Selected 2017 Publications

Cycling CD4+ T cells in HIV-infected immune nonresponders have mitochondrial dysfunction.

Younes SA, Talla A, Pereira Ribeiro S, Saidakova EV, Korolevskaya LB, Shmagel KV, Shive CL, Freeman ML, Panigrahi S, Zweig S, Balderas R, Margolis L, Douek DC, Anthony DD, Pandiyan P, Cameron M, Sieg SF, Calabrese LH, Rodriguez B, Lederman MM.

J. Clin. Invest. 2018 Oct;():. doi: 10.1172/JCI120245. Epub.

Abstract: Immune nonresponder (INR) HIV-1-infected subjects are characterized by their inability to reconstitute the CD4+ T cell pool after antiretroviral therapy. This is linked to poor clinical outcome. Mechanisms underlying immune reconstitution failure are poorly understood, although, counterintuitively, INRs often have increased frequencies of circulating CD4+ T cells in the cell cycle. While cycling CD4+ T cells from healthy controls and HIV+ patients with restored CD4+ T cell numbers complete cell division in vitro, cycling CD4+ T cells from INRs do not. Here, we show that cells with the phenotype and transcriptional profile of Tregs were enriched among cycling cells in health and in HIV infection. Yet there were diminished frequencies and numbers of Tregs among cycling CD4+ T cells in INRs, and cycling CD4+ T cells from INR subjects displayed transcriptional profiles associated with the impaired development and maintenance of functional Tregs. Flow cytometric assessment of TGF-β activity confirmed the dysfunction of Tregs in INR subjects. Transcriptional profiling and flow cytometry revealed diminished mitochondrial fitness in Tregs among INRs, and cycling Tregs from INRs had low expression of the mitochondrial biogenesis regulators peroxisome proliferator-activated receptor γ coactivator 1-α (PGC1α) and transcription factor A for mitochondria (TFAM). In vitro exposure to IL-15 allowed cells to complete division, restored the expression of PGC1α and TFAM, and regenerated mitochondrial fitness in the cycling Tregs of INRs. Our data suggest that rescuing mitochondrial function could correct the immune dysfunction characteristic of Tregs in HIV-1-infected subjects who fail to restore CD4+ T cells during antiretroviral therapy. © The Journal Of Clinical Investigation.

HIV-1 proviral landscapes distinguish posttreatment controllers from noncontrollers.

Sharaf R, Lee GQ, Sun X, Etemad B, Aboukhater LM, Hu Z, Brumme ZL, Aga E, Bosch RJ, Wen Y, Namazi G, Gao C, Acosta EP, Gandhi RT, Jacobson JM, Skiest D, Margolis DM, Mitsuyasu R, Volberding P, Connick E, Kuritzkes DR, Lederman MM, Yu XG, Lichterfeld M, Li JZ.

J. Clin. Invest. 2018 Aug;128(9):4074-4085. doi: 10.1172/JCI120549. Epub.

Abstract: HIV posttreatment controllers (PTCs) represent a natural model of sustained HIV remission, but they are rare and little is known about their viral reservoir. We obtained 1,450 proviral sequences after near-full-length amplification for 10 PTCs and 16 posttreatment noncontrollers (NCs). Before treatment interruption, the median intact and total reservoir size in PTCs was 7-fold lower than in NCs, but the proportion of intact, defective, and total clonally expanded proviral genomes was not significantly different between the 2 groups. Quantification of total but not intact proviral genome copies predicted sustained HIV remission as 81% of NCs, but none of the PTCs had a total proviral genome greater than 4 copies per million peripheral blood mononuclear cells (PBMCs). The results highlight the restricted intact and defective HIV reservoir in PTCs and suggest that total proviral genome burden could act as the first biomarker for identifying PTCs. Total and defective but not intact proviral copy numbers correlated with levels of cell-associated HIV RNA, activated NK cell percentages, and both HIV-specific CD4+ and CD8+ responses. These results support the concept that defective HIV genomes can lead to viral antigen production and interact with both the innate and adaptive immune systems. © The Journal Of Clinical Investigation.

A System of Cytokines Encapsulated in ExtraCellular Vesicles.

Fitzgerald W, Freeman ML, Lederman MM, Vasilieva E, Romero R, Margolis L.

Sci Rep 2018 Jun;8(1):8973. doi: 10.1038/s41598-018-27190-x. Epub.

Abstract: Cytokines are soluble factors that mediate cell-cell communications in multicellular organisms. Recently, another system of cell-cell communication was discovered, which is mediated by extracellular vesicles (EVs). Here, we demonstrate that these two systems are not strictly separated, as many cytokines in vitro, ex vivo, and in vivo are released in EV-encapsulated forms and are capable of eliciting biological effects upon contact with sensitive cells. Association with EVs is not necessarily a property of a particular cytokine but rather of a biological system and can be changed upon system activation. EV-encapsulated cytokines were not detected by standard cytokine assays. Deciphering the regulatory mechanisms of EV-encapsulation will lead to a better understanding of cell-cell communications in health and disease. © Scientific Reports.

Lymphoid tissue fibrosis is associated with impaired vaccine responses.

Kityo C, Makamdop KN, Rothenberger M, Chipman JG, Hoskuldsson T, Beilman GJ, Grzywacz B, Mugyenyi P, Ssali F, Akondy RS, Anderson J, Schmidt TE, Reimann T, Callisto SP, Schoephoerster J, Schuster J, Muloma P, Ssengendo P, Moysi E, Petrovas C, Lanciotti R, Zhang L, Arévalo MT, Rodriguez B, Ross TM, Trautmann L, Sekaly RP, Lederman MM, Koup RA, Ahmed R, Reilly C, Douek DC, Schacker TW.

J. Clin. Invest. 2018 Jul;128(7):2763-2773. doi: 10.1172/JCI97377. Epub.

Abstract: Vaccine responses vary by geographic location. We have previously described how HIV-associated inflammation leads to fibrosis of secondary lymph nodes (LNs) and T cell depletion. We hypothesized that other infections may cause LN inflammation and fibrosis, in a process similar to that seen in HIV infection, which may lead to T cell depletion and affect vaccine responses. We studied LNs of individuals from Kampala, Uganda, before and after yellow fever vaccination (YFV) and found fibrosis in LNs that was similar to that seen in HIV infection. We found blunted antibody responses to YFV that correlated to the amount of LN fibrosis and loss of T cells, including T follicular helper cells. These data suggest that LN fibrosis is not limited to HIV infection and may be associated with impaired immunologic responses to vaccines. This may have an impact on vaccine development, especially for infectious diseases prevalent in the developing world. © The Journal Of Clinical Investigation.

Effect of antiretroviral therapy on plasma concentrations of chloroquine and desethyl-chloroquine.

Ippolito MM, Jacobson JM, Lederman MM, Winterberg M, Tarning J, Shapiro TA, Flexner C.

Clin. Infect. Dis. 2018 May;():. doi: 10.1093/cid/ciy405. Epub.

Abstract: The effect of antiretroviral therapy (ART) on chloroquine and desethyl-chloroquine plasma concentrations was evaluated in clinical trial participants. Concentrations did not differ among participants on protease inhibitor-based ART (n=9), efavirenz-based ART (n=15), other ART (n=8), and those not on ART (n=31). Efavirenz appeared to inhibit chloroquine desethylation. © Clinical Infectious Diseases : An Official Publication Of The Infectious Diseases Society Of America.

Telmisartan Therapy Does Not Improve Lymph Node or Adipose Tissue Fibrosis More Than Continued Antiretroviral Therapy Alone.

Utay NS, Kitch DW, Yeh E, Fichtenbaum CJ, Lederman MM, Estes JD, Deleage C, Magyar C, Nelson SD, Klingman KL, Bastow B, Luque AE, McComsey GA, Douek DC, Currier JS, Lake JE, .

J. Infect. Dis. 2018 May;217(11):1770-1781. doi: 10.1093/infdis/jiy064. Epub.

Abstract: Fibrosis in lymph nodes may limit CD4+ T-cell recovery, and lymph node and adipose tissue fibrosis may contribute to inflammation and comorbidities despite antiretroviral therapy (ART). We hypothesized that the angiotensin receptor blocker and peroxisome proliferator-activated receptor γ agonist telmisartan would decrease lymph node or adipose tissue fibrosis in treated human immunodeficiency virus type 1 (HIV) infection. © The Journal Of Infectious Diseases.

Anisocytosis and leukocytosis are independently related to survival after transcatheter aortic valve replacement.

Attizzani GF, Al-Kindi SG, Dalton JE, Alkhalil A, DeCicco A, Mayuga M, Funderburg NT, Blackstone EH, Parikh S, Longenecker CT, Lederman MM, Simon DI, Costa MA, Zidar DA.

J Cardiovasc Med (Hagerstown) 2018 Apr;19(4):191-194. doi: . Epub.

Abstract: © Journal Of Cardiovascular Medicine (Hagerstown, Md.).

Changes in Inflammation but Not in T-Cell Activation Precede Non-AIDS-Defining Events in a Case-Control Study of Patients on Long-term Antiretroviral Therapy.

Angelidou K, Hunt PW, Landay AL, Wilson CC, Rodriguez B, Deeks SG, Bosch RJ, Lederman MM.

J. Infect. Dis. 2018 Jun;218(2):239-248. doi: 10.1093/infdis/jix666. Epub.

Abstract: We examined changes in soluble inflammatory cytokines and T-cell activation after antiretroviral therapy (ART) initiation in an AIDS Clinical Trials Group (ACTG) nested case-control study. © The Journal Of Infectious Diseases.

Pre-vaccine plasma levels of soluble inflammatory indices negatively predict responses to HAV, HBV, and tetanus vaccines in HCV and HIV infection.

Shive CL, Judge CJ, Clagett B, Kalayjian RC, Osborn M, Sherman KE, Fichtenbaum C, Gandhi RT, Kang M, Popkin DL, Sieg SF, Lederman MM, Rodriguez B, Anthony DD.

Vaccine 2018 01;36(4):453-460. doi: 10.1016/j.vaccine.2017.12.018. Epub.

Abstract: Chronic hepatitis C virus (HCV) and HIV infections are associated with impaired responses to neo-antigens contained in hepatitis A virus (HAV)/hepatitis B virus (HBV) vaccines, yet responsible mechanisms are unclear. © Vaccine.

Effect of IL-7 Therapy on Phospho-Ribosomal Protein S6 and TRAF1 Expression in HIV-Specific CD8 T Cells in Patients Receiving Antiretroviral Therapy.

Wang C, Edilova MI, Wagar LE, Mujib S, Singer M, Bernard NF, Croughs T, Lederman MM, Sereti I, Fischl MA, Kremmer E, Ostrowski M, Routy JP, Watts TH.

J. Immunol. 2018 01;200(2):558-564. doi: 10.4049/jimmunol.1601254. Epub.

Abstract: IL-7 therapy has been evaluated in patients who do not regain normal CD4 T cell counts after virologically successful antiretroviral therapy. IL-7 increases total circulating CD4 and CD8 T cell counts; however, its effect on HIV-specific CD8 T cells has not been fully examined. TRAF1, a prosurvival signaling adaptor required for 4-1BB-mediated costimulation, is lost from chronically stimulated virus-specific CD8 T cells with progression of HIV infection in humans and during chronic lymphocytic choriomeningitis infection in mice. Previous results showed that IL-7 can restore TRAF1 expression in virus-specific CD8 T cells in mice, rendering them sensitive to anti-4-1BB agonist therapy. In this article, we show that IL-7 therapy in humans increases the number of circulating HIV-specific CD8 T cells. For a subset of patients, we also observed an increased frequency of TRAF1 HIV-specific CD8 T cells 10 wk after completion of IL-7 treatment. IL-7 treatment increased levels of phospho-ribosomal protein S6 in HIV-specific CD8 T cells, suggesting increased activation of the metabolic checkpoint kinase mTORC1. Thus, IL-7 therapy in antiretroviral therapy-treated patients induces sustained changes in the number and phenotype of HIV-specific T cells. © Journal Of Immunology (Baltimore, Md. : 1950).