Major Areas of Research
- Mechanisms of viral persistence in HIV-infected individuals receiving antiretroviral therapy
- Dynamics of immunologic and virologic parameters in HIV infection
- Therapeutic strategies aiming at achieving sustained virologic control of HIV infection
Program Description
Our research program focuses on delineation of the mechanism by which HIV persists in infected individuals receiving clinically effective antiretroviral therapy. We utilize a variety of highly sensitive cellular and molecular assays to examine the dynamics of HIV burden in subsets of CD4+ T cells and immune cells that mediate virologic control in infected individuals. We also conduct phase I clinical trials to develop safe and effective therapeutic strategies for control of HIV infection in HIV-infected individuals in the absence of daily antiretroviral drugs.
Biography
Dr. Blazkova received her Ph.D. in Immunology at the Mediterranean University of Aix-Marseille II, France in 2006. Afterwards she conducted postdoctoral research at the Institute of Molecular Genetics, Academy of Sciences of the Czech Republic in Prague. In 2010, Dr. Blazkova joined the Laboratory of Immunoregulation at NIAID as a Visiting Fellow. In 2015, she worked at the Systems Biology Department, Division of Translational Medicine, Sidra Medical and Research Center, Doha, Qatar, for one year as a Senior Postdoctoral Fellow. In 2016, Dr. Blazkova returned to the NIAID and was appointed as a Staff Scientist in the HIV Immunovirology section, LIR.
Selected Publications
Blazkova J, Gao F, Marichannegowda MH, Justement JS, Shi V, Whitehead EJ, Schneck RF, Huiting ED, Gittens K, Cottrell M, Benko E, Kovacs C, Lack J, Sneller MC, Moir S, Fauci AS, Chun TW. Distinct mechanisms of long-term virologic control in two HIV-infected individuals after treatment interruption of anti-retroviral therapy. Nat Med. 2021 Nov;27(11):1893-1898.
Blazkova J, Huiting ED, Boddapati AK, Shi V, Whitehead EJ, Justement JS, Nordstrom JL, Moir S, Lack J, Chun TW. Correlation Between TIGIT Expression on CD8+ T Cells and Higher Cytotoxic Capacity. J Infect Dis. 2021 Nov 16;224(9):1599-1604.
Blazkova J, Refsland EW, Clarridge KE, Shi V, Justement JS, Huiting ED, Gittens KR, Chen X, Schmidt SD, Liu C, Doria-Rose N, Mascola JR, Heredia A, Moir S, Chun TW. Glycan-dependent HIV-specific neutralizing antibodies bind to cells of uninfected individuals. J Clin Invest. 2019 Nov 1;129(11):4832-4837.
Wang CY, Wong WW, Tsai HC, Chen YH, Kuo BS, Lynn S, Blazkova J, Clarridge KE, Su HW, Lin CY, Tseng FC, Lai A, Yang FH, Lin CH, Tseng W, Lin HY, Finstad CL, Wong-Staal F, Hanson CV, Chun TW, Liao MJ. Effect of Anti-CD4 Antibody UB-421 on HIV-1 Rebound after Treatment Interruption. N Engl J Med. 2019 Apr 18;380(16):1535-1545.
Our research program focuses on delineation of the mechanism by which HIV persists in infected individuals receiving clinically effective antiretroviral therapy. We utilize a variety of highly sensitive cellular and molecular assays to examine the dynamics of HIV burden in subsets of CD4+ T cells and immune cells that mediate virologic control in infected individuals. We also conduct phase I clinical trials to develop safe and effective therapeutic strategies for control of HIV infection in HIV-infected individuals in the absence of daily antiretroviral drugs.
Blazkova J, Gao F, Marichannegowda MH, Justement JS, Shi V, Whitehead EJ, Schneck RF, Huiting ED, Gittens K, Cottrell M, Benko E, Kovacs C, Lack J, Sneller MC, Moir S, Fauci AS, Chun TW. Distinct mechanisms of long-term virologic control in two HIV-infected individuals after treatment interruption of anti-retroviral therapy. Nat Med. 2021 Nov;27(11):1893-1898.
Blazkova J, Huiting ED, Boddapati AK, Shi V, Whitehead EJ, Justement JS, Nordstrom JL, Moir S, Lack J, Chun TW. Correlation Between TIGIT Expression on CD8+ T Cells and Higher Cytotoxic Capacity. J Infect Dis. 2021 Nov 16;224(9):1599-1604.
Blazkova J, Refsland EW, Clarridge KE, Shi V, Justement JS, Huiting ED, Gittens KR, Chen X, Schmidt SD, Liu C, Doria-Rose N, Mascola JR, Heredia A, Moir S, Chun TW. Glycan-dependent HIV-specific neutralizing antibodies bind to cells of uninfected individuals. J Clin Invest. 2019 Nov 1;129(11):4832-4837.
Wang CY, Wong WW, Tsai HC, Chen YH, Kuo BS, Lynn S, Blazkova J, Clarridge KE, Su HW, Lin CY, Tseng FC, Lai A, Yang FH, Lin CH, Tseng W, Lin HY, Finstad CL, Wong-Staal F, Hanson CV, Chun TW, Liao MJ. Effect of Anti-CD4 Antibody UB-421 on HIV-1 Rebound after Treatment Interruption. N Engl J Med. 2019 Apr 18;380(16):1535-1545.
- Mechanisms of viral persistence in HIV-infected individuals receiving antiretroviral therapy
- Dynamics of immunologic and virologic parameters in HIV infection
- Therapeutic strategies aiming at achieving sustained virologic control of HIV infection
Soma Ghosh, Ph.D.
Major Areas of Research
- Within-host evolution of Gram-negative bacterial pathogens in the context of chronic infection and immunodeficiency
- Transcriptional and metabolic reprogramming that occurs during host adaptation
- DNA methylation and epigenetic regulation of bacterial virulence and antibiotic resistance
Program Description
Bacterial pathogens may undergo dramatic evolution in the context of chronic infection, facilitating host adaptation and the development of antibiotic resistance. Recent studies have illustrated that many general evolutionary processes can be discerned in this context, including genetic diversification of lineages with purifying selection, clonal succession events, and balanced fitness trade-offs. Dr. Ghosh’s research within the Bacterial Pathogenesis and Antimicrobial Resistance Unit (BPARU) focuses on the mechanisms of bacterial pathoadaptation that occurs in the context of persistent infection in the immunocompromised host. These questions are investigated with a combination of genomic sequencing, transcriptome analysis, DNA methylome characterization, and metabolomic profiling. This work aims to understand transcriptional and metabolic reprograming that underlies host adaptation, with implications for clinical treatment of persistent host-adapted infections.
Biography
Dr. Ghosh received her Ph.D. in 2015 from the Indian Institute of Science, Bangalore, India, where she used Systems Biology approaches to study host-pathogen interactions in the context of iron acquisition by M. tuberculosis. She joined Johns Hopkins University, Baltimore in 2015 as a post-doctoral research fellow with Dr. Tamara O’Connor in the department of Biological Chemistry. There, she studied convergent evolution in Legionella and how the combined selective pressures of residing in multiple protozoan hosts have equipped Legionella to infect mammalian hosts, including humans. Dr. Ghosh joined the BPARU as a Staff Scientist in December 2021, where she is using her combined training in computational and experimental methods to study bacterial pathogenesis.
Selected Publications
Park JM, Ghosh S, O'Connor TJ. Combinatorial selection in amoebal hosts drives the evolution of the human pathogen Legionella pneumophila. Nat Microbiol. 2020 Apr;5(4):599-609.
Ghosh S, O'Connor TJ. Beyond Paralogs: The Multiple Layers of Redundancy in Bacterial Pathogenesis. Front Cell Infect Microbiol. 2017 Nov 15;7:467.
O'Connor TJ, Zheng H, VanRheenen SM, Ghosh S, Cianciotto NP, Isberg RR. Iron Limitation Triggers Early Egress by the Intracellular Bacterial Pathogen Legionella pneumophila. Infect Immun. 2016 Jul 21;84(8):2185-2197.
Ghosh S, Chandra N, Vishveshwara S. Mechanism of Iron-Dependent Repressor (IdeR) Activation and DNA Binding: A Molecular Dynamics and Protein Structure Network Study. PLoS Comput Biol. 2015 Dec 23;11(12):e1004500.
Ghosh S, Baloni P, Mukherjee S, Anand P, Chandra N. A multi-level multi-scale approach to study essential genes in Mycobacterium tuberculosis. BMC Syst Biol. 2013 Dec 5;7:132.
Ghosh S, Prasad KV, Vishveshwara S, Chandra N. Rule-based modelling of iron homeostasis in tuberculosis. Mol Biosyst. 2011 Oct;7(10):2750-68.
Bacterial pathogens may undergo dramatic evolution in the context of chronic infection, facilitating host adaptation and the development of antibiotic resistance. Recent studies have illustrated that many general evolutionary processes can be discerned in this context, including genetic diversification of lineages with purifying selection, clonal succession events, and balanced fitness trade-offs. Dr. Ghosh’s research within the Bacterial Pathogenesis and Antimicrobial Resistance Section (BPARS) focuses on the mechanisms of bacterial pathoadaptation that occurs in the context of persistent infection in the immunocompromised host. These questions are investigated with a combination of genomic sequencing, transcriptome analysis, DNA methylome characterization, and metabolomic profiling. This work aims to understand transcriptional and metabolic reprograming that underlies host adaptation, with implications for clinical treatment of persistent host-adapted infections.
Park JM, Ghosh S, O'Connor TJ. Combinatorial selection in amoebal hosts drives the evolution of the human pathogen Legionella pneumophila. Nat Microbiol. 2020 Apr;5(4):599-609.
Ghosh S, O'Connor TJ. Beyond Paralogs: The Multiple Layers of Redundancy in Bacterial Pathogenesis. Front Cell Infect Microbiol. 2017 Nov 15;7:467.
O'Connor TJ, Zheng H, VanRheenen SM, Ghosh S, Cianciotto NP, Isberg RR. Iron Limitation Triggers Early Egress by the Intracellular Bacterial Pathogen Legionella pneumophila. Infect Immun. 2016 Jul 21;84(8):2185-2197.
Ghosh S, Chandra N, Vishveshwara S. Mechanism of Iron-Dependent Repressor (IdeR) Activation and DNA Binding: A Molecular Dynamics and Protein Structure Network Study. PLoS Comput Biol. 2015 Dec 23;11(12):e1004500.
Ghosh S, Baloni P, Mukherjee S, Anand P, Chandra N. A multi-level multi-scale approach to study essential genes in Mycobacterium tuberculosis. BMC Syst Biol. 2013 Dec 5;7:132.
Ghosh S, Prasad KV, Vishveshwara S, Chandra N. Rule-based modelling of iron homeostasis in tuberculosis. Mol Biosyst. 2011 Oct;7(10):2750-68.
- Within-host evolution of Gram-negative bacterial pathogens in the context of chronic infection and immunodeficiency
- Transcriptional and metabolic reprogramming that occurs during host adaptation
- DNA methylation and epigenetic regulation of bacterial virulence and antibiotic resistance
Ray Y. Chen
Major Areas of Research
Tuberculosis
Program Description
Clinical trials focused on diagnostics, novel treatment strategies, and treatment shortening methodologies for tuberculosis.
Biography
Dr. Chen graduated from the Medical College of Virginia/Virginia Commonwealth University in Richmond, Virginia, then trained in Internal Medicine at the Thomas Jefferson University Hospital in Philadelphia, Pennsylvania and in Infectious Diseases at the University of Alabama at Birmingham (UAB). While at UAB, he also earned a Master of Science in Public Health with a concentration in epidemiology.
Dr. Chen came to NIAID in 2003 to the Division of AIDS (DAIDS) and was based in Beijing, China for DAIDS from 2004-2012, working with Chinese investigators. In 2012, he returned to Bethesda, MD and joined the Tuberculosis Research Section in the Laboratory of Clinical Immunology and Microbiology, Division of Intramural Research.
Selected Publications
Chen RY, Yu X, Smith B, Liu X, Gao J, Diacon AH, Dawson R, Tameris M, Zhu H, Qu Y, Zhang R, Pan S, Jin X, Goldfeder LC, Cai Y, Arora K, Wang J, Vincent J, Malherbe ST, Thienemann F, Wilkinson RJ, Walzl G, Barry CE 3rd. Radiological and functional evidence of the bronchial spread of tuberculosis: an observational analysis. Lancet Microbe. 2021 Oct;2(10):e518-e526.
Xie YL, de Jager VR, Chen RY, Dodd LE, Paripati P, Via LE, Follmann D, Wang J, Lumbard K, Lahouar S, Malherbe ST, Andrews J, Yu X, Goldfeder LC, Cai Y, Arora K, Loxton AG, Vanker N, Duvenhage M, Winter J, Song T, Walzl G, Diacon AH, Barry CE 3rd. Fourteen-day PET/CT imaging to monitor drug combination activity in treated individuals with tuberculosis. Sci Transl Med. 2021 Feb 3;13(579):eabd7618.
Lee A, Xie YL, Barry CE, Chen RY. Current and future treatments for tuberculosis. BMJ. 2020 Mar 2;368:m216.
Xie YL, Chakravorty S, Armstrong DT, Hall SL, Via LE, Song T, Yuan X, Mo X, Zhu H, Xu P, Gao Q, Lee M, Lee J, Smith LE, Chen RY, Joh JS, Cho Y, Liu X, Ruan X, Liang L, Dharan N, Cho SN, Barry CE 3rd, Ellner JJ, Dorman SE, Alland D. Evaluation of a Rapid Molecular Drug-Susceptibility Test for Tuberculosis. N Engl J Med. 2017 Sep 14;377(11):1043-1054.
Malherbe ST, Shenai S, Ronacher K, Loxton AG, Dolganov G, Kriel M, Van T, Chen RY, Warwick J, Via LE, Song T, Lee M, Schoolnik G, Tromp G, Alland D, Barry CE 3rd, Winter J, Walzl G; Catalysis TB–Biomarker Consortium, Lucas L, Spuy GV, Stanley K, Thiart L, Smith B, Du Plessis N, Beltran CG, Maasdorp E, Ellmann A, Choi H, Joh J, Dodd LE, Allwood B, Koegelenberg C, Vorster M, Griffith-Richards S. Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure. Nat Med. 2016 Oct;22(10):1094-1100.
Chen RY, Dodd LE, Lee M, Paripati P, Hammoud DA, Mountz JM, Jeon D, Zia N, Zahiri H, Coleman MT, Carroll MW, Lee JD, Jeong YJ, Herscovitch P, Lahouar S, Tartakovsky M, Rosenthal A, Somaiyya S, Lee S, Goldfeder LC, Cai Y, Via LE, Park SK, Cho SN, Barry CE 3rd. PET/CT imaging correlates with treatment outcome in patients with multidrug-resistant tuberculosis. Sci Transl Med. 2014 Dec 3;6(265):265ra166.
Clinical trials focused on diagnostics, novel treatment strategies, and treatment shortening methodologies for tuberculosis.
Chen RY, Yu X, Smith B, Liu X, Gao J, Diacon AH, Dawson R, Tameris M, Zhu H, Qu Y, Zhang R, Pan S, Jin X, Goldfeder LC, Cai Y, Arora K, Wang J, Vincent J, Malherbe ST, Thienemann F, Wilkinson RJ, Walzl G, Barry CE 3rd. Radiological and functional evidence of the bronchial spread of tuberculosis: an observational analysis. Lancet Microbe. 2021 Oct;2(10):e518-e526.
Xie YL, de Jager VR, Chen RY, Dodd LE, Paripati P, Via LE, Follmann D, Wang J, Lumbard K, Lahouar S, Malherbe ST, Andrews J, Yu X, Goldfeder LC, Cai Y, Arora K, Loxton AG, Vanker N, Duvenhage M, Winter J, Song T, Walzl G, Diacon AH, Barry CE 3rd. Fourteen-day PET/CT imaging to monitor drug combination activity in treated individuals with tuberculosis. Sci Transl Med. 2021 Feb 3;13(579):eabd7618.
Lee A, Xie YL, Barry CE, Chen RY. Current and future treatments for tuberculosis. BMJ. 2020 Mar 2;368:m216.
Xie YL, Chakravorty S, Armstrong DT, Hall SL, Via LE, Song T, Yuan X, Mo X, Zhu H, Xu P, Gao Q, Lee M, Lee J, Smith LE, Chen RY, Joh JS, Cho Y, Liu X, Ruan X, Liang L, Dharan N, Cho SN, Barry CE 3rd, Ellner JJ, Dorman SE, Alland D. Evaluation of a Rapid Molecular Drug-Susceptibility Test for Tuberculosis. N Engl J Med. 2017 Sep 14;377(11):1043-1054.
Malherbe ST, Shenai S, Ronacher K, Loxton AG, Dolganov G, Kriel M, Van T, Chen RY, Warwick J, Via LE, Song T, Lee M, Schoolnik G, Tromp G, Alland D, Barry CE 3rd, Winter J, Walzl G; Catalysis TB–Biomarker Consortium, Lucas L, Spuy GV, Stanley K, Thiart L, Smith B, Du Plessis N, Beltran CG, Maasdorp E, Ellmann A, Choi H, Joh J, Dodd LE, Allwood B, Koegelenberg C, Vorster M, Griffith-Richards S. Persisting positron emission tomography lesion activity and Mycobacterium tuberculosis mRNA after tuberculosis cure. Nat Med. 2016 Oct;22(10):1094-1100.
Chen RY, Dodd LE, Lee M, Paripati P, Hammoud DA, Mountz JM, Jeon D, Zia N, Zahiri H, Coleman MT, Carroll MW, Lee JD, Jeong YJ, Herscovitch P, Lahouar S, Tartakovsky M, Rosenthal A, Somaiyya S, Lee S, Goldfeder LC, Cai Y, Via LE, Park SK, Cho SN, Barry CE 3rd. PET/CT imaging correlates with treatment outcome in patients with multidrug-resistant tuberculosis. Sci Transl Med. 2014 Dec 3;6(265):265ra166.
- Tuberculosis