Publications by authors named "Tricia Burdo"

108 Publications

Hot Flashes and Cardiovascular Disease Risk Indices Among Women With HIV.

Open Forum Infect Dis 2021 Feb 12;8(2):ofab011. Epub 2021 Jan 12.

Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Women with HIV (WWH) transitioning through menopause have heightened cardiovascular disease (CVD) risk. In the general population, hot flash burden relates to CVD risk indices. We found higher hot flash burden among women with vs without HIV. Further, among WWH, hot flash burden related to select CVD risk indices.

Clinicaltrialsgov Registration: NCT02874703.
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http://dx.doi.org/10.1093/ofid/ofab011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7863866PMC
February 2021

Pro-Inflammatory Interleukin-18 is Associated with Hepatic Steatosis and Elevated Liver Enzymes in People with HIV Monoinfection.

AIDS Res Hum Retroviruses 2021 Jan 25. Epub 2021 Jan 25.

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

People with HIV (PWH) are at an increased risk of developing nonalcoholic fatty liver disease (NAFLD). Interleukin (IL)-18 is regulated by inflammasomes in response to pathogens and danger signals and has been implicated in both the pathogenesis of NAFLD and HIV disease progression. We hypothesized that increased IL-18 may be associated with NAFLD and liver injury in PWH. This was an observational study of 125 PWH and 59 individuals without HIV in the Boston area. Participants with known hepatitis B, hepatitis C, and excessive alcohol use were excluded. IL-18 was measured in serum by enzyme-linked immunosorbent assay. Liver lipid content was assessed by liver-to-spleen computed tomography (CT) attenuation ratio. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), and IL-18 levels were higher in PWH than in controls. In PWH, log IL-18 was associated with logAST ( = 0.34,  = .0001), logALT ( = 0.33,  = .0002), logHIV RNA ( = 0.29,  = .002), and inversely associated with liver-to-spleen ratio ( = -0.24,  = .02). In addition, log IL-18 was associated with log triglycerides ( = 0.26,  = .003), log MCP-1 (monocyte chemoattractant protein-1;  = 0.33,  = .0004), logcaspase-1 ( = 0.35,  < .0001), logLPS ( = 0.28,  = .004), and inversely associated with high-density lipoprotein ( = -0.28,  = .002), and CD4/CD8 T cell ratio ( = -0.24,  = .007). In controls without HIV, log IL-18 was also associated with logALT ( = 0.44,  = .0005). After adjusting for potential confounders, the relationships between IL-18 and AST ( = .004) and ALT ( = .003) remained significant, and the relationship between IL-18 and liver-to-spleen ratio ( = .02). Increased inflammasome activation and subsequent monocyte recruitment in PWH may contribute to the development and progression of NAFLD. Clinical Trials Registration. NCT00455793.
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http://dx.doi.org/10.1089/AID.2020.0177DOI Listing
January 2021

CRISPR based editing of SIV proviral DNA in ART treated non-human primates.

Nat Commun 2020 11 27;11(1):6065. Epub 2020 Nov 27.

Department of Neuroscience, Center for Neurovirology, Lewis Katz School of Medicine at Temple University, 3500N. Broad Street, 7th Floor, Philadelphia, PA, 19140, USA.

Elimination of HIV DNA from infected individuals remains a challenge in medicine. Here, we demonstrate that intravenous inoculation of SIV-infected macaques, a well-accepted non-human primate model of HIV infection, with adeno-associated virus 9 (AAV9)-CRISPR/Cas9 gene editing construct designed for eliminating proviral SIV DNA, leads to broad distribution of editing molecules and precise cleavage and removal of fragments of the integrated proviral DNA from the genome of infected blood cells and tissues known to be viral reservoirs including lymph nodes, spleen, bone marrow, and brain among others. Accordingly, AAV9-CRISPR treatment results in a reduction in the percent of proviral DNA in blood and tissues. These proof-of-concept observations offer a promising step toward the elimination of HIV reservoirs in the clinic.
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http://dx.doi.org/10.1038/s41467-020-19821-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695718PMC
November 2020

Characterization of Nef expression in different brain regions of SIV-infected macaques.

PLoS One 2020 2;15(11):e0241667. Epub 2020 Nov 2.

Department of Neuroscience, Center for Neurovirology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, United States of America.

Objective: HIV-associated CNS dysfunction is a significant problem among people with HIV (PWH), who now live longer due to viral suppression from combined anti-retroviral therapy (ART). Over the course of infection, HIV generates toxic viral proteins and induces inflammatory cytokines that have toxic effects on neurons in the CNS. Among these viral proteins, HIV Nef has been found in neurons of postmortem brain specimens from PWH. However, the source of Nef and its impact on neuronal cell homeostasis are still elusive.

Methods And Results: Here, in using a simian immunodeficiency virus (SIV) infected rhesus macaque model of neuroHIV, we find SIV Nef reactivity in the frontal cortex, hippocampus and cerebellum of SIV-infected animals using immunohistochemistry (IHC). Interestingly, SIV-infected macaques treated with ART also showed frequent Nef positive cells in the cerebellum and hippocampus. Using dual quantitative RNAscope and IHC, we observed cells that were positive for Nef, but were not for SIV RNA, suggesting that Nef protein is present in cells that are not actively infected with SIV. Using cell specific markers, we observed Nef protein in microglia/macrophages and astrocytes. Importantly, we also identified a number of NeuN-positive neurons, which are not permissive to SIV infection, but contained Nef protein. Further characterization of Nef-positive neurons showed caspase 3 activation, indicating late stage apoptosis in the CNS neurons.

Conclusions: Our results suggest that regardless of ART status, Nef is expressed in the brain of SIV infected macaques and may contribute to neurological complications seen in PWH.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241667PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605674PMC
December 2020

Effects of Integrase Inhibitor-Based ART on the NLRP3 Inflammasome Among ART-Naïve People With HIV.

Open Forum Infect Dis 2020 Oct 29;7(10):ofaa459. Epub 2020 Sep 29.

Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

The NOD-like receptor protein family pyrin domain containing 3 (NLRP3) inflammasome, activated in the setting of HIV, contributes to pro-atherogenic inflammation. Among antriretroviral therapy-naïve people with HIV (vs controls), levels of caspase-1-a key component of the NLRP3 inflammasome-were significantly increased. Six months of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate significantly decreased caspase-1 levels in association with CD4+/CD8+ ratio recovery.

. ClinicalTrials.gov NCT01766726.
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http://dx.doi.org/10.1093/ofid/ofaa459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7588107PMC
October 2020

Asymptomatic Malaria Co-infection of HIV-Infected Adults in Nigeria: Prevalence of and Impact on Cognition, Mood, and Biomarkers of Systemic Inflammation.

J Acquir Immune Defic Syndr 2021 Jan;86(1):91-97

University of Maryland, School of Medicine, Baltimore, MD.

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.
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http://dx.doi.org/10.1097/QAI.0000000000002516DOI Listing
January 2021

Pathogenesis of Aging and Age-related Comorbidities in People with HIV: Highlights from the HIV ACTION Workshop.

Pathog Immun 2020 17;5(1):143-174. Epub 2020 Jun 17.

Department of Medicine; University of California; San Francisco, California.

People with HIV (PWH) experience accentuated biological aging, as defined by markers of inflammation, immune dysfunction, and the epigenetic clock. They also have an elevated risk of multiple age-associated comorbidities. To discuss current knowledge, research gaps, and priorities in aging and age-related comorbidities in treated HIV infection, the NIH program staff organized a workshop held in Bethesda, Maryland in September 2019. This review article describes highlights of discussions led by the Pathogenesis/Basic Science Research working group that focused on three high priority topics: immunopathogenesis; the microbiome/virome; and aging and senescence. We summarize knowledge in these fields and describe key questions for research on the pathogenesis of aging and age-related comorbidities in PWH. Understanding the drivers and mechanisms underlying accentuated biological aging is a high priority that will help identify potential therapeutic targets to improve healthspan in older PWH.
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http://dx.doi.org/10.20411/pai.v5i1.365DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7449259PMC
June 2020

Comparison of [11C]-PBR28 Binding Between Persons Living With HIV and HIV-Uninfected Individuals.

J Acquir Immune Defic Syndr 2020 10;85(2):244-251

Department of Neurology, Washington University in St. Louis, St. Louis, MO.

Objective: Despite combined antiretroviral therapy, neuroinflammation may persist in persons living with HIV (PLWH) and contribute to cognitive impairment in this population. Positron emission tomography (PET) imaging targeting 18 kDa translocator protein (TSPO) has been used to localize neuroinflammation. We aimed to use TSPO-PET imaging to evaluate neuroinflammation in PLWH.

Design: Twenty-four virologically suppressed PLWH on combined antiretroviral therapy and 13 HIV-negative (HIV-) controls completed TSPO-PET imaging using the radiotracer [C]PBR28. Because of tracer complexity and differing procedures used in previous studies, we employed an expansive methodological approach, using binding potential (BP) and standard uptake value ratio and multiple different reference regions to estimate [C]PBR28 binding.

Methods: [C]PBR28 binding was measured in 30 cortical and subcortical regions and compared between PLWH and HIV- controls. Pearson correlation evaluated the association between [C]PBR28 binding and cognition and clinical measures of HIV.

Results: Analyses conducted using multiple reference regions and measures of tracer uptake revealed no significant differences between [C]PBR28 binding in PLWH compared with HIV- controls. In addition, [C]PBR28 binding in PLWH was not significantly associated with clinical measures of HIV or plasma biomarkers of inflammation. [C]PBR28 binding was not significantly elevated in cognitively impaired PLWH compared with unimpaired PLWH, but there were inverse relationships between cognitive performance (executive and global function) and [C]PBR28 binding in PLWH.

Conclusions: Our results suggest that neuroinflammation may play a role in cognitive deficits, but overall neuroinflammatory levels as measured by TSPO-PET imaging in PLWH are not significantly different from those seen in HIV- controls.
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http://dx.doi.org/10.1097/QAI.0000000000002435DOI Listing
October 2020

Correlates and Timing of Reproductive Aging Transitions in a Global Cohort of Midlife Women With Human Immunodeficiency Virus: Insights From the REPRIEVE Trial.

J Infect Dis 2020 07;222(Suppl 1):S20-S30

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Background: Reproductive aging may contribute to cardiometabolic comorbid conditions. We integrated data on gynecologic history with levels of an ovarian reserve marker (anti-müllerian hormone [AMH)] to interrogate reproductive aging patterns and associated factors among a subset of cisgender women with human immunodeficiency virus (WWH) enrolled in the REPRIEVE trial.

Methods: A total of 1449 WWH were classified as premenopausal (n = 482) (menses within 12 months; AMH level ≥20 pg/mL; group 1), premenopausal with reduced ovarian reserve (n = 224) (menses within 12 months; AMH <20 pg/mL; group 2), or postmenopausal (n = 743) (no menses within12 months; AMH <20 pg/mL; group 3). Proportional odds models, adjusted for chronologic age, were used to investigate associations of cardiometabolic and demographic parameters with reproductive aging milestones (AMH <20 pg/mL or >12 months of amenorrhea). Excluding WWH with surgical menopause, age at final menstrual period was summarized for postmenopausal WWH (group 3) and estimated among all WWH (groups 1-3) using an accelerated failure-time model.

Results: Cardiometabolic and demographic parameters associated with advanced reproductive age (controlling for chronologic age) included waist circumference (>88 vs ≤88 cm) (odds ratio [OR], 1.38; 95% confidence interval, 1.06-1.80; P = .02), hemoglobin (≥12 vs <12 g/dL) (2.32; 1.71-3.14; P < .01), and region of residence (sub-Saharan Africa [1.50; 1.07-2.11; P = .02] and Latin America and the Caribbean [1.59; 1.08-2.33; P = .02], as compared with World Health Organization Global Burden of Disease high-income regions). The median age (Q1, Q3) at the final menstrual period was 48 (45, 51) years when described among postmenopausal WWH, and either 49 (46, 52) or 50 (47, 53) years when estimated among all WWH, depending on censoring strategy.

Conclusions: Among WWH in the REPRIEVE trial, more advanced reproductive age is associated with metabolic dysregulation and region of residence. Additional research on age at menopause among WWH is needed.

Clinical Trials Registration: NCT0234429.
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http://dx.doi.org/10.1093/infdis/jiaa214DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347076PMC
July 2020

Myocardial Steatosis Among Antiretroviral Therapy-Treated People With Human Immunodeficiency Virus Participating in the REPRIEVE Trial.

J Infect Dis 2020 07;222(Suppl 1):S63-S69

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA.

Background: People with human immunodeficiency virus (PWH) face increased risks for heart failure and adverse heart failure outcomes. Myocardial steatosis predisposes to diastolic dysfunction, a heart failure precursor. We aimed to characterize myocardial steatosis and associated potential risk factors among a subset of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) participants.

Methods: Eighty-two PWH without known heart failure successfully underwent cardiovascular magnetic resonance spectroscopy, yielding data on intramyocardial triglyceride (IMTG) content (a continuous marker for myocardial steatosis extent). Logistic regression models were applied to investigate associations between select clinical characteristics and odds of increased or markedly increased IMTG content.

Results: Median (Q1, Q3) IMTG content was 0.59% (0.28%, 1.15%). IMTG content was increased (> 0.5%) among 52% and markedly increased (> 1.5%) among 22% of participants. Parameters associated with increased IMTG content included age (P = .013), body mass index (BMI) ≥ 25 kg/m2 (P = .055), history of intravenous drug use (IVDU) (P = .033), and nadir CD4 count < 350 cells/mm³ (P = .055). Age and BMI ≥ 25 kg/m2 were additionally associated with increased odds of markedly increased IMTG content (P = .049 and P = .046, respectively).

Conclusions: A substantial proportion of antiretroviral therapy-treated PWH exhibited myocardial steatosis. Age, BMI ≥ 25 kg/m2, low nadir CD4 count, and history of IVDU emerged as possible risk factors for myocardial steatosis in this group.

Clinical Trials Registration: NCT02344290; NCT03238755.
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http://dx.doi.org/10.1093/infdis/jiaa245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347082PMC
July 2020

Brief Report: Vascular Dysfunction and Monocyte Activation Among Women With HIV.

J Acquir Immune Defic Syndr 2020 10;85(2):233-238

Metabolism Unit, Division of Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Objective: Women with HIV (WHIV) on antiretroviral therapy (ART) face an increased risk of cardiovascular disease (CVD) in the context of heightened systemic immune activation. Aortic stiffness, a measure of vascular dysfunction and a robust predictor of CVD outcomes, is highly influenced by immune activation. We compared aortic stiffness among women with and without HIV and examined interrelationships between aortic stiffness and key indices of systemic immune activation.

Methods: Twenty WHIV on ART and 14 women without HIV group-matched on age and body mass index (BMI) were prospectively recruited and underwent cardiovascular magnetic resonance imaging, as well as metabolic and immune phenotyping.

Results: Age and BMI did not differ significantly across groups (age: 52 ± 4 vs. 53 ± 6 years; BMI: 32 ± 7 vs. 32 ± 7 kg/m). Aortic pulse wave velocity (aPWV) was higher among WHIV (8.6 ± 1.3 vs. 6.5 ± 1.3 m/s, P < 0.0001), reflecting increased aortic stiffness. Among the whole group and among WHIV, aPWV related to sCD163 levels (whole group: R = 0.65, P < 0.0001; WHIV: R = 0.73, P = 0.0003) and to myocardial fibrosis (extracellular volume; whole group: R = 0.54, P = 0.001; WHIV: R = 0.47, P = 0.04). Both HIV status and sCD163 levels independently predicted aPWV, controlling for age, BMI, cigarette smoking status, and systolic blood pressure (HIV status: β-estimate = 0.69, 95% CI [0.1 to 1.3], P = 0.02; sCD163: β-estimate = 0.002, 95% CI [0.0006 to 0.004], P = 0.01). Among WHIV, sCD163 levels independently predicted aPWV, controlling for duration of HIV, CD4 count, and HIV viral load (sCD163: β-estimate = 0.004, 95% CI [0.002 to 0.005], P = 0.0005).

Conclusions: Asymptomatic WHIV on ART have increased aortic stiffness as compared to matched control subjects. Among WHIV, aPWV related to heightened monocyte activation (sCD163) and to downstream CVD pathology (myocardial fibrosis). CLINICALTRIALS.

Gov Registration: NCT02874703.
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http://dx.doi.org/10.1097/QAI.0000000000002419DOI Listing
October 2020

Atrophy and Death of Nonpeptidergic and Peptidergic Nociceptive Neurons in SIV Infection.

Am J Pathol 2020 07 1;190(7):1530-1544. Epub 2020 Apr 1.

Department of Neuroscience, Temple University, Lewis Katz School of Medicine, Philadelphia, Pennsylvania. Electronic address:

HIV-associated sensory neuropathy is a common neurologic comorbidity of HIV infection and prevails in the post-antiretroviral therapy (ART) era. HIV infection drives pathologic changes in the dorsal root ganglia (DRG) through inflammation, altered metabolism, and neuronal dysfunction. Herein, we characterized specific neuronal populations in an SIV-infected macaque model with or without ART. DRG neuronal populations were identified by neurofilament H-chain 200, I-B isolectin (IB4), or tropomyosin receptor kinase A expression and assessed for cell body diameter, population size, apoptotic markers, and regeneration signaling. IB4 and tropomyosin receptor kinase A-positive neurons showed a reduced cell body size (atrophy) and decreased population size (cell death) in the DRG of SIV-infected animals compared with uninfected animals. IB4 nonpeptidergic neurons were less affected in the presence of ART. DRG neurons showed accumulation of cleaved caspase 3 (apoptosis) and nuclear-localized activating transcription factor 3 (regeneration) in SIV infection, which was significantly lower in uninfected animals and SIV-infected animals receiving ART. Nonpeptidergic neurons predominantly colocalized with cleaved caspase 3 staining. Nonpeptidergic and peptidergic neurons colocalized with nuclear-accumulated activating transcription factor 3, showing active regeneration in sensory neurons. These data suggest that nonpeptidergic and peptidergic neurons are susceptible to pathologic changes from SIV infection, and intervention with ART did not fully ameliorate damage to the DRG, specifically to peptidergic neurons.
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http://dx.doi.org/10.1016/j.ajpath.2020.03.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7322364PMC
July 2020

Magnetic resonance imaging of neuroinflammation in chronic pain: a role for astrogliosis?

Pain 2020 07;161(7):1555-1564

Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States.

Noninvasive measures of neuroinflammatory processes in humans could substantially aid diagnosis and therapeutic development for many disorders, including chronic pain. Several proton magnetic resonance spectroscopy (H-MRS) metabolites have been linked with glial activity (ie, choline and myo-inositol) and found to be altered in chronic pain patients, but their role in the neuroinflammatory cascade is not well known. Our multimodal study evaluated resting functional magnetic resonance imaging connectivity and H-MRS metabolite concentration in insula cortex in 43 patients suffering from fibromyalgia, a chronic centralized pain disorder previously demonstrated to include a neuroinflammatory component, and 16 healthy controls. Patients demonstrated elevated choline (but not myo-inositol) in anterior insula (aIns) (P = 0.03), with greater choline levels linked with worse pain interference (r = 0.41, P = 0.01). In addition, reduced resting functional connectivity between aIns and putamen was associated with both pain interference (whole brain analysis, pcorrected < 0.01) and elevated aIns choline (r = -0.37, P = 0.03). In fact, aIns/putamen connectivity statistically mediated the link between aIns choline and pain interference (P < 0.01), highlighting the pathway by which neuroinflammation can impact clinical pain dysfunction. To further elucidate the molecular substrates of the effects observed, we investigated how putative neuroinflammatory H-MRS metabolites are linked with ex vivo tissue inflammatory markers in a nonhuman primate model of neuroinflammation. Results demonstrated that cortical choline levels were correlated with glial fibrillary acidic protein, a known marker for astrogliosis (Spearman r = 0.49, P = 0.03). Choline, a putative neuroinflammatory H-MRS-assessed metabolite elevated in fibromyalgia and associated with pain interference, may be linked with astrogliosis in these patients.
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http://dx.doi.org/10.1097/j.pain.0000000000001815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305954PMC
July 2020

Antiretroviral Therapy Adherence Interruptions Are Associated With Systemic Inflammation Among Ugandans Who Achieved Viral Suppression.

J Acquir Immune Defic Syndr 2019 12;82(4):386-391

Massachusetts General Hospital and Harvard Medical School, Boston, MA.

Background: Residual systemic inflammation, which is associated with non-AIDS clinical outcomes, may persist despite viral suppression. We assessed the effect of antiretroviral therapy (ART) adherence interruptions on systemic inflammation among Ugandans living with HIV who were virally suppressed.

Setting: We evaluated adults initiating first-line ART at a regional referral hospital clinic in Mbarara, Uganda.

Methods: Plasma concentrations of interleukin-6 (IL-6), D-dimer, soluble sCD14, sCD163, the kynurenine/tryptophan (K/T) ratio, and CD8 T-cell activation (HLA-DR/CD38 coexpression) were measured at baseline and 6 months after ART initiation among participants who achieved viral suppression (<400 copies/mL) at 6 months. ART adherence was monitored electronically. Time spent in an adherence interruption was computed as the percentage of days when the running average adherence was ≤10%. We fit adjusted linear regressions to evaluate the effect of time spent in an interruption on the log-transformed plasma concentrations of the inflammation biomarkers.

Results: Of 282 participants, 70% were women, and the median age was 34 years. At baseline, median CD4 and median log viral load were 135 cells per microliter and 5.1 copies per milliliter, respectively. In the adjusted analysis, a running average adherence of <10% was associated with higher sCD14 (+3%; P < 0.008), sCD163 (+5%; P = 0.002), D-dimer (+10%; P = 0.007), HLA-DR/CD8 (+3%; P < 0.025), IL-6 (+14%; P = 0.008), and K:T ratio (+5%; P = 0.002). These findings were largely robust to adjustment for average adherence, as well as higher thresholds of running average adherence, albeit with decreased statistical significance.

Conclusions: Increased time spent in adherence interruptions is associated with increased levels of inflammation, despite viral suppression above and beyond average adherence.
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http://dx.doi.org/10.1097/QAI.0000000000002148DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6820698PMC
December 2019

Suppression of Zika Virus Infection in the Brain by the Antiretroviral Drug Rilpivirine.

Mol Ther 2019 12 11;27(12):2067-2079. Epub 2019 Oct 11.

Department of Neuroscience, Center for Neurovirology, Lewis Katz School of Medicine at Temple University, 3500 N. Broad Street, Philadelphia, PA 19140, USA. Electronic address:

Zika virus (ZIKV) infection is associated with microcephaly in neonates and Guillain-Barré syndrome in adults. ZIKV produces a class of nonstructural (NS) regulatory proteins that play a critical role in viral transcription and replication, including NS5, which possesses RNA-dependent RNA polymerase (RdRp) activity. Here we demonstrate that rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor (NNRTI) used in the treatment of HIV-1 infection, inhibits the enzymatic activity of NS5 and suppresses ZIKV infection and replication in primary human astrocytes. Similarly, other members of the NNRTI family, including etravirine and efavirenz, showed inhibitory effects on viral infection of brain cells. Site-directed mutagenesis identified 14 amino acid residues within the NS5 RdRp domain (AA265-903), which are important for the RPV interaction and the inhibition of NS5 polymerase activity. Administration of RPV to ZIKV-infected interferon-alpha/beta receptor (IFN-A/R) knockout mice improved the clinical outcome and prevented ZIKV-induced mortality. Histopathological examination of the brains from infected animals revealed that RPV reduced ZIKV RNA levels in the hippocampus, frontal cortex, thalamus, and cerebellum. Repurposing of NNRTIs, such as RPV, for the inhibition of ZIKV replication offers a possible therapeutic strategy for the prevention and treatment of ZIKV-associated disease.
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http://dx.doi.org/10.1016/j.ymthe.2019.10.006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6904669PMC
December 2019

HIV-Associated Neurocognitive Impairment in the Modern ART Era: Are We Close to Discovering Reliable Biomarkers in the Setting of Virological Suppression?

Front Aging Neurosci 2019 2;11:187. Epub 2019 Aug 2.

Infectious Disease Unit, Department of Internal Medicine, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.

The prevalence of the most severe forms of HIV-associated neurocognitive disorders (HAND) is decreasing due to worldwide availability and high efficacy of antiretroviral treatment (ART). However, several grades of HIV-related cognitive impairment persist with effective ART and remain a clinical concern for people with HIV (PWH). The pathogenesis of these cognitive impairments has yet to be fully understood and probably multifactorial. In PWH with undetectable peripheral HIV-RNA, the presence of viral escapes in cerebrospinal fluid (CSF) might explain a proportion of cases, but not all. Many other mechanisms have been hypothesized to be involved in disease progression, in order to identify possible therapeutic targets. As potential indicators of disease staging and progression, numerous biomarkers have been used to characterize and implicate chronic inflammation in the pathogenesis of neuronal injuries, such as certain phenotypes of activated monocytes/macrophages, in the context of persistent immune activation. Despite none of them being disease-specific, the correlation of several CSF cellular biomarkers to HIV-induced neuronal damage has been investigated. Furthermore, recent studies have been evaluating specific microRNA (miRNA) profiles in the CSF of PWH with neurocognitive impairment (NCI). The aim of the present study is to review the body of evidence on different biomarkers use in research and clinical settings, focusing on PWH on ART with undetectable plasma HIV-RNA.
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http://dx.doi.org/10.3389/fnagi.2019.00187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6687760PMC
August 2019

Intramyocardial Triglycerides Among Women With vs Without HIV: Hormonal Correlates and Functional Consequences.

J Clin Endocrinol Metab 2019 12;104(12):6090-6100

Metabolism Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Context: Women with HIV (WHIV) on anti-retroviral therapy (ART) are living longer but facing heightened vulnerability to heart failure.

Objective: We investigated metabolic/hormonal/immune parameters relating to diastolic dysfunction-a precursor to heart failure-among WHIV without known cardiovascular disease (CVD).

Design And Outcome Measures: Nineteen ART-treated WHIV and 11 non-HIV-infected women without known CVD enrolled and successfully completed relevant study procedures [cardiac magnetic resonance spectroscopy (MRS) and cardiac MRI]. Groups were matched on age and body mass index. Primary outcome measures included intramyocardial triglyceride content (cardiac MRS) and diastolic function (cardiac MRI). Relationships between intramyocardial triglyceride content and clinical parameters were also assessed.

Results: Among WHIV (vs non-HIV-infected women), intramyocardial triglyceride content was threefold higher [1.2 (0.4, 3.1) vs 0.4 (0.1, 0.5)%, P = 0.01], and diastolic function was reduced (left atrial passive ejection fraction: 27.2 ± 9.6 vs 35.9 ± 6.4%, P = 0.007). There was a strong inverse relationship between intramyocardial triglyceride content and diastolic function (ρ = -0.62, P = 0.004). Among the whole group, intramyocardial triglyceride content did not relate to chronologic age but did increase across the reproductive aging spectrum (P = 0.02). HIV status and reproductive aging status remained independent predictors of intramyocardial triglyceride content after adjusting for relevant cardiometabolic parameters (overall model R2 = 0.56, P = 0.003; HIV status P = 0.01, reproductive aging status P = 0.02).

Conclusions: For asymptomatic WHIV, increased intramyocardial triglyceride content is associated with diastolic dysfunction. Moreover, relationships between intramyocardial triglyceride accumulation and women's reproductive aging are noted.
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http://dx.doi.org/10.1210/jc.2019-01096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954489PMC
December 2019

Caspase-1 Activation Is Related With HIV-Associated Atherosclerosis in an HIV Transgenic Mouse Model and HIV Patient Cohort.

Arterioscler Thromb Vasc Biol 2019 09 18;39(9):1762-1775. Epub 2019 Jul 18.

From the Department of Neuroscience, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (A.C.K., F.L., S.D., J.A.R., E.K., X.P., J.G., T.H.B., X.Q.).

Objective: Atherosclerotic cardiovascular disease (ASCVD) is an increasing cause of morbidity and mortality in people with HIV since the introduction of combination antiretroviral therapy. Despite recent advances in our understanding of HIV ASCVD, controversy still exists on whether this increased risk of ASCVD is due to chronic HIV infection or other risk factors. Mounting biomarker studies indicate a role of monocyte/macrophage activation in HIV ASCVD; however, little is known about the mechanisms through which HIV infection mediates monocyte/macrophage activation in such a way as to engender accelerated atherogenesis. Here, we experimentally investigated whether HIV expression is sufficient to accelerate atherosclerosis and evaluated the role of caspase-1 activation in monocytes/macrophages in HIV ASCVD. Approach and Results: We crossed a well-characterized HIV mouse model, Tg26 mice, which transgenically expresses HIV-1, with ApoE mice to promote atherogenic conditions (Tg26/ApoE). Tg26/ApoE have accelerated atherosclerosis with increased caspase-1 pathway activation in inflammatory monocytes and atherosclerotic vasculature compared with ApoE. Using a well-characterized cohort of people with HIV and tissue-banked aortic plaques, we documented that serum IL (interleukin)-18 was higher in people with HIV compared with non-HIV-infected controls, and in patients with plaques, IL-18 levels correlated with monocyte/macrophage activation markers and noncalcified inflammatory plaques. In autopsy-derived aortic plaques, caspase-1+ cells and CD (clusters of differentiation) 163+ macrophages correlated.

Conclusions: These data demonstrate that expression of HIV is sufficient to accelerate atherogenesis. Further, it highlights the importance of caspase-1 and monocyte/macrophage activation in HIV atherogenesis and the potential of Tg26/ApoE as a tool for mechanistic studies of HIV ASCVD.
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http://dx.doi.org/10.1161/ATVBAHA.119.312603DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6703939PMC
September 2019

Serum Lipocalin 2 (Neutrophil Gelatinase-Associated Lipocalin) in Relation to Biomarkers of Inflammation and Cardiac Stretch During Activation of the Renin-Angiotensin-Aldosterone System in Human Immunodeficiency Virus.

J Infect Dis 2019 09;220(9):1420-1424

Program in Nutritional Metabolism, Massachusetts General Hospital and Harvard Medical School, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, Pennsylvania.

Purpose: To evaluate the relationship of lipocalin 2 to inflammation and cardiac injury with increased aldosterone in human immunodeficiency virus (HIV).

Methods: A standardized 6-day low-sodium diet was used to stimulate renin-angiotensin-aldosterone system (RAAS) activation, and serum lipocalin 2 and biomarkers of inflammation and cardiac stretch were assessed among persons with or without HIV.

Results: Lipocalin 2 levels increased with RAAS activation compared with suppression in the HIV group (median level [interquartile range], 71.3 [59.2-99.7] vs 67.0 [51.8-86.3] ng/mL; P = .01). During RAAS activation, lipocalin 2 was related to biomarkers of inflammation (tumor necrosis factor α [P = .007]), monocyte/macrophage activation (soluble CD163 [P = .005] and chemokine [C-C motif] ligand 2 [P = .03]), and markers of cardiac stretch (brain natriuretic peptide [P < .001] and N-terminal fragment of the prohormone brain natriuretic peptide [P = .001]) in HIV.

Conclusion: Lipocalin 2 may be important in modulating aldosterone-induced inflammation, monocyte activation, and cardiac stretch during RAAS activation in HIV.

Clinical Trial Registration: NCT01407237.
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http://dx.doi.org/10.1093/infdis/jiz346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6761935PMC
September 2019

SIV-Mediated Synaptic Dysfunction Is Associated with an Increase in Synapsin Site 1 Phosphorylation and Impaired PP2A Activity.

J Neurosci 2019 08 3;39(35):7006-7018. Epub 2019 Jul 3.

Department of Neuroscience, Comprehensive NeuroAIDS Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania 19140

Although the reduction of viral loads in people with HIV undergoing combination antiretroviral therapy has mitigated AIDS-related symptoms, the prevalence of neurological impairments has remained unchanged. HIV-associated CNS dysfunction includes impairments in memory, attention, memory processing, and retrieval. Here, we show a significant site-specific increase in the phosphorylation of Syn I serine 9, site 1, in the frontal cortex lysates and synaptosome preparations of male rhesus macaques infected with simian immunodeficiency virus (SIV) but not in uninfected or SIV-infected antiretroviral therapy animals. Furthermore, we found that a lower protein phosphatase 2A (PP2A) activity, a phosphatase responsible for Syn I (S9) dephosphorylation, is primarily associated with the higher S9 phosphorylation in the frontal cortex of SIV-infected macaques. Comparison of brain sections confirmed higher Syn I (S9) in the frontal cortex and greater coexpression of Syn I and PP2A A subunit, which was observed as perinuclear aggregates in the somata of the frontal cortex of SIV-infected macaques. Synaptosomes from SIV-infected animals were physiologically tested using a synaptic vesicle endocytosis assay and FM4-64 dye showing a significantly higher baseline depolarization levels in synaptosomes of SIV-infected than uninfected control or antiretroviral therapy animals. A PP2A-activating FDA-approved drug, FTY720, decreased the higher synaptosome depolarization in SIV-infected animals. Our results suggest that an impaired distribution and lower activity of serine/threonine phosphatases in the context of HIV infection may cause an indirect effect on the phosphorylation levels of essential proteins involving in synaptic transmission, supporting the occurrence of specific impairments in the synaptic activity during SIV infection. Even with antiretroviral therapy, neurocognitive deficits, including impairments in attention, memory processing, and retrieval, are still major concerns in people living with HIV. Here, we used the rhesus macaque simian immunodeficiency virus model with and without antiretroviral therapy to study the dynamics of phosphorylation of key amino acid residues of synapsin I, which critically impacts synaptic vesicle function. We found a significant increase in synapsin I phosphorylation at serine 9, which was driven by dysfunction of serine/threonine protein phosphatase 2A in the nerve terminals. Our results suggest that an impaired distribution and lower activity of serine/threonine phosphatases in the context of HIV infection may cause an indirect effect on the phosphorylation levels of essential proteins involved in synaptic transmission.
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http://dx.doi.org/10.1523/JNEUROSCI.0178-19.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733569PMC
August 2019

Sequential LASER ART and CRISPR Treatments Eliminate HIV-1 in a Subset of Infected Humanized Mice.

Nat Commun 2019 07 2;10(1):2753. Epub 2019 Jul 2.

Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, 68198-5880, USA.

Elimination of HIV-1 requires clearance and removal of integrated proviral DNA from infected cells and tissues. Here, sequential long-acting slow-effective release antiviral therapy (LASER ART) and CRISPR-Cas9 demonstrate viral clearance in latent infectious reservoirs in HIV-1 infected humanized mice. HIV-1 subgenomic DNA fragments, spanning the long terminal repeats and the Gag gene, are excised in vivo, resulting in elimination of integrated proviral DNA; virus is not detected in blood, lymphoid tissue, bone marrow and brain by nested and digital-droplet PCR as well as RNAscope tests. No CRISPR-Cas9 mediated off-target effects are detected. Adoptive transfer of human immunocytes from dual treated, virus-free animals to uninfected humanized mice fails to produce infectious progeny virus. In contrast, HIV-1 is readily detected following sole LASER ART or CRISPR-Cas9 treatment. These data provide proof-of-concept that permanent viral elimination is possible.
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http://dx.doi.org/10.1038/s41467-019-10366-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6606613PMC
July 2019

Immune Correlates of Diffuse Myocardial Fibrosis and Diastolic Dysfunction Among Aging Women With Human Immunodeficiency Virus.

J Infect Dis 2020 03;221(8):1315-1320

Cardiac MR PET CT Program, Division of Cardiology and Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston.

Human immunodeficiency virus (HIV) imparts increased heart failure risk to women. Among women with HIV (WHIV), immune pathways relating to heart failure precursors may intimate targets for heart failure prevention strategies. Twenty asymptomatic, antiretroviral-treated WHIV and 14 non-HIV-infected women matched on age and body mass index underwent cardiac magnetic resonance imaging and immune phenotyping. WHIV (vs non-HIV-infected women) exhibited increased myocardial fibrosis (extracellular volume fraction, 0.34 ± 0.06 vs 0.29 ± 0.04; P = .002), reduced diastolic function (diastolic strain rate, 1.10 ± 0.23 s-1 vs 1.39 ± 0.27 s-1; P = .003), and heightened systemic monocyte activation. Among WHIV, soluble CD163 levels correlated with myocardial fibrosis (r = 0.53; P = .02), while circulating inflammatory CD14+CD16+ monocyte CCR2 expression related directly to myocardial fibrosis (r = 0.48; P = .04) and inversely to diastolic function (r = -0.49; P = .03). Clinical Trials Registration. NCT02874703.
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http://dx.doi.org/10.1093/infdis/jiz184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325805PMC
March 2020

Anti-Inflammatory Interleukin 10 Inversely Relates to Coronary Atherosclerosis in Persons With Human Immunodeficiency Virus.

J Infect Dis 2020 02;221(4):510-515

Program in Nutritional Metabolism, Massachusetts General Hospital and Harvard Medical School.

Interleukin 10 (IL-10) is an anti-inflammatory cytokine that may be protective against coronary atherosclerosis. In an observational study of persons with human immunodeficiency virus (PWH) and uninfected controls, IL-10 was measured in serum samples by means of enzyme-linked immunosorbent assay, and coronary atherosclerosis was assessed using computed tomographic angiography. Among PWH, a 10-fold decrease in IL-10 was associated with a 2.6-fold increase in the odds of coronary plaque (P = .01), after controlling for traditional and nontraditional cardiovascular risk factors. IL-10 was also inversely associated with total coronary plaque (ρ = -0.19; P = .02) and noncalcified coronary plaque (ρ = -0.24; P = .004). Our findings suggest a role for IL-10 in mitigating atherosclerosis in PWH. Clinical Trials Registration. NCT00455793.
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http://dx.doi.org/10.1093/infdis/jiz254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7325621PMC
February 2020

Rationale and design of the Mechanistic Substudy of the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE): Effects of pitavastatin on coronary artery disease and inflammatory biomarkers.

Am Heart J 2019 06 4;212:1-12. Epub 2019 Mar 4.

MGH Program in Nutritional Metabolism and Harvard Medical School, Boston, MA.

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.
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http://dx.doi.org/10.1016/j.ahj.2019.02.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6596304PMC
June 2019

Editor's Commentary for Special Issue: "The Role of Macrophages in HIV Persistence".

Authors:
Tricia H Burdo

J Neuroimmune Pharmacol 2019 03 9;14(1):2-5. Epub 2019 Feb 9.

Department of Neuroscience, Temple University School of Medicine, 3500 North Broad Street, MERB 755, Philadelphia, PA, 19140, USA.

Macrophages as reservoirs for persistent HIV infection has gained renewed importance, with an intense research focus dedicated to eradication strategies. Clearance of both latent and productive HIV from these important reservoirs is essential for successful eradication. This spe cial theme issue contains 11 papers, including 6 Invited Reviews, 1 Brief Report and 4 Original Articles, that focus on the various aspects of the macrophage as pertains to HIV persistence, latency and cure. These topics include: functional latency of macrophages and microglia, the link between peripheral monocytes and pathogenesis, macrophages as sources of HIV RNA and DNA in virally suppressed patients, brain imaging of neuroinflammation, macrophages as drug delivery vehicles, therapeutic strategies of infected macrophages for cure, and the role of drugs of abuse in enhancing macrophage viral persistence.
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http://dx.doi.org/10.1007/s11481-019-09836-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6424350PMC
March 2019

I-FABP Is Higher in People With Chronic HIV Than Elite Controllers, Related to Sugar and Fatty Acid Intake and Inversely Related to Body Fat in People With HIV.

Open Forum Infect Dis 2018 Nov 5;5(11):ofy288. Epub 2018 Nov 5.

Program in Nutritional Metabolism, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Background: Intestinal fatty acid binding protein (I-FABP) has been shown to be a marker of intestinal damage among people living with HIV. We hypothesized that I-FABP would be increased in chronically HIV-infected patents more than elite controllers and would relate to specific nutrient intake and body composition.

Methods: In an observational study, serum I-FABP was measured by enzyme-linked immunosorbent assay. Anthropometric measurements, dual-energy x-ray absorptiometry, and single-slice abdominal computed tomography were obtained to assess body composition, as well as visceral and subcutaneous adipose tissue areas (VAT and SAT). Dietary intake was assessed using 4-day food records.

Results: One hundred forty-nine people with chronic HIV (65% male, 47 ± 7 years of age, 54.7% white, and 14 ± 6 years of known HIV), 10 elite controllers (60% male, 53 ± 8 years, 60% white, and 20 ± 7 years of known HIV), and 69 HIV-negative controls (59.4% male, 46 ± 7 years, and 52.2% white) were included in the analysis. I-FABP was significantly higher in HIV progressors relative to HIV-negative controls and elite controllers. In the chronic HIV group, I-FABP was positively associated with dietary intake of added sugar and with saturated fatty acids. I-FABP was inversely associated with body mass index, VAT, and SAT. I-FABP also correlated with MCP-1, CXCL10, sCD163, and lipopolysaccharide (LPS) among all participants.

Conclusions: I-FABP was increased among chronically HIV-infected patients to a greater degree than in elite controllers and was related to nutrient intake and body composition in HIV progressors. Future studies to investigate the role of intestinal damage on nutrient absorption are needed to elucidate the mechanisms of these relationships.

Trial Registration Identifier: NCT00455793.
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http://dx.doi.org/10.1093/ofid/ofy288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262112PMC
November 2018

Dysregulation of Neuronal Cholesterol Homeostasis upon Exposure to HIV-1 Tat and Cocaine Revealed by RNA-Sequencing.

Sci Rep 2018 11 2;8(1):16300. Epub 2018 Nov 2.

Department of Neuroscience, Center for Neurovirology, Comprehensive NeuroAIDS Center, Lewis Katz School of Medicine at Temple University, 3500N. Broad Street, Philadelphia, PA, 19140, USA.

HIV-1 Tat protein is released from HIV-1-infected cells and can enter non-permissive cells including neurons. Tat disrupts neuronal homeostasis and may contribute to the neuropathogenesis in people living with HIV (PLWH). The use of cocaine by PLWH exacerbates neuronal dysfunction. Here, we examined the mechanisms by which Tat and cocaine facilitate alterations in neuronal homeostatic processes. Bioinformatic interrogation of the results from RNA deep sequencing of rat hippocampal neurons exposed to Tat alone indicated the dysregulation of several genes involved in lipid and cholesterol metabolism. Following exposure to Tat and cocaine, the activation of cholesterol biosynthesis genes led to increased levels of free cholesterol and cholesteryl esters in rat neurons. Results from lipid metabolism arrays validated upregulation of several processes implicated in the biogenesis of β-amyloid and Alzheimer's disease (AD), including sterol o-acyltransferase 1/acetyl-coenzyme A acyltransferase 1 (SOAT1/ACAT1), sortilin-related receptor L1 (SORL1) and low-density lipoprotein receptor-related protein 12 (LRP12). Further studies in Tat-treated primary neuronal cultures and brain tissues from HIV-1 transgenic mice as well as SIV-infected macaques confirmed elevated levels of SOAT1/ACAT 1 proteins. Our results offer novel insights into the molecular events involved in HIV and cocaine-mediated neuronal dysfunction that may also contribute to neuropathogenic events associated with the development of AD.
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http://dx.doi.org/10.1038/s41598-018-34539-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6215004PMC
November 2018

Significant Association of Aldosterone and Liver Fat Among HIV-Infected Individuals With Metabolic Dysregulation.

J Endocr Soc 2018 Oct 3;2(10):1147-1157. Epub 2018 Sep 3.

Program in Nutritional Metabolism, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Objective: Fatty liver disease is increased among individuals with HIV. We sought to explore how aldosterone, a key hormone linked to insulin resistance and inflammation, relates to liver fat in the large population of individuals with HIV and metabolic abnormalities.

Methods: Forty-six individuals with HIV and increased waist circumference and dysglycemia were assessed for liver fat using proton magnetic resonance spectroscopy. Serum aldosterone level was obtained following strictly controlled posture conditions and a standardized sodium diet and was related to liver fat.

Results: Among the entire group [median (interquartile range) liver fat: 5% (3%, 12%) and homeostatic model assessment of insulin resistance: 1.74 (1.21, 2.83)], serum aldosterone significantly correlated with liver fat ( = 0.31; = 0.049). Liver fat level was significantly higher in those with aldosterone above vs below the median [8% (3%, 20%) vs 4% (2%, 10%); = 0.02]. In the presence of metabolic syndrome, individuals with aldosterone levels above vs below the median had markedly elevated liver fat values [14% (9%, 23%) vs 5% (3%, 12%); = 0.005] and increased presence of fatty liver disease (FLD; 92% vs 50%; = 0.02). Controlling for metabolic syndrome, hepatitis C virus, and alcohol use, aldosterone was a significant and independent predictor of liver fat ( estimate: 0.6038, = 0.01; overall model = 0.41, = 0.0005) and FLD (OR: 1.38, = 0.02; overall model = 0.28, = 0.002).

Conclusion: These data highlight a robust association between aldosterone and liver fat among individuals with HIV and metabolic dysregulation. Increased aldosterone may be a risk factor for liver fat accumulation among the population with HIV.
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http://dx.doi.org/10.1210/js.2018-00194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6162603PMC
October 2018

Temporal/compartmental changes in viral RNA and neuronal injury in a primate model of NeuroAIDS.

PLoS One 2018 11;13(5):e0196949. Epub 2018 May 11.

Department of Radiology, Neuroradiology Division, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Charlestown, MA, United States of America.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0196949PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5947913PMC
July 2018

Randomized, Placebo-Controlled Trial to Evaluate Effects of Eplerenone on Metabolic and Inflammatory Indices in HIV.

J Clin Endocrinol Metab 2018 06;103(6):2376-2384

Program in Nutritional Metabolism, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts.

Context: HIV-infected individuals demonstrate increased renin-angiotensin-aldosterone system activation in association with visceral adiposity, insulin resistance, and inflammation. A physiologically based treatment approach targeting mineralocorticoid receptor (MR) blockade may improve metabolic and inflammatory indices in HIV.

Objective: To investigate effects of eplerenone on insulin sensitivity, inflammatory indices, and other metabolic parameters in HIV.

Design: Six-month, double-blind, randomized, placebo-controlled trial.

Setting: Academic clinical research center.

Participants: HIV-infected individuals with increased waist circumference and abnormal glucose homeostasis.

Intervention: Eplerenone 50 mg or placebo daily.

Outcome: The primary end point was change in insulin sensitivity measured by the euglycemic-hyperinsulinemic clamp technique. Secondary end points included change in body composition and inflammatory markers.

Results: Forty-six individuals were randomized to eplerenone (n = 25) vs placebo (n = 21). Eplerenone did not improve insulin sensitivity [0.48 (-1.28 to 1.48) vs 0.43 (-1.95 to 2.55) mg/min/μIU/mL insulin; P = 0.71, eplerenone vs placebo] when measured by the gold standard euglycemic-hyperinsulinemic clamp technique. Intramyocellular lipids (P = 0.04), monocyte chemoattractant protein-1 (P = 0.04), and high-density lipoprotein (P = 0.04) improved among those randomized to eplerenone vs placebo. Trends toward decreases in interleukin-6 (P = 0.10) and high-sensitivity C-reactive protein (P = 0.10) were also seen with eplerenone vs placebo. Plasma renin activity and aldosterone levels increased in the eplerenone vs placebo-treated group, demonstrating expected physiology. MR antagonism with eplerenone was well tolerated among the HIV population, with no considerable changes in blood pressure or potassium.

Conclusion: MR blockade may improve selected metabolic and inflammatory indices in HIV-infected individuals. Further studies are necessary to understand the clinical potential of MR antagonism in HIV.
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http://dx.doi.org/10.1210/jc.2018-00330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6370281PMC
June 2018