflect their preferences; Voter strategies and equilibria.