Pittsburgh HIV Mentored Training for Investigation of Comorbidities and Cure (HIV MeTrICC)

Mentors: Shyam Kottilil, M.D., Ph.D., and Henry Masur, M.D.

Research Summary

Dr. Mathur has been able to use the samples collected from CALIBER to develop preliminary data on studying the effects of HIV-induced T cell activation and possible end-organ disease in HIV. Specifically, she has used these samples to look at CD38 expression in HIV and this will be used for preliminary data for additional grants.

Though ART has increased the life expectancy of People with HIV (PWH), the number of age-associated non-communicable comorbidities has also increased, out of proportion to age-matched HIV-negative individuals. One potential mechanism underlying this accelerated aging is on the cellular level, and due to CD38. CD38 is an ectoenzyme, catalyzing the breakdown of nicotinamide adenine dinucleotide (NAD+), which is essential for cellular metabolism. CD38 levels increase with age and concomitantly decrease NAD+ levels. Decreasing NAD+ levels are associated with increased mitochondrial dysfunction, cellular aging, and comorbidities. Dr. Mathur has demonstrated that CD38 and NAD+ are inversely correlated. As NAD+ is essential for cellular metabolism, decline in NAD+ is associated with increased mitochondrial dysfunction and cellular aging. These data suggest that the CD38-NAD+ axis is a potential target for reducing accelerated cellular aging in PWH.

Because blocking CD38 may result in immunodeficiency, strategies to increase NAD+ while bypassing CD38 are necessary. Recently, she demonstrated, in vitro, that NAD+ levels were increased following addition of the NAD+ precursor, nicotinamide riboside (NR). In human studies, use of NR not only increases NAD+ levels, but also improves mitochondrial function, and decreases cytokine production in whole blood and peripheral blood mononuclear cells (PBMCs) of HIV-negative individuals. However, there remains a gap in linking the effects of the CD38-NAD+ axis on accelerated cellular aging in PWH, and to what extent NR may attenuate this effect. Her central hypothesis is that HIV-induced CD38 expression on T cells of PWH correlates with decreased NAD+ levels, decreased mitochondrial function, and increased cytokine production in PWH as compared to HIV-negative individuals. Her overall goal is to demonstrate a novel use of NR to reduce end-organ disease in PWH.

Dr. Mathur has generated preliminary data for CD38 effects on NAD+, cytokine production, and mitochondrial function and has submitted this data as a manuscript to the Journal of Infectious Diseases as first author. Additionally, she will be submitting an R01 grant proposal to the NIA this May.

Publications

Wilson E, Covert E, Hoffmann J, Comstock E, Emmanuel B, Tang L, Husson J, Chua J, Price A, Mathur P, Rosenthal E, Kattakuzhy S, Masur H, Kottilil S. A pilot study of safety and efficacy of HCV retreatment with sofosbuvir/velpatasvir/voxilaprevir in patients with or without HIV (RESOLVE STUDY). J Hepatol. 2019 Sep;71(3):498-504. Epub 2019 Jun 5. PMID: 31173815.

Mathur P, Kottilil S. Hepatitis C Core Antigen Testing: Still an Effective Diagnostic Method for Global Elimination of Hepatitis C. Clin Infect Dis. 2020 Feb 3;70(4):674-675. PMCID: PMC8204483.

Rosenthal ES, Silk R, Mathur P, Gross C, Eyasu R, Nussdorf L, Hill K, Brokus C, D’Amore A, Sidique N, Bijole P, Jones M, Kier R, McCullough D, Sternberg D, Stafford K, Sun J, Masur H, Kottilil S, Kattakuzhy S. Concurrent Initiation of Hepatitis C and Opioid Use Disorder Treatment in People Who Inject Drugs. Clin Infect Dis. 2020 Oct 23;71(7):1715-1722. PMCID: PMC7755091.

Bunn HT, Rosenthal E, Mathur P, McLaughlin M, Proschan M, Vijan A, Aepfelbacher J, Kottilil S, Masur H, Kattakuzhy S, George JM. The Effect of GS-548351 on the Pharmacokinetics of Midazolam Following Multiple Doses of ANS-6637 in Healthy Adults. J Clin Pharmacol. 2020 Dec;60(12):1598-1605. PMID: 32578227.

Doub JB, Mathur P. Duration of posaconazole therapy for Aspergillus fumigatus osteomyelitis dictated by serial monitoring of 1,3-beta-D glucan. Infection. 2020 Dec;48(6):959-963. PMID: 32720130.

Dugan E, Blach S, Biondi M, Cai Z, DePaola M, Estes C, Feld J, Gamkrelidze I, Kottilil S, Ma S, Mathur P, Montoya S, Razavi-Shearer D, Razavi-Shearer K, Robbins-Scott S, Schmelzer J, Razavi H. Global prevalence of hepatitis C virus in women of childbearing age in 2019: a modelling study. Lancet Gastroenterol Hepatol. 2021 Mar;6(3):169-184. PMID: 33515496.

Hill K, Nussdorf L, Mount JD, Silk R, Gross C, Sternberg D, Bijole P, Jones M, Kier R, Mccullough D, Mathur P, Kottilil S, Masur H, Kattakuzhy S, Rosenthal ES. Initiation of Low-threshold Buprenorphine in Nontreatment Seeking Patients With Opioid Use Disorder Engaged in Hepatitis C Treatment. J Addict Med. 2021 Feb 5. Epub ahead of print. PMCID: PMC8923533.

Malave Sanchez M, Saleeb P, Kottilil S, Mathur P. Oral Polio Vaccine to Protect Against COVID-19: Out of the Box Strategies? Open Forum Infect Dis. 2021 Jul 9;8(8):ofab367. PMCID: PMC8344522.

Khalsa JH, Mathur P. Hepatitis C Virus Infection in Persons Who Inject Drugs in the Middle East and North Africa: Intervention Strategies. Viruses. 2021 Jul 14;13(7):1363. PMCID: PMC8310161.

Brokus C, Kattakuzhy S, Gayle B, Narayanan S, Davis A, Cover A, Eyasu R, Ebah E, Ogbumbadiugha-Weekes O, Hoffmann J, Silk R, Stevens J, Mount J, Gannon C, Nussdorf L, Mathur P, Bijole P, Jones M, Kier R, Sternberg D, Greenblatt A, Weintraub E, Masur H, Kottilil S, Rosenthal E. Suboptimal Uptake, Retention, and Adherence of Daily Oral Prexposure Prophylaxis Among People With Opioid Use Disorder Receiving Hepatitis C Virus Treatment. Open Forum Infect Dis. 2021 Dec 29;9(3):ofab658. PMCID: PMC8849288.

Shah D, Kularni M, Mathur P. The Impact of Neocolonialism on India’s COVID-19 Response. Ann Glob Health. 2022 May 17;88(1):33. PMCID: PMC9122003.

Mentors: Shyam Kottilil, M.D., Ph.D., and Eleanor Wilson, M.D., M.H.S.

Research Summary

Dr. Malavé Sánchez’s research suggests that exogenous estrogen therapy can reduce cardiovascular risk and age acceleration in transgender women with or without HIV who receive gender-affirming or feminizing hormone therapy. In the pilot, intervention non-randomized, controlled prospective study, the Kottilil lab will enroll 60 transgender women into the following 2 groups: (1) 30 Transgender women with or without HIV, not on hormonal therapy (No HT) and (2) 30 Transgender women with or without HIV, on hormonal (on HT).

Dr. Malavé Sánchez will determine the effect of estrogen hormone therapy (HT) on CVD risk/accelerated aging (AA) using a validated set of immune biomarkers for aging, cellular and soluble markers of immune activation, and cardiac biomarkers. She will also determine the effect of HIV on age acceleration, chronic immune activation, and cardiovascular disease risk in transgender women on estrogen HT.

Currently the study has been enrolling patients from the HIPS clinic in Washington D.C. in collaboration with Dr. Rosenthal and her team. Thus far, 25 patients have provided samples, which Dr. Malavé Sánchez will analyze for cardiac biomarkers (high sensitivity CRP, high sensitivity TRP, and D dimer), soluble cytokines/chemokines markers of immune activation (IFN-ϒ, TNF-α, IL-2, IL-6, CCL-2, CCL3, CCL-4, CCL-5, IL-18, sCD163, sCD14, CXCL9, CXCL10, CXCL11), and novel age acceleration immune markers (CD16 56, CD 19, CD4 38, CD4 HLA-DR, CD8, CD8 38 HLA-DR, CD8 HLA-DR, naive CD8 cells, lymphocytes, monocytes, and basophils). These will be analyzed and used for a longitudinal analysis that will include markers that denote cellular activation and exhaustion that reflect cellular aging (HLA-DR+, CD38+, CD25, PD-1, CTLA-4, Tim-3, CD69, and Ki67, IFN-g, TNF, IL-2 on CD4 and CD8 T cells).

Future plans include using the data analysis for an abstract submission for ID week. Dr. Malavé Sánchez expects future data from the study can be used as preliminary data to develop grant proposals focused on age acceleration and immune activation in HIV positive individuals.

Publications

Malave Sanchez M, Saleeb P, Kottilil S, Mathur P. Oral Polio Vaccine to Protect Against COVID-19: Out of the Box Strategies? Open Forum Infect Dis. 2021 Jul 9;8(8):ofab367. PMCID: PMC8344522.

O’Brien MP, Forleo-Neto E, Musser BJ, Isa F, Chan KC, Sarkar N, Bar KJ, Barnabas RV, Barouch DH, Cohen MS, Hurt CB, Burwen DR, Marovich MA, Hou P, Heirman I, Davis JD, Turner KC, Ramesh D, Mahmood A, Hooper AT, Hamilton JD, Kim Y, Purcell LA, Baum A, Kyratsous CA, Krainson J, Perez-Perez R, Mohseni R, Kowal B, DiCioccio AT, Stahl N, Lipsich L, Braunstein N, Herman G, Yancopoulos GD, Weinreich DM; Covid-19 Phase 3 Prevention Trial Team. Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19. N Engl J Med. 2021 Sep 23;385(13):1184-1195. PMCID: PMC8362593.

O’Brien MP, Forleo-Neto E, Sarkar N, Isa F, Hou P, Chan KC, Musser BJ, Bar KJ, Barnabas RV, Barouch DH, Cohen MS, Hurt CB, Burwen DR, Marovich MA, Brown ER, Heirman I, Davis JD, Turner KC, Ramesh D, Mahmood A, Hooper AT, Hamilton JD, Kim Y, Purcell LA, Baum A, Kyratsous CA, Krainson J, Perez-Perez R, Mohseni R, Kowal B, DiCioccio AT, Geba GP, Stahl N, Lipsich L, Braunstein N, Herman G, Yancopoulos GD, Weinreich DM; COVID-19 Phase 3 Prevention Trial Team. Effect of Subcutaneous Casirivimab and Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-19 in Early Asymptomatic SARS-CoV-2 Infection: A Randomized Clinical Trial. JAMA. 2022 Feb 1;327(5):432-441. PMCID: PMC8808333.

Traver EC, Malavé Sánchez M. Pulmonary aspergillosis and cryptococcosis as a complication of COVID-19. Med Mycol Case Rep. 2022 Mar;35:22-25. PMCID: PMC8734106.

Mentors: Alison Morris, M.D., M.S., and Katie Suda, Pharm.D.

Research Summary

Dr. Konstantinidis’s research examines the risk factors for COPD exacerbation and guideline-concordance of COPD care in people living with HIV. He is also working to examine the trajectories of pulmonary function in people living with HIV using data from the Multicenter AIDS Cohort Study/Women’s Interagency HIV Study Combined Cohort Study and Pittsburgh AIDS Center for Treatment cohort with a manuscript drafted. Additionally, Dr. Konstantinidis is looking at Covid-19’s impact on psychosocial well-being of people living with HIV and/or COPD.

Dr. Konstantinidis’s research examines the burden of pulmonary disease, health care utilization and costs, and outcomes in people living with HIV using claims databases.  He is working to examine the impact of ambient air pollution and socioeconomic factors on the prevalence of self-reported pulmonary diagnose and symptoms, lung function (spirometry, DLCO), radiographic emphysema, lung cancer incidence, and all-cause mortality in people living with HIV using epidemiological cohort data (MACS/WIHS). His research will also work to examine longitudinal pulmonary function trajectories among people living with HIV and identify factors associated with group membership in different trajectories using epidemiological cohort data (MACS).

Dr. Konstantinidis is currently translating his findings to multiple manuscripts including one submitted using data from the Multicenter AIDS Cohort Study / Women’s Interagency HIV Study Combined Cohort Study and Pittsburgh Area Center for Treatment cohort (“Trajectories of pulmonary function in people living with HIV”); one focused on a systematic review and meta-analysis of lung disease burden in people living with HIV; and an invited Nature Reviews Disease Primers on HIV-associated lung disease. Additionally, he is assisting in the cohort development for “Risk factors for COPD exacerbation and guideline-concordance of COPD care in people living with HIV.”

Publications

Konstantinidis I, Kitsios GD, Morris A. The Impact of Acute Illness Severity on Post-COVID-19 Sequelae Remains an Unsettled Question. Ann Am Thorac Soc. 2021 Oct;18(10):1753. PMCID: PMC8522298.

Popescu I, Snyder ME, Iasella CJ, Hannan SJ, Koshy R, Burke R, Das A, Brown MJ, Lyons EJ, Lieber SC, Chen X, Sembrat JC, Bhatt P, Deng E, An X, Linstrum K, Kitsios G, Konstantinidis I, Saul M, Kass DJ, Alder JK, Chen BB, Lendermon EA, Kilaru S, Johnson B, Pilewski JM, Kiss JE, Wells AH, Morris A, McVerry BJ, McMahon DK, Triulzi DJ, Chen K, Sanchez PG, McDyer JF. CD4+ T-Cell Dysfunction in Severe COVID-19 Disease Is Tumor Necrosis Factor-α/Tumor Necrosis Factor Receptor 1-Dependent. Am J Respir Crit Care Med. 2022 Jun 15;205(12):1403-1418. PMID: 35348444.

Mentors: Sanjay Patel, M.D., M.S., and Bernard Macatangay, M.D.

Research Summary

Dr. Borker’s long-term career goal is to become an independent physician-scientist focused on understanding the mechanisms by which poor sleep leads to inflammation and immune dysfunction.

Her research investigates the pathophysiologic basis by which sleep affects inflammation and immunologic functions, focusing particularly on the profile among persons living with HIV. Dr. Borker is pursuing these questions through collaborations and training with her mentors, Dr. Patel and Dr. Macatangay, utilizing the Pittsburgh HIV Lung Research Cohort, Sleep and Adenosine Signaling in HIV Cohort, and the Multicenter AIDS Cohort Study. She is also learning immunologic laboratory techniques such as ELISA, Luminex and flow cytometry. Current projects include poor sleep and monocyte activation in chronic HIV (SASH cohort) and poor sleep and lymphocyte subsets in chronic HIV (MACS), as well as serving as a co-investigator on the SUPRA/aerSleep II Clinical Study. This year she will continue data generation and analysis of palmitate stimulation on monocyte integrin expression and monocyte flow cytometry.

In the previous year, Dr. Borker focused on establishing preliminary data and a bibliography to bolster her candidacy for a successful K23 grant submission. This year, her foremost career development goal is to submit a fundable K23 grant application in June. Additionally, she will apply for foundation grants this year in order to facilitate further lab work.

Publications

Borker PV, Patel SR. Monocyte Activation: The Link Between Obstructive Sleep Apnea and Cardiovascular Disease? Am J Respir Crit Care Med. 2022 Apr 18. PMID: 35436168.

Mentors: Joann Flynn, Ph.D., and Philana Lin, Ph.D.
Current Position: Assistant Professor, Department of Biology, Chatham University

Research Summary

As part of the Flynn lab, Dr. Winchell studied the role of unconventional T cells in HIV/Mtb. At necropsy, Dr. Winchell determined overall pathology and bacterial burden (CFU), finding that CD8 depletion resulted in animals having more overall pathology and extrapulmonary disease. CD8 depletion also resulted in higher thoracic CFU, however both CD8 and CD8 depletion resulted in higher CFU in the lymph nodes. These data indicate that CD8 expressing cells are important for early control of TB disease. CD8 may be important for dissemination in the lymph nodes, as they had similar burden as the CD8 depleted NHPs.

Publications

Ziegler CGK, Allon SJ, Nyquist SK, Mbano IM, Miao VN, Tzouanas CN, Cao Y, Yousif AS, Bals J, Hauser BM, Feldman J, Muus C, Wadsworth MH 2nd, Kazer SW, Hughes TK, Doran B, Gatter GJ, Vukovic M, Taliaferro F, Mead BE, Guo Z, Wang JP, Gras D, Plaisant M, Ansari M, Angelidis I, Adler H, Sucre JMS, Taylor CJ, Lin B, Waghray A, Mitsialis V, Dwyer DF, Buchheit KM, Boyce JA, Barrett NA, Laidlaw TM, Carroll SL, Colonna L, Tkachev V, Peterson CW, Yu A, Zheng HB, Gideon HP, Winchell CG, Lin PL, Bingle CD, Snapper SB, Kropski JA, Theis FJ, Schiller HB, Zaragosi LE, Barbry P, Leslie A, Kiem HP, Flynn JL, Fortune SM, Berger B, Finberg RW, Kean LS, Garber M, Schmidt AG, Lingwood D, Shalek AK, Ordovas-Montanes J; HCA Lung Biological Network. Electronic address: lung-network@humancellatlas.org; HCA Lung Biological Network. SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues. Cell. 2020 May 28;181(5):1016-1035.e19. PMCID: PMC7252096.

Winchell CG, Mishra BB, Phuah JY, Saqib M, Nelson SJ, Maiello P, Causgrove CM, Ameel CL, Stein B, Borish HJ, White AG, Klein EC, Zimmerman MD, Dartois V, Lin PL, Sassetti CM, Flynn JL. Evaluation of IL-1 Blockade as an Adjunct to Linezolid Therapy for Tuberculosis in Mice and Macaques. Front Immunol. 2020 May 12;11:891. PMCID: PMC7235418.

Gideon HP, Hughes TK, Tzouanas CN, Wadsworth MH 2nd, Tu AA, Gierahn TM, Peters JM, Hopkins FF, Wei JR, Kummerlowe C, Grant NL, Nargan K, Phuah JY, Borish HJ, Maiello P, White AG, Winchell CG, Nyquist SK, Ganchua SKC, Myers A, Patel KV, Ameel CL, Cochran CT, Ibrahim S, Tomko JA, Frye LJ, Rosenberg JM, Shih A, Chao M, Klein E, Scanga CA, Ordovas-Montanes J, Berger B, Mattila JT, Madansein R, Love JC, Lin PL, Leslie A, Behar SM, Bryson B, Flynn JL, Fortune SM, Shalek AK. Multimodal profiling of lung granulomas in macaques reveals cellular correlates of tuberculosis control. Immunity. 2022 May 10;55(5):827-846.e10. PMCID: PMC9122264.