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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.

Background HIV and malaria are associated with immunological perturbations and neurocognitive disorders even when asymptomatic. However, the effect of asymptomatic malaria (AM) in HIV-infected adults on neurocognitive impairment (NCI) is not well understood. This study investigated the biomarkers of systemic inflammation and neurocognition in dually infected Nigerian adults. Methods We assessed the HIV and AM status of 269 adults and measured their global and domain-specific neurocognition and depression using standardized measures. Blood levels of sCD14 and sCD163 were also measured. Results The mean age of the participants (n = 269) was 33 years, 62% were women, and AM among HIV+ and HIV- was similar (36% versus 37%). NCI was found in 23% (62/269) of participants. HIV+/AM+ had a higher prevalence of impaired learning and executive functions and were more depressed than HIV-/AM- or HIV+/AM-. HIV+ with CD4 T-cell counts ≤200/µL were more impaired in the learning domain than those with >200/µL. HIV+/AM+ group had higher levels of sCD14 compared to the other 3 groups and higher levels of sCD163 than the HIV-/AM- group. Higher levels of sCD14 and sCD163 were each associated with NCI. The sCD163 (log10) levels were higher for those with 1+ versus 2+ parasitemia level. Conclusions HIV and AM coinfection was associated with an increased risk of reduced learning and executive functions, and elevated systemic inflammation. Mood was more depressed in HIV patients with than those without AM. The mechanisms and long-term effects on neurocognition and depression among HIV+/AM+ individuals should be studied because this coinfection is common globally.

Background People with HIV (PWH) have increased cardiovascular events, inflammation, and high-risk coronary atherosclerosis. Statin therapy has been shown to lower the risk of cardiovascular disease (CVD) in the general population, but whether this results from reductions in coronary atherosclerosis and is mediated by decreased inflammation remains unknown. Methods REPRIEVE is a randomized, placebo-controlled trial of pitavastatin calcium (4 mg/day) vs. placebo enrolling at least 7500 PWH between 40–75 years, on antiretroviral therapy (ART), with low to moderate traditional CVD risk. The Mechanistic Substudy of REPRIEVE (A5333s) is co-enrolling 800 participants from 31 US sites. These participants undergo serial contrast enhanced coronary computed tomography angiography (CCTA) and measurements of biomarkers of inflammation and immune activation at baseline and after 2 years of follow-up. The primary objectives are to determine the effects of pitavastatin on noncalcified coronary atherosclerotic plaque (NCP) volume, low attenuation plaque, and positive remodeling and on changes in immune activation and inflammation and to assess relationships between the two. Changes in CAD will be assessed in a standardized fashion by a core lab with expert readers blinded to time points and participant information; immune activation and inflammation assessment is also performed centrally. Results To date the Mechanistic Substudy has completed planned enrollment, with 805 participants. Conclusion This study represents the first large, randomized, CCTA-based assessment of the effects of a primary prevention strategy for CVD on high-risk CAD, immune activation and inflammation among PWH. The study will assess pitavastatin’s effects on coronary plaque, and the interrelationship of these changes with biomarkers of immune activation and inflammation in PWH to determine mechanisms of CVD prevention and improved outcomes in this population.

Background. 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.Results. 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. S ignificant 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.Conclusions. 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 .

BackgroundDespite 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.ResultsWe 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.ConclusionsOur 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.

OBJECTIVE: Monocyte/macrophage activation is increased among people with HIV, and may contribute to the heightened risk of atherosclerosis and neurocognitive dysfunction in this population. Insulin-like growth factor 1 (IGF-1) has been shown to attenuate the innate immune response in animal models of atherosclerosis and inflammatory bowel disease. We investigated for the first time relationships of circulating IGF-1 with monocyte/macrophage-specific indices among HIV-infected individuals and uninfected controls. DESIGN: Observational. METHODS: 131 HIV-infected subjects and 65 well-matched controls without known cardiac disease or viral hepatitis were recruited previously. IGF-1, expressed as a z-score relative to the age- and sex-adjusted population mean, was related to log-transformed inflammatory markers within HIV and non-HIV groups. RESULTS: In HIV, IGF-1 inversely related to sCD163 (r = −0.28, P = 0.002), sCD14 (r = −0.29, P = 0.002), and high-sensitivity IL-6 (r = −0.27, P = 0.006). There was no association of IGF-1 with high-sensitivity CRP, MCP-1, IL-18, or LPS in HIV, or between IGF-1 and any inflammatory marker in controls. Relationships of IGF-1 with sCD163 and sCD14 remained significant in HIV after controlling for age, sex, smoking, body mass index, visceral fat, statin use, viral load, and antiretroviral therapy. For every 1-unit decline in IGF-1 z-score, sCD163 and sCD14 increased by 14% (95% CI, 0.23%, 29%) and 29% (95% CI, 1.4%, 63%), respectively. CONCLUSIONS: Low IGF-1 was robustly associated with high sCD163 and sCD14 in HIV. Prospective studies are needed to investigate augmentation of IGF-1 as a novel strategy to reduce monocyte/macrophage activation in this population.

Non-human primate models of AIDS and neuroAIDS are critical to study HIV infection of the CNS, neuropathology, and immune activation and macrophage accumulation that occurs in HAND. SIV, similar to HIV, infects CD4+ T lymphocytes and monocytes/macrophages. Virus enters the CNS early, and macrophage activation correlates with CNS disease, as well as inflammation outside of the CNS. Antiretroviral in HIV+ humans and SIV+ Rhesus macaques results in non-detectable plasma virus, decreased or non-detectable viral RNA or protein in the CNS. But, viral DNA rebounds following therapy interruption, demonstrating the presence of replication competent virus in the CNS within myeloid cells. In this brief review, we discuss our findings using a Rhesus macaque model of SIV-associated CNS infection and pathology, focusing on monocyte/macrophage activation and the link between CNS and cardiac disease. We conclude with recent studies using adjunctive therapy targeting monocytes/macrophages with ART to prevent or diminish CNS pathology that may be associated with HAND.

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.

Key Points Question What is the extent of coronary artery disease among people with well-controlled HIV and low to moderate risk of atherosclerotic cardiovascular disease (ASCVD), and how is coronary artery disease associated with traditional risk, inflammatory, and immune activation indices? Findings In this cohort study of 755 people with HIV, coronary plaque was highly prevalent. Critical stenosis was rare, but higher-risk plaque features, including vulnerable plaque and high Leaman scores, were seen in approximately one-fifth of participants; plaque indices were associated with ASCVD risk scores and, independently, indices of inflammation and immune activation. Meaning These findings suggest that people with HIV at low to moderate risk of cardiovascular disease have a significant prevalence of coronary plaque associated with inflammation and immune activation markers., This cohort study examines the prevalence of coronary artery disease (CAD) among adults with well-controlled HIV and low to moderate risk of atherosclerotic cardiovascular disease using computed tomography angiography and assessment of inflammation and immune activation biomarkers., Importance Cardiovascular disease (CVD) is increased among people with HIV (PWH), but little is known regarding the prevalence and extent of coronary artery disease (CAD) and associated biological factors in PWH with low to moderate traditional CVD risk. Objectives To determine unique factors associated with CVD in PWH and to assess CAD by coronary computed tomography angiography (CTA) and critical pathways of arterial inflammation and immune activation. Design, Setting, and Participants This cohort study among male and female PWH, aged 40 to 75 years, without known CVD, receiving stable antiretroviral therapy, and with low to moderate atherosclerotic cardiovascular disease (ASCVD) risk according to the 2013 American College of Cardiology/American Heart Association pooled cohort equation, was part of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), a large, ongoing primary prevention trial of statin therapy among PWH conducted at 31 US sites. Participants were enrolled from May 2015 to February 2018. Data analysis was conducted from May to December 2020. Exposure HIV disease. Main Outcomes and Measures The primary outcome was the prevalence and composition of CAD assessed by coronary CTA and, secondarily, the association of CAD with traditional risk indices and circulating biomarkers, including insulin, monocyte chemoattractant protein 1 (MCP-1), interleukin (IL) 6, soluble CD14 (sCD14), sCD163, lipoprotein-associated phospholipase A2 (LpPLA2), oxidized low-density lipoprotein (oxLDL), and high-sensitivity C-reactive protein (hsCRP). Results The sample included 755 participants, with a mean (SD) age of 51 (6) years, 124 (16%) female participants, 267 (35%) Black or African American participants, 182 (24%) Latinx participants, a low median (interquartile range) ASCVD risk (4.5% [2.6%-6.8%]), and well-controlled viremia. Overall, plaque was seen in 368 participants (49%), including among 52 of 175 participants (30%) with atherosclerotic CVD (ASCVD) risk of less than 2.5%. Luminal obstruction of at least 50% was rare (25 [3%]), but vulnerable plaque and high Leaman score (ie, >5) were more frequently observed (172 of 755 [23%] and 118 of 743 [16%], respectively). Overall, 251 of 718 participants (35%) demonstrated coronary artery calcium score scores greater than 0. IL-6, LpPLA2, oxLDL, and MCP-1 levels were higher in those with plaque compared with those without (eg, median [IQR] IL-6 level, 1.71 [1.05-3.04] pg/mL vs 1.45 [0.96-2.60] pg/mL; P = .008). LpPLA2 and IL-6 levels were associated with plaque in adjusted modeling, independent of traditional risk indices and HIV parameters (eg, IL-6: adjusted odds ratio, 1.07; 95% CI, 1.02-1.12; P = .01). Conclusions and Relevance In this study of a large primary prevention cohort of individuals with well-controlled HIV and low to moderate ASCVD risk, CAD, including noncalcified, nonobstructive, and vulnerable plaque, was highly prevalent. Participants with plaque demonstrated higher levels of immune activation and arterial inflammation, independent of traditional ASCVD risk and HIV parameters.

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. {"type":"clinical-trial","attrs":{"text":"NCT01407237","term_id":"NCT01407237"}}NCT01407237.

Non-human primate models of AIDS and neuroAIDS are the premiere model of HIV infection of the CNS and neuropathogenesis. This review discusses current SIV infection models of neuroAIDS emphasizing findings in the last two years. Consistent in these findings is the interplay between host factors that regulated immune responses to virus and viral replication. Several rapid models of AIDS with consistent CNS pathogenesis exist, each of which modulates by antibody treatment or viruses that cause rapid immune suppression and replicate well in macrophages. Consistent in all of these models are data underscoring the importance of monocyte and macrophage activation, infection and accumulation in the CNS.

The emergence of a distinct subpopulation of human or simian immunodeficiency virus (HIV/SIV) sequences within the brain (compartmentalization) during infection is hypothesized to be linked to AIDS-related central nervous system (CNS) neuropathology. However, the exact evolutionary mechanism responsible for HIV/SIV brain compartmentalization has not been thoroughly investigated. Using extensive viral sampling from several different peripheral tissues and cell types and from three distinct regions within the brain from two well-characterized rhesus macaque models of the neurological complications of HIV infection (neuroAIDS), we have been able to perform in-depth evolutionary analyses that have been unattainable in HIV-infected subjects. The results indicate that, despite multiple introductions of virus into the brain over the course of infection, brain sequence compartmentalization in macaques with SIV-associated CNS neuropathology likely results from late viral entry of virus that has acquired through evolution in the periphery sufficient adaptation for the distinct microenvironment of the CNS. IMPORTANCE HIV-associated neurocognitive disorders remain prevalent among HIV type 1-infected individuals, whereas our understanding of the critical components of disease pathogenesis, such as virus evolution and adaptation, remains limited. Building upon earlier findings of specific viral subpopulations in the brain, we present novel yet fundamental results concerning the evolutionary patterns driving this phenomenon in two well-characterized animal models of neuroAIDS and provide insight into the timing of entry of virus into the brain and selective pressure associated with viral adaptation to this particular microenvironment. Such knowledge is invaluable for therapeutic strategies designed to slow or even prevent neurocognitive impairment associated with AIDS.

The American College of Cardiology (ACC)/American Heart Association (AHA) guidelines suggest statin therapy for primary prevention in patients with an estimated 10-year atherosclerotic cardiovascular disease risk ≥7.5%1 as calculated by the Pooled Cohorts Equation. We recently demonstrated that only 53% of individuals eligible for statins based on the ≥7.5% risk criterion would have been eligible for a statin randomized control trial (RCT) in which benefit was demonstrated.2 We sought (1) to evaluate whether the recently published HOPE-3 trial (Heart Outcomes Prevention Evaluation)3 improves the evidence base for the ACC/AHA guidelines and (2) to estimate whether HOPE-3 increases the number of individuals eligible for statins in primary prevention beyond those recommended by the ACC/AHA guidelines. Data from the National Health and Nutrition Examination Survey (NHANES) collected between 2005 and 2010 were used to create a sample of 2134 participants representing 71.8 million Americans without atherosclerotic cardiovascular disease who were not currently taking statins. Participants were categorized based on the following criteria: (1) a 10-year risk of ≥7.5% by Pooled Cohorts Equation; (2) an expected absolute risk reduction of ≥2.3% based on Pooled Cohorts Equation risk and individualized relative risk reductions, as previously described2; …

6089 Background: Although mortality among black women diagnosed with uterine cancer is higher than in white women, the reason for this difference is not completely understood. We proposed to investigate the differences in the incidence and presentation of uterine cancer histology among black women compared to white women. Methods: Data were obtained from the United States Cancer Statistics (USCS) and the National Cancer Database (NCDB) between 2004 and 2016. Chi-squared tests were used for statistical analyses. Results: Of 488,811 patients with uterine cancer, 411,904 (84.3%) were white and 51,093 (10.5%) were black. Based on USCS data, the incidence of endometrioid carcinoma in white women was 19.63 (per 100,000 per year) compared to 12.53 in black women. However, the incidence of high-risk histologies was higher in black women, particularly for serous tumors (3.32 vs. 1.29), clear cell tumors (0.59 vs. 0.31), carcinosarcoma (2.88 vs. 1.05), and leiomyosarcoma (1.02 vs. 0.48). Using the NCDB database, we evaluated the proportion of these histologies based on race. Compared to white women, black women have a higher proportion of serous (14.2% vs. 5.6%), clear cell (2.4% vs. 1.3%), carcinosarcoma (12.3% vs. 4.5%), and leiomyosarcoma (4.3% vs. 1.7%). black women were less likely to have endometrioid (52.7% vs. 75.9%) and mucinous (0.4% vs. 0.8%) tumors. In addition, black women were more likely to have stage III or IV disease at presentation when all histological subtypes were combined (22.8% vs. 17.7%). However, of those with endometrioid and grade 1 tumors, black women did not have more advanced stage at presentation compared to white women (3.8% vs. 4.7%). Conclusions: Compared to white women, black women are more likely to be diagnosed with serous, clear cell, carcinosarcoma, and leiomyosarcomas at a more advanced stage upon presentation, but they are less likely to have endometrioid tumors. More research is needed to understand why this disparity exists.

BackgroundLike many bacteria, Vibrio cholerae, which causes fatal cholera, deploys a harpoon-like Type VI Secretion System (T6SS) to compete against other microbes in environmental and host settings. The T6SS punctures adjacent cells and delivers toxic effector proteins that are harmless to bacteria carrying cognate immunity factors. Only four effector/immunity pairs encoded on one large and three auxiliary gene clusters have been characterized from largely clonal, patient-derived strains of V. cholerae.ResultsWe sequenced two dozen V. cholerae strain genomes from diverse sources and developed a novel and adaptable bioinformatic tool based on Hidden Markov Models. We identified two new T6SS auxiliary gene clusters; one, Aux 5, is described here. Four Aux 5 loci are present in the host strain, each with an atypical effector/immunity gene organization. Structural prediction of the putative effector indicated it is a lipase, which we name TleV1 (Type VI lipase effector Vibrio, TleV1). Ectopic TleV1 expression induced toxicity in E. coli, which was rescued by co-expression of the TleV1 immunity factor. A clinical V. cholerae reference strain expressing the Aux 5 cluster used TleV1 to lyse its parental strain upon contact via its T6SS but was unable to kill parental cells expressing TleV1’s immunity factor.ConclusionWe developed a novel bioinformatic method and identified new T6SS gene clusters in V. cholerae. We also showed the TleV1 toxin is delivered in a T6SS-manner by V. cholerae and can lyse other bacterial cells. Our web-based tool may be modified to identify additional novel T6SS genomic loci in diverse bacterial species.

Human immunodeficiency virus (HIV) RNA and DNA have been isolated from patient monocytes, an immune cell population that is quite different in several aspects from the canonical T-cell viral target. Because monocytes are migratory and resilient to both natural and synthetic antiviral defenses, knowledge of the contribution of monocyte infection to ongoing viral evolution and spread \textit{in vivo} is of significant interest for drug development and treatment strategies. Using single viral genome sequencing from different peripheral blood compartments and phyloanatomic statistical inference, we demonstrate that productively infected monocytes follow an evolutionary trajectory that is distinct from peripheral T cells during multiple stages of disease progression. Gene flow and selection analysis reveal plasticity in the source of monocyte infection and in the region of the HIV envelope glycoprotein that experiences selection pressure across individuals. The findings, thus, point to a potential reservoir showing a range of infection and transmission dynamics, for which the current universal, T cell-targeted treatment strategies would be inadequate.

Dextrans have been used extensively as medical therapies and labeling agents in biomedical research to investigate the blood-brain barrier and CSF flow and absorption. Adverse effects from dextrans include anaphylactic reaction and dilation of the cerebral ventricles due to administration into the subarachnoid space. This retrospective study describes 51 rhesus macaques (Macaca mulatta) that received dextran intrathecally. The purpose of intrathecal administration was to enable detection of long-lived, dextran-labeled macrophages and to study monocyte-macrophage turnover in the CNS of SIV- or SHIV- infected and uninfected animals by using immunofluorescence. Of the 51 dextran-treated macaques, 8 that received dextran diluted in saline developed hydrocephalus; 6 of these 8 animals exhibited neurologic signs. In contrast, none of the macaques that received intrathecal dextran diluted in PBS developed hydrocephalus. These data suggest the use of saline diluent and the duration of dextran exposure as potential factors contributing to hydrocephalus after intrathecal dextran in rhesus macaques.

It is difficult to study the pathogenesis of human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) in living patients because central nervous system (CNS) tissues are only available post mortem. Rodent and nonhuman primate (NHP) models of HAND allow for longitudinal analysis of HIV-associated CNS pathology and efficacy studies of novel therapeutics. Rodent models of HAND allow for studies with large sample sizes, short duration, and relatively low cost. These models include humanized mice used to study HIV-associated neuropathogenesis and transgenic mice used to study neurotoxic effects of viral proteins without infection. Simian immunodeficiency virus (SIV)-infected NHP are the premier model of neuroAIDS; SIV-associated CNS pathology is similar to HIV-associated CNS pathology with HAND. Additionally, the size, lifespan of NHP, and time to acquired immune deficiency syndrome (AIDS) progression make SIV-infected NHP models optimal for studies of viral latency and reservoirs, and assessing novel therapeutics for neuroAIDS. NHP models of neuroAIDS generally include conventional progressors (AIDS within 2-3 years) and those that have rapid disease (AIDS within 150 days). Rapid AIDS models are achieved by immune modulation and/or infection with neurovirulent and neurosuppressive viral strains and result in a high incidence of SIV-associated encephalitis. In this chapter, we briefly review rodent and NHP models of neuroAIDS, including contributions made using these models to our understanding of HIV-associated CNS disease.

While a clear understanding of the events leading to successful establishment of host-specific viral populations and productive infection in the central nervous system (CNS) has not yet been reached, the simian immunodeficiency virus (SIV)-infected rhesus macaque provides a powerful model for the study of human immunodeficiency virus (HIV) intrahost evolution and neuropathogenesis. The evolution of the gp120 and nef genes, which encode two key proteins required for the establishment and maintenance of infection, was assessed in macaques that were intravenously inoculated with the same viral swarm and allowed to naturally progress to simian AIDS and potential SIV-associated encephalitis (SIVE). Longitudinal plasma samples and immune markers were monitored until terminal illness. Single-genome sequencing was employed to amplify full-length env through nef transcripts from plasma over time and from brain tissues at necropsy. nef sequences diverged from the founder virus faster than gp120 diverged. Host-specific sequence populations were detected in nef (∼92 days) before they were detected in gp120 (∼182 days). At necropsy, similar brain nef sequences were found in different macaques, indicating convergent evolution, while gp120 brain sequences remained largely host specific. Molecular clock and selection analyses showed weaker clock-like behavior and stronger selection pressure in nef than in gp120, with the strongest nef selection in the macaque with SIVE. Rapid nef diversification, occurring prior to gp120 diversification, indicates that early adaptation of nef in the new host is essential for successful infection. Moreover, the convergent evolution of nef sequences in the CNS suggests a significant role for nef in establishing neurotropic strains. IMPORTANCE The SIV-infected rhesus macaque model closely resembles HIV-1 immunopathogenesis, neuropathogenesis, and disease progression in humans. Macaques were intravenously infected with identical viral swarms to investigate evolutionary patterns in the gp120 and nef genes leading to the emergence of host-specific viral populations and potentially linked to disease progression. Although each macaque exhibited unique immune profiles, macaque-specific nef sequences evolving under selection were consistently detected in plasma samples at 3 months postinfection, significantly earlier than in gp120 macaque-specific sequences. On the other hand, nef sequences in brain tissues, collected at necropsy of two animals with detectable infection in the central nervous system (CNS), revealed convergent evolution. The results not only indicate that early adaptation of nef in the new host may be essential for successful infection, but also suggest that specific nef variants may be required for SIV to efficiently invade CNS macrophages and/or enhance macrophage migration, resulting in HIV neuropathology.

BACKGROUND Residual systemic inflammation persists despite suppressive antiretroviral therapy (ART) and is associated with non-AIDS clinical outcomes. We aimed to evaluate the association between ART adherence and inflammation in Ugandans living with HIV who were predominantly receiving nevirapine-based ART with a thymidine analog backbone and were virologically suppressed by conventional assays. METHODS Plasma concentrations of interleukin-6 (IL-6), D-dimer, soluble (s)CD14, sCD163, and the kynurenine/tryptophan ratio, in addition to CD8 T-cell activation, were measured at baseline and 6 months after ART initiation in treatment-naive adults who achieved an undetectable plasma HIV RNA (

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.

It is difficult to study the pathogenesis of human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) in living patients because central nervous system (CNS) tissues are only available post mortem. Rodent and nonhuman primate (NHP) models of HAND allow for longitudinal analysis of HIV-associated CNS pathology and efficacy studies of novel therapeutics. Rodent models of HAND allow for studies with large sample sizes, short duration, and relatively low cost. These models include humanized mice used to study HIV-associated neuropathogenesis and transgenic mice used to study neurotoxic effects of viral proteins without infection. Simian immunodeficiency virus (SIV)-infected NHP are the premier model of neuroAIDS; SIV-associated CNS pathology is similar to HIV-associated CNS pathology with HAND. Additionally, the size, lifespan of NHP, and time to acquired immune deficiency syndrome (AIDS) progression make SIV-infected NHP models optimal for studies of viral latency and reservoirs, and assessing novel therapeutics for neuroAIDS. NHP models of neuroAIDS generally include conventional progressors (AIDS within 2-3 years) and those that have rapid disease (AIDS within 150 days). Rapid AIDS models are achieved by immune modulation and/or infection with neurovirulent and neurosuppressive viral strains and result in a high incidence of SIV-associated encephalitis. In this chapter, we briefly review rodent and NHP models of neuroAIDS, including contributions made using these models to our understanding of HIV-associated CNS disease.

Analyses using conventional statistical methodologies have yielded conflicting results as to whether low-density lipoprotein cholesterol (LDL-C) or non-high-density lipoprotein cholesterol (non-HDL-C) or apolipoprotein B (apoB) is the best marker of the apoB-associated risk of coronary heart disease. The aim of this study was to determine the additional value of apoB beyond LDL-C or non-HDL-C as a predictor of coronary heart disease.For each patient from the Framingham Offspring Cohort aged 40-75 years (n = 2966), we calculated the extent to which the observed apoB differed from the expected apoB based on their LDL-C or non-HDL-C. We added this difference to a Cox model predicting new onset coronary heart disease over a maximum of 20 years adjusting for standard risk factors plus LDL-C or non-HDL. The difference between observed and expected apoB over LDL-C or non-HDL-C was highly prognostic of future coronary heart disease events: adjusted hazard ratios 1.26 (95% confidence interval: 1.15, 1.37) and 1.20 (1.11, 1.29), respectively, for each standard deviation increase beyond expected apoB levels. When this difference between observed and expected apoB was added to standard coronary heart disease prediction models including LDL-C or non-HDL-C, prediction improved significantly (likelihood ratio test p-values0.0001) and discrimination c-statistics increased from 0.72 to 0.73. The corresponding relative integrated discrimination improvements were 11% and 8%, respectively.apoB improves risk assessment of future coronary heart disease events over and beyond LDL-C or non-HDL-C, which is consistent with coronary risk being more closely related to the number of atherogenic apoB particles than to the mass of cholesterol within them.

A thorough understanding of the role of human immunodeficiency virus (HIV) intrahost evolution in AIDS pathogenesis has been limited by the need for longitudinally sampled viral sequences from the vast target space within the host, which are often difficult to obtain from human subjects. CD8 + lymphocyte-depleted macaques infected with simian immunodeficiency virus (SIV) provide an increasingly utilized model of pathogenesis due to clinical manifestations similar to those for HIV-1 infection and AIDS progression, as well as a characteristic rapid disease onset. Comparison of this model with SIV-infected non-CD8 + lymphocyte-depleted macaques also provides a unique opportunity to investigate the role of CD8 + cells in viral evolution and population dynamics throughout the duration of infection. Using several different phylogenetic methods, we analyzed viral gp120 sequences obtained from extensive longitudinal sampling of multiple tissues and enriched leukocyte populations from SIVmac251-infected macaques with or without CD8 + lymphocyte depletion. SIV evolutionary and selection patterns in non-CD8 + lymphocyte-depleted animals were characterized by sequential population turnover and continual viral adaptation, a scenario readily comparable to intrahost evolutionary patterns during human HIV infection in the absence of antiretroviral therapy. Alternatively, animals that were depleted of CD8 + lymphocytes exhibited greater variation in population dynamics among tissues and cell populations over the course of infection. Our findings highlight the major role for CD8 + lymphocytes in prolonging disease progression through continual control of SIV subpopulations from various anatomical compartments and the potential for greater independent viral evolutionary behavior among these compartments in response to immune modulation. IMPORTANCE Although developments in combined antiretroviral therapy (cART) strategies have successfully prolonged the time to AIDS onset in HIV-1-infected individuals, a functional cure has yet to be found. Improvement of drug interventions for a virus that is able to infect a wide range of tissues and cell types requires a thorough understanding of viral adaptation and infection dynamics within this target milieu. Although it is difficult to accomplish in the human host, longitudinal sampling of multiple anatomical locations is readily accessible in the SIV-infected macaque models of neuro-AIDS. The significance of our research is in identifying the impact of immune modulation, through differing immune selective pressures, on viral evolutionary behavior in a multitude of anatomical compartments. The results provide evidence encouraging the development of a more sophisticated model that considers a network of individual viral subpopulations within the host, with differing infection and transmission dynamics, which is necessary for more effective treatment strategies.

Peripheral neuropathy (PN) is a major comorbidity of HIV infection that is caused in part by chronic immune activation. HIV-PN is associated with infiltration of monocytes/macrophages to the dorsal root ganglia (DRG) causing neuronal loss and formation of Nageotte nodules. Here, we used an oral form of methylglyoxal-bis-guanylhydrazone (MGBG), a polyamine biosynthesis inhibitor, to specifically reduce activation of myeloid cells. MGBG is selectively taken up by monocyte/macrophages in vitro and inhibits HIV p24 expression and DNA viral integration in macrophages. Here, MGBG was administered to nine SIV-infected, CD8-depleted rhesus macaques at 21days post-infection (dpi). An additional nine SIV-infected, CD8-depleted rhesus macaques were used as untreated controls. Cell traffic to tissues was measured by in vivo BrdU pulse labeling. MGBG treatment significantly diminished DRG histopathology and reduced the number of CD68+ and CD163+ macrophages in DRG tissue. The number of recently trafficked BrdU+ cells in the DRG was significantly reduced with MGBG treatment. Despite diminished DRG pathology, intraepidermal nerve fiber density (IENFD) did not recover after treatment with MGBG. These data suggest that MGBG alleviated DRG pathology and inflammation.

Context In the general population, high-density lipoprotein (HDL) cholesterol efflux capacity (HCEC) relates inversely to incident cardiovascular events. Previous studies have suggested that HCEC is decreased in HIV and that antiretroviral therapy (ART) initiation might improve HCEC. Objective To evaluate HCEC in the context of ART initiation and immune activation in HIV. Design and outcome measures Baseline HCEC from 10 ART-naive HIV-infected males and 12 prospectively matched non-HIV-infected males were analyzed. In the HIV cohort, HCEC 6 months after elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (E/C/F/TDF) therapy was evaluated. HCEC served as the primary outcome and was measured by the ability of J774 mouse macrophages to efflux cholesterol. Our ex vivo assay used two cholesterol acceptors [apolipoprotein B (apoB)-depleted sera or purified HDL] and modulation of cellular efflux pathways using a liver X receptor (LXR) agonist. Results The median age was 34 years [interquartile range (IQR), 27 to 51], and baseline HDL was 46 mg/dL (IQR, 38 to 61). HCEC was significantly greater in the non-HIV-infected subjects than in the HIV-infected subjects at baseline. HCEC, assessed using apoB-depleted sera, significantly increased after ART (no LXR agonist, baseline: median, 8.1%; IQR, 7.0% to 11.9%; after ART: median, 12.9%; IQR, 10.4% to 21.1%; P = 0.006; LXR agonist, baseline, 1.3% ± 1.3%; after ART, 2.5% ± 1.0%; P = 0.02), although not to the levels in the non-HIV-infected subjects (no LXR agonist: median, 14.9%; IQR, 11.5% to 19.1%; LXR agonist: 5.8% ± 1.3%). HCEC, assessed using purified HDL, did not significantly increase after ART. The change in HCEC with ART related inversely to the change in the percentage of CD14-CD16+ (nonclassical) monocytes (ρ = -0.74, P = 0.04) and directly to the change in the percentage of CD14+CD16- (classical) monocytes (ρ = 0.72, P = 0.045). Conclusions Our data suggest improvement of HCEC with E/C/F/TDF and a relationship between the ART-induced decrease in immune activation and ART-induced improvement in HCEC.

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.

Background Despite effective combination antiretroviral therapy, HIV-infected individuals develop comorbidities, including cardiovascular disease, where activated macrophages play a key role. To date, few therapies target activated monocytes and macrophages. Methods We evaluated a novel oral form of the polyamine biosynthesis inhibitor methylglyoxal-bis-guanylhydrazone (MGBG) on cardiovascular inflammation, carotid artery intima-media thickness (cIMT), and fibrosis in a simian immunodeficiency virus infection model of AIDS. Eleven simian immunodeficiency virus-infected animals received MGBG (30 mg/kg) once daily and 8 received a placebo control both beginning at 21 days postinfection (dpi). Animals were time sacrificed at 49 days post infection (dpi), when their matched placebo controls developed AIDS (63, 70, 77, 80), or at the study end-point (84 dpi). Aorta, carotid artery, and cardiac tissues were analyzed. Quantitative analyses of macrophage populations and T lymphocytes were done and correlated with cIMT and fibrosis. Results MGBG treatment resulted in 2.19-fold (CD163), 1.86-fold (CD68), 2.31-fold (CD206), and 2.12-fold (MAC387) decreases in macrophages in carotid arteries and significant 2.07-fold (CD163), 1.61-fold (CD68), 1.95-fold (MAC387), and 1.62-fold (CD206) decreases in macrophages in cardiac tissues. cIMT (1.49-fold) and fibrosis (2.05-fold) also were significantly decreased with MGBG treatment. Numbers of macrophage and the degree of fibrosis in treated animals were similar to uninfected animals. A positive correlation between decreased macrophage in the carotid artery and cIMT, and cardiac macrophages and fibrosis was found. Conclusions These data demonstrate that directly targeting macrophages with MGBG can reduce cardiovascular inflammation, cIMT, and fibrosis. They suggest that therapies targeting macrophages with HIV could be used in conjunction with combination antiretroviral therapy.

Persistent immune activation is thought to contribute to increased cardiovascular disease risk in HIV and statins may help modulate systemic immune activation. We aimed to compare the effects of two key statins on markers of systemic immune activation and arterial inflammation in the HIV population.Double-blind, active-controlled, parallel-group comparative trial performed in 45 sites.Two hundred and fifty-two antiretroviral therapy-treated HIV-infected participants with dyslipidemia were randomized (1 : 1) to pitavastatin 4 mg daily vs. pravastatin 40 mg daily in the HIV-infected patieNts and TREatment with PItavastatin vs. pravastatin for Dyslipidemia (INTREPID) trial. In this analysis of the INTREPID trial, we assessed markers of immune activation and arterial inflammation using a modified intent-to-treat population. This trial is registered with ClinicalTrials.gov (NCT01301066).One hundred and twenty-six participants were randomized to receive pitavastatin and 126 to pravastatin. Ninety-nine participants in the pitavastatin group and 91 participants in the pravastatin group completed the study. Median age was 50 (45, 56) years [median (interquartile range)]. Baseline, low-density lipoprotein-cholestrol (LDL-C) was 153 (135, 171) mg/dl, log HIV-1 viral load was 1.1 ± 0.2 copies/ml, and CD4 cell count was 580 (439, 794) cells/μl. At week 52, the pitavastatin group had a significantly greater reduction (% change) compared with pravastatin in soluble CD14 (sCD14), (-10.0 vs. 0.6%, P = 0.02), oxidized LDL (oxLDL) (-26.9 vs. -17.5%, P = 0.02), and lipoprotein-associated phospholipase 2 (Lp-PLA2) (-26.6 vs. -15.5%, P = 0.005) (pitavastatin vs. pravastatin).Fifty-two weeks of pitavastatin 4 mg daily (vs. pravastatin 40 mg daily) led to a greater reduction in select markers of immune activation and arterial inflammation (sCD14, oxLDL, and LpPLA2) among HIV-infected participants. Further work is needed to assess whether immune-modulatory effects of pitavastatin reduce cardiovascular disease risk in HIV.

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.

Despite the success of combined antiretroviral therapy in controlling viral replication in human immunodeficiency virus (HIV)-infected individuals, HIV-associated neurocognitive disorders, commonly referred to as neuroAIDS, remain a frequent and poorly understood complication. Infection of CD8+lymphocyte-depleted rhesus macaques with the SIVmac251 viral swarm is a well-established rapid disease model of neuroAIDS that has provided critical insight into HIV-1-associated neurocognitive disorder onset and progression. However, no studies so far have characterized in depth the relationship between intra-host viral evolution and pathogenesis in this model. Simian immunodeficiency virus (SIV)env gp120sequences were obtained from six infected animals. Sequences were sampled longitudinally from several lymphoid and non-lymphoid tissues, including individual lobes within the brain at necropsy, for four macaques; two animals were sacrificed at 21 days post-infection (p.i.) to evaluate early viral seeding of the brain. Bayesian phylodynamic and phylogeographic analyses of the sequence data were used to ascertain viral population dynamics and gene flow between peripheral and brain tissues, respectively. A steady increase in viral effective population size, with a peak occurring at ~50–80 days p.i., was observed across all longitudinally monitored macaques. Phylogeographic analysis indicated continual viral seeding of the brain from several peripheral tissues throughout infection, with the last migration event before terminal illness occurring in all macaques from cells within the bone marrow. The results strongly supported the role of infected bone marrow cells in HIV/SIV neuropathogenesis. In addition, our work demonstrated the applicability of Bayesian phylogeography to intra-host studies in order to assess the interplay between viral evolution and pathogenesis.

Telomere length (TL) and immune activation markers were measured in a cohort of HIV-infected (n=102) and age-matched non-HIV-infected (n=41) men. TL was significantly shorter in HIV-infected compared to non-HIV-infected subjects (P = 0.04). Univariate analysis revealed a strong inverse relationship of TL to sCD163, and thus, monocyte/macrophage activation, among the HIV group (ρ = −0.30, P = 0.003). In multivariate modeling among the whole group, HIV positive serostatus (P = 0.06) and sCD163 (P = 0.05) were independent predictors of TL controlling for age and smoking status. Our data demonstrate that increased immune activation relates to shorter TL in HIV.

Objectives. We estimated the distribution of predicted long-term cardiovascular disease (CVD) risk among young adults in the United States. Methods. Our data were derived from National Longitudinal Study of Adolescent Health participants (n = 14 333; average age: 28.9 years). We used a Framingham-derived risk prediction function to calculate 30-year risks of “hard” and “general” CVD by gender and race/ethnicity. Results. Average 30-year risks for hard and general CVD were 10.4% (95% confidence interval [CI] = 10.1%, 10.7%) and 17.3% (95% CI = 17.0%, 17.7%) among men and 4.4% (95% CI = 4.3%, 4.6%) and 9.2% (95% CI = 8.9%, 9.5%) among women. Average age-adjusted risks of hard and general CVD were higher among Blacks and American Indians than among Whites and lower among Asian/Pacific Islander women than White women. American Indian men continued to have a higher risk of general CVD after adjustment for socioeconomic status. Four percent of women (95% CI = 3.6%, 5.0%) and 26.2% of men (95% CI = 24.7%, 27.8%) had a 20% or higher risk of general CVD. Racial differences were detected but were not significant after adjustment for socioeconomic status. Conclusions. Average CVD risk among young adults is high. Population-based prevention strategies and improved detection and treatment of high-risk individuals are needed to reduce the future burden of CVD.

The role of macrophage activation, traffic, and accumulation on cardiac pathology was examined in 23 animals. Seventeen animals were simian immunodeficiency virus (SIV) infected, 12 were CD8 lymphocyte depleted, and the remaining six were uninfected controls (two CD8 lymphocyte depleted, four nondepleted). None of the uninfected controls had cardiac pathology. One of five (20%) SIV-infected, non-CD8 lymphocyte-depleted animals had minor cardiac pathology with increased numbers of macrophages in ventricular tissue compared to controls. Seven of the 12 (58%) SIV-infected, CD8 lymphocyte-depleted animals had cardiac pathology in ventricular tissues, including macrophage infiltration and myocardial degeneration. The extent of fibrosis (measured as the percentage of collagen per tissue area) was increased 41% in SIV-infected, CD8 lymphocyte-depleted animals with cardiac pathology compared to animals without pathological abnormalities. The number of CD163+ macrophages increased significantly in SIV-infected, CD8 lymphocyte-depleted animals with cardiac pathology compared to ones without pathology (1.66-fold) and controls (5.42-fold). The percent of collagen (percentage of collagen per total tissue area) positively correlated with macrophage numbers in ventricular tissue in SIV-infected animals. There was an increase of BrdU+ monocytes in the heart during late SIV infection, regardless of pathology. These data implicate monocyte/macrophage activation and accumulation in the development of cardiac pathology with SIV infection.

Laser capture microdissection (LCM) is used to extract cells or tissue regions for analysis of RNA, DNA or protein. Several methods of LCM are established for different applications, but a protocol for consistently obtaining lentiviral RNA from LCM captured immune cell populations is not described. Obtaining optimal viral RNA for analysis of viral genes from immune-captured cells using immunohistochemistry (IHC) and LCM is challenging. IHC protocols have long antibody incubation times that increase risk of RNA degradation. But, immune capture of specific cell populations like macrophages without staining for virus cannot result in obtaining only a fraction of cells which are productively lentivirally infected. In this study we sought to obtain simian immunodeficiency virus (SIV) RNA from SIV gp120+ and CD68+ monocyte/macrophages in bone marrow (BM) and CD163+ perivascular macrophages in brain of SIV-infected rhesus macaques. Here, we report an IHC protocol with RNase inhibitors that consistently results in optimal quantity and yield of lentiviral RNA from LCM-captured immune cells.

Background Proprotein convertase subtilisin/kexin 9 (PCSK9) is known to mediate homeostasis of low-density lipoprotein cholesterol (LDL-c), but it may also participate in immune reactivity and atherogenesis. Methods We compared circulating PCSK9 levels among asymptomatic individuals with and without HIV. Further, within each group, we assessed the relationship between PCSK9 levels, traditional cardiovascular disease risk factors, immune activation, and subclinical coronary atherosclerotic plaque. Results PCSK9 levels were higher among HIV-infected (n = 149) vs matched non-HIV-infected subjects (n = 69; 332 [272, 412] ng/mL vs 304 [257, 375] ng/mL; P = .047). Among HIV-infected subjects, significant albeit modest positive associations were noted between PCSK9 levels and markers of systemic monocyte activation including sCD14 (rho = 0.22; P = .009) and sCD163 (rho = 0.23; P = .006). In this group, PCSK9 levels related weakly to LDL-c (rho = 0.16; P = .05) and also to Framingham Point Score but did not relate to subclinical coronary atherosclerotic plaque parameters. Conclusions Among HIV-infected individuals, circulating PCSK9 levels are elevated and related to systemic markers of monocyte activation but not to coronary plaque parameters. Additional studies are needed to determine the effects of PCSK9 on immune activation and atherogenesis in HIV and to assess whether PCSK9 inhibition reduces immune activation and coronary atherosclerotic plaque burden. Clinical Trial Registration NCT00455793.

OBJECTIVES We sought to describe blood pressure (BP) changes after antiretroviral therapy (ART) initiation and evaluate the association of markers of inflammation with incident hypertension in a cohort of HIV-infected individuals in Uganda. METHODS We used mixed effects linear regression to model changes in systolic BP over time among a cohort of HIV-infected individuals initiating ART in Uganda. After exclusion of participants with preexisting hypertension, we identified participants with normal BP throughout follow-up (controls) and those with elevated BP on ≥3 consecutive visits (cases). Before ART initiation, participants had testing for interleukin 6, kynurenine/tryptophan ratio, lipopolysaccharide, soluble CD14, soluble CD163, and D-dimer and those with viral suppression at 6 months during ART had repeat tests. We fit logistic regression models to estimate associations between biomarkers and risk of incident hypertension. RESULTS In the entire cohort, systolic BP increased by 9.6 mm Hg/yr (95% CI: 7.3 to 11.8) in the first 6 months of ART, then plateaued. Traditional factors: male gender (adjusted odds ratio (AOR) 2.76, 95% CI: 1.34 to 5.68), age (AOR 1.09, 95% CI: 1.04 to 1.13), overweight (AOR 4.48, 95% CI: 1.83 to 10.97), and a CD4 count

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.

Traffic of activated monocytes into the dorsal root ganglia (DRG) is critical for pathology in HIV peripheral neuropathy. We have shown that accumulation of recently recruited (bromodeoxyuridine + MAC387 + ) monocytes is associated with severe DRG pathology and loss of intraepidermal nerve fibers in SIV-infected macaques. Herein, we blocked leukocyte traffic by treating animals with natalizumab, which binds to α4-integrins. SIV-infected CD8-depleted macaques treated with natalizumab either early (the day of infection) or late (28 days after infection) were compared with untreated SIV-infected animals sacrificed at similar times. Histopathology showed diminished DRG pathology with natalizumab treatment, including decreased inflammation, neuronophagia, and Nageotte nodules. Natalizumab treatment resulted in a decrease in the number of bromodeoxyuridine + (early), MAC387 + (late), CD68 + (early and late), and SIVp28 + (late) macrophages in DRG tissues. The number of CD3 + T lymphocytes in DRGs was not affected by natalizumab treatment. Vascular cell adhesion molecule 1, an adhesion molecule that mediates leukocyte traffic, was diminished in DRGs of all natalizumab-treated animals. These data show that blocking monocyte, but not T lymphocyte, traffic to the DRG results in decreased inflammation and pathology, supporting a role for monocyte traffic and activation in HIV peripheral neuropathy.

HIV-1 elite controllers spontaneously maintain suppressed levels of viremia, but exhibit significant immune activation. We investigated coronary atherosclerosis by coronary computed tomography angiography (CTA) in elite controllers, nonelite controller, chronically HIV-1 infected, antiretroviral therapy (ART)-treated patients with undetectable viral load ('chronic HIV'), and HIV-negative controls. Prevalence of atherosclerosis (78 vs. 42%, P < 0.05) and markers of immune activation were increased in elite controllers compared with HIV-negative controls. sCD163, a monocyte activation marker, was increased in elite controllers compared with chronic HIV-1 (P < 0.05) and compared with HIV-negative controls (P < 0.05). These data suggest a significant degree of coronary atherosclerosis and monocyte activation among elite controllers.

Summary Context The relationship of monocyte/macrophage activation to insulin resistance in obesity is unknown. Objective To investigate a marker of macrophage activation, soluble CD163 (sCD163), in relationship to insulin resistance and metabolic parameters in obese and normal-weight subjects. Design and Participants Ninety-five healthy subjects (65 obese and 30 normal-weight) were studied. Plasma concentrations of sCD163 were assessed, as well as markers of glucose homeostasis, anthropometrics, cytokines and adipokines. The relationships between sCD163 and these parameters were investigated, and multiple regression modelling assessing the contribution of sCD163 to insulin resistance (HOMA-IR) was performed. Results Soluble CD163 was significantly increased in obese subjects compared with normal-weight controls [974 (657, 1272) ng/ml vs 599 (423, 892) ng/ml, median (IQR); P

HIV-associated sensory neuropathy (HIV-SN) is currently the most common neurological complication of chronic HIV infection and continues to substantially affect patient quality of life. Mechanisms underlying the neuronal damage and loss observed in sensory ganglia of HIV-infected individuals have not been sufficiently studied. The present study aimed to develop and characterize a model of HIV-SN using SIV-infected CD8 T-lymphocyte-depleted rhesus macaques (Macaca mulatta). Uninfected controls (n = 5), SIV-infected CD8-depleted (n = 4), and SIV-infected non-CD8-depleted (n = 6) animals were used. Of the six non-CD8-depleted animals, three were conventional progressors (progressing to AIDS >1 year after infection) and three were rapid progressors (AIDS within 6 months). Dorsal root ganglia (DRG) were examined for histological hallmarks of HIV-SN, including satellitosis, presence of Nageotte nodules, and neuronophagia, as well as increased numbers of CD68+ macrophages and abundant viral replication. In contrast to non-CD8-depleted animals, which had mild to moderate DRG pathology, the CD8-depleted SIV-infected animals had moderate to severe DRG damage, with increased numbers of CD68+ satellite cells. Additionally, there was marked active viral replication in the affected DRG. These findings confirm that many features of HIV-SN can be recapitulated in the CD8-depleted SIV-infected rhesus macaque model within a short time frame and illustrate the importance of this model for study of sensory neuropathy.