Publications by authors named "Tricia H Burdo"

97 Publications

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

Authors:
Mabel Toribio Evelynne S Fulda Sarah M Chu Zsofia D Drobni Magid Awadalla Madeline Cetlin Takara L Stanley Crystal M North Michael D Nelson Michael Jerosch-Herold Lidia S Szczepaniak Tricia H Burdo Sara E Looby Tomas G Neilan Markella V Zanni

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.

Authors:
Jae H Sim Julia B Sherman Takara L Stanley Kathleen E Corey Kathleen V Fitch Sara E Looby Jake A Robinson Michael T Lu Tricia H Burdo Janet Lo

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.

Authors:
Pietro Mancuso Chen Chen Rafal Kaminski Jennifer Gordon Shuren Liao Jake A Robinson Mandy D Smith Hong Liu Ilker K Sariyer Rahsan Sariyer Tiffany A Peterson Martina Donadoni Jaclyn B Williams Summer Siddiqui Bruce A Bunnell Binhua Ling Andrew G MacLean Tricia H Burdo Kamel Khalili

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.

Authors:
Shadan S Yarandi Jake A Robinson Sarah Vakili Martina Donadoni Tricia H Burdo Ilker K Sariyer

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.

Authors:
Mabel Toribio Tricia H Burdo Evelynne S Fulda Madeline Cetlin Sarah M Chu Meghan N Feldpausch Gregory K Robbins Tomas G Neilan Kathleen Melbourne Steven K Grinspoon Markella V Zanni

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

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

Authors:
Dana Gabuzda Beth D Jamieson Ronald G Collman Michael M Lederman Tricia H Burdo Steven G Deeks Dirk P Dittmer Howard S Fox Nicholas T Funderburg Savita G Pahwa Ivona Pandrea Cara C Wilson Peter W Hunt

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

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

Authors:
Markella V Zanni Judith S Currier Amy Kantor Laura Smeaton Corinne Rivard Jana Taron Tricia H Burdo Sharlaa Badal-Faesen Umesh G Lalloo Jorge A Pinto Wadzanai Samaneka Javier Valencia Karin Klingman Beverly Allston-Smith Katharine Cooper-Arnold Patrice Desvigne-Nickens Michael T Lu Kathleen V Fitch Udo Hoffman Steven K Grinspoon Pamela S Douglas Sara E Looby

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.

Authors:
Tomas G Neilan Kim-Lien Nguyen Vlad G Zaha Kara W Chew Leavitt Morrison Ntobeko A B Ntusi Mabel Toribio Magid Awadalla Zsofia D Drobni Michael D Nelson Tricia H Burdo Marije Van Schalkwyk Paul E Sax Daniel J Skiest Karen Tashima Raphael J Landovitz Eric Daar Alysse G Wurcel Gregory K Robbins Robert K Bolan Kathleen V Fitch Judith S Currier Gerald S Bloomfield Patrice Desvigne-Nickens Pamela S Douglas Udo Hoffmann Steven K Grinspoon Heather Ribaudo Rodney Dawson Matthew Bidwell Goetz Mamta K Jain Alberta Warner Lidia S Szczepaniak Markella V Zanni

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.

Authors:
Mabel Toribio Magid Awadalla Madeline Cetlin Evelynne S Fulda Takara L Stanley Zsofia D Drobni Lidia S Szczepaniak Michael D Nelson Michael Jerosch-Herold Tricia H Burdo Tomas G Neilan Markella V Zanni

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.

Authors:
Jake A Robinson Guy Guenthner Rebecca Warfield Jessica R Kublin Mandy D Smith Masoud Shekarabi Andrew D Miller Tricia H Burdo

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

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

Authors:
Nicholas Musinguzi Jose Castillo-Mancilla Mary Morrow Helen Byakwaga Samantha Mawhinney Tricia H Burdo Yap Boum Conrad Muzoora Bosco M Bwana Mark J Siedner Jeffrey N Martin Peter W Hunt David R Bangsberg Jessica E Haberer

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.

Authors:
Ilker Kudret Sariyer Jennifer Gordon Tricia H Burdo Hassen S Wollebo Eleonora Gianti Martina Donadoni Anna Bellizzi Stephanie Cicalese Regina Loomis Jake A Robinson Vincenzo Carnevale Joseph Steiner Mehmet H Ozdener Andrew D Miller Shohreh Amini Michael L Klein Kamel Khalili

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?

Authors:
Alessandra Bandera Lucia Taramasso Giorgio Bozzi Antonio Muscatello Jake A Robinson Tricia H Burdo Andrea Gori

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.

Authors:
Mabel Toribio Tomas G Neilan Magid Awadalla Lauren A Stone Adam Rokicki Corinne Rivard Connor P Mulligan Diana Cagliero Lindsay T Fourman Takara L Stanley Jennifer E Ho Virginia A Triant Tricia H Burdo Michael D Nelson Lidia S Szczepaniak Markella V Zanni

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.

Authors:
Alison C Kearns Fengming Liu Shen Dai Jake A Robinson Elizabeth Kiernan Lediya Tesfaye Cheru Xiao Peng Jennifer Gordon Susan Morgello Aishazhan Abuova Janet Lo Markella V Zanni Steven K Grinspoon Tricia H Burdo Xuebin Qin 秦学斌

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.

Authors:
Milana Bogorodskaya Kathleen V Fitch Tricia H Burdo Patrick Maehler Rebecca M Easly Gillian R Murray Meghan Feldpausch Gail K Adler Steven K Grinspoon Suman Srinivasa

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.

Authors:
Masoud Shekarabi Jake A Robinson Mandy D Smith Tricia H Burdo

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.

Authors:
Prasanta K Dash Rafal Kaminski Ramona Bella Hang Su Saumi Mathews Taha M Ahooyi Chen Chen Pietro Mancuso Rahsan Sariyer Pasquale Ferrante Martina Donadoni Jake A Robinson Brady Sillman Zhiyi Lin James R Hilaire Mary Banoub Monalisha Elango Nagsen Gautam R Lee Mosley Larisa Y Poluektova JoEllyn McMillan Aditya N Bade Santhi Gorantla Ilker K Sariyer Tricia H Burdo Won-Bin Young Shohreh Amini Jennifer Gordon Jeffrey M Jacobson Benson Edagwa Kamel Khalili Howard E Gendelman

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.

Authors:
Markella V Zanni Magid Awadalla Mabel Toribio Jake Robinson Lauren A Stone Diana Cagliero Adam Rokicki Connor P Mulligan Jennifer E Ho Anne M Neilan Mark J Siedner Virginia A Triant Takara L Stanley Lidia S Szczepaniak Michael Jerosch-Herold Michael D Nelson Tricia H Burdo Tomas G Neilan

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

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.

Authors:
Udo Hoffmann Michael T Lu Devvora Olalere Elizabeth C Adami Michael T Osborne Alex Ivanov John Sukumar Aluru Saeyun Lee Nadja Arifovic Edgar Turner Overton Carl J Fichtenbaum Judith A Aberg Beverly Alston-Smith Karin L Klingman Myron Waclawiw Tricia H Burdo Kenneth C Williams Markella V Zanni Patrice Desvigne-Nickens Katharine Cooper-Arnold Kathleen V Fitch Heather Ribaudo Pamela S Douglas Steven K Grinspoon

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.

Authors:
Lediya T Cheru Elli A Park Charles F Saylor Tricia H Burdo Kathleen V Fitch Sara Looby Jeffrey Weiner Jake A Robinson Jane Hubbard Martin Torriani Janet Lo

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.

Authors:
Taha Mohseni Ahooyi Masoud Shekarabi Bahareh Torkzaban T Dianne Langford Tricia H Burdo Jennifer Gordon Prasun K Datta Shohreh Amini Kamel Khalili

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.

Authors:
Suman Srinivasa Kathleen V Fitch Nabiha Quadri Patrick Maehler Timothy K O'Malley Edgar L Martinez-Salazar Tricia H Burdo Meghan Feldpausch Martin Torriani Gail K Adler Steven K Grinspoon

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.

Authors:
R Gilberto González Robert Fell Julian He Jennifer Campbell Tricia H Burdo Patrick Autissier Lakshmanan Annamalai Faramarz Taheri Termara Parker Jeffrey D Lifson Elkan F Halpern Mark Vangel Eliezer Masliah Susan V Westmoreland Kenneth C Williams Eva-Maria Ratai

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.

Authors:
Suman Srinivasa Kathleen V Fitch Kimberly Wong Timothy K O'Malley Patrick Maehler Karen L Branch Sara E Looby Tricia H Burdo Edgar L Martinez-Salazar Martin Torriani Shannon H Lyons Julian Weiss Meghan Feldpausch Takara L Stanley Gail K Adler Steven K Grinspoon

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

Caspase-1-associated immune activation in an accelerated SIV-infected rhesus macaque model.

Authors:
Alison C Kearns Jake A Robinson Masoud Shekarabi Fengming Liu Xuebin Qin Tricia H Burdo

J Neurovirol 2018 08 2;24(4):420-431. Epub 2018 Apr 2.

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

In the antiretroviral therapy (ART) era, chronic HIV infection is primarily associated with chronic inflammation driving comorbidities such as cardiovascular disease and neurocognitive impairment. Caspase-1 activation in leukocytes has been documented in HIV infection; however, whether caspase-1 activation and the downstream pro-inflammatory cytokines interleukin-1beta (IL-1β) and interleukin-18 (IL-18) contribute to chronic inflammation in HIV comorbidities remains undetermined. The relationship between the caspase-1 cascade and persistent inflammation in HIV has not been investigated. Here, we used an accelerated simian immunodeficiency virus (SIV)-infected rhesus macaque model with or without ART to investigate the dynamics of caspase-1 and immune cell activation before infection, 21 days post infection (dpi), and necropsy. Caspase-1, IL-18, IL-1β, and immune markers were measured both in the circulation and lymphoid tissues. We found a significant increase in caspase-1 and IL-18 in SIV infection that positively correlated with inflammatory monocytes and negatively correlated with CD4 T cell counts. ART attenuated these effects at necropsy in the circulation. Further, lymph nodes from SIV+ or SIV+ART animals had increased activation of caspase-1 and potential upstream priming of the NF-κB pathway, indicating that tissue-specific immune activation persists with ART. Together, these results shed light on the interconnectedness of the caspase-1 pathway and peripheral immune activation and further indicate that ART is not sufficient for suppressing inflammation. The caspase-1 pathway may provide novel therapeutic targets to improve HIV-associated comorbidities and health outcomes in the context of viral suppression.
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http://dx.doi.org/10.1007/s13365-018-0630-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6526524PMC
August 2018

Sex Differences in Subclinical Coronary Atherosclerotic Plaque Among Individuals With HIV on Antiretroviral Therapy.

Authors:
Borek Foldyna Lindsay T Fourman Michael T Lu Martin E Mueller Balint Szilveszter Tomas G Neilan Jennifer E Ho Tricia H Burdo Emily S Lau Lauren A Stone Mabel Toribio Suman Srinivasa Sara E Looby Janet Lo Kathleen V Fitch Markella V Zanni

J Acquir Immune Defic Syndr 2018 08;78(4):421-428

Endocrine Division, Program in Nutritional Metabolism, Massachusetts General Hospital, Harvard Medical School, Boston, MA.

Background: In high-resource settings, the HIV-attributable risk of myocardial infarction (MI) is higher among women than among men. The extent to which unique mechanisms contribute to MI risk among women vs. men with HIV remains unclear.

Methods: Subclinical coronary atherosclerotic plaque characteristics-including high-risk morphology plaque features-were compared among 48 HIV-infected women [48 (41, 54) years] and 97 HIV-infected men [48 (42, 52) years] on stable antiretroviral therapy (ART) without known cardiovascular disease. These individuals had previously completed coronary computed tomography angiography and metabolic/immune phenotyping as part of a prospective study.

Results: Extending previous analyses, now focusing exclusively on ART-treated participants, we found that HIV-infected women had a lower prevalence of any subclinical coronary atherosclerotic plaque (35% vs. 62%, P = 0.003) and a lower number of segments with plaque (P = 0.01), compared with HIV-infected men. We also report for the first time that ART-treated HIV-infected women had a lower prevalence of high-risk positively remodeled plaque (25% vs. 51%, P = 0.003) and a lower number of positively remodeled plaque segments (P = 0.002). In models adjusting for cardiovascular risk factors, we further showed that male sex remained associated with any coronary plaque [odds ratio 3.8, 95% confidence interval: (1.4 to 11.4)] and with positively remodeled plaque [odds ratio 3.7, 95% confidence interval: (1.4, 10.9)].

Conclusions: ART-treated HIV-infected women (vs. HIV-infected men) had a lower prevalence and burden of subclinical coronary plaque and high-risk morphology plaque. Thus, unique sex-specific mechanisms beyond subclinical plaque may drive the higher HIV-attributable risk of MI among women vs. men.
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http://dx.doi.org/10.1097/QAI.0000000000001686DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6019171PMC
August 2018

Insulin-like growth factor 1 inversely relates to monocyte/macrophage activation markers in HIV.

Authors:
Lindsay T Fourman Natalia Czerwonka Sofia D Shaikh Takara L Stanley Tricia H Burdo Kenneth C Williams Kathleen V Fitch Janet Lo Steven K Grinspoon

AIDS 2018 04;32(7):927-932

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

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: One hundred and thirty-one HIV-infected patients 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-adjusted 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, BMI, visceral fat, statin use, viral load, and antiretroviral therapy. For every one-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.

Conclusion: 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.
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http://dx.doi.org/10.1097/QAD.0000000000001775DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5869172PMC
April 2018

Brief Report: Higher ART Adherence Is Associated With Lower Systemic Inflammation in Treatment-Naive Ugandans Who Achieve Virologic Suppression.

Authors:
Jose R Castillo-Mancilla Mary Morrow Yap Boum Helen Byakwaga Jessica E Haberer Jeffrey N Martin David Bangsberg Samantha Mawhinney Nicholas Musinguzi Yong Huang Russell P Tracy Tricia H Burdo Kenneth Williams Conrad Muzzora Peter W Hunt Mark J Siedner

J Acquir Immune Defic Syndr 2018 04;77(5):507-513

Faculty of Medicine, Mbarara University of Science and Technology, Mbarara, Uganda.

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 (<400 copies/mL) at their 6-month visit. Adherence was measured through medication event monitoring system and calculated as the ratio of observed/prescribed device openings per participant. We fit adjusted linear regression models to estimate the association between ART adherence and the log-transformed plasma concentrations of inflammatory biomarkers.

Results: We evaluated 282 participants (median age, 35 years; 70% women). The median (interquartile range) adherence was 93% (84-98). In the adjusted analyses, for every 10% increase in average ART adherence, we found a 15% [P < 0.0001; 95% confidence interval (CI), -21.0 to -7.9], 11% (P = 0.017; 95% CI, -18.3 to -2.0), and 3% (P = 0.028; 95% CI, -5.0 to -0.3) decrease in IL-6, D-dimer, and sCD14, respectively.

Conclusions: Higher ART adherence was associated with lower levels of biomarkers of inflammation, immune activation, and coagulopathy among Ugandans living with HIV who achieved viral suppression shortly after ART initiation. This suggests that ART adherence could have biological consequences beyond viral suppression. Whether ART adherence optimization in virologically suppressed individuals could reduce residual inflammation remains unknown.
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http://dx.doi.org/10.1097/QAI.0000000000001629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5844840PMC
April 2018