Pathogenesis and Molecular Biology of Viruses
Gary P. Wang, MD, PhD, FIDSA
Title: Associate Professor
Department: Medicine; Division of Infectious Diseases and Global Medicine
Research Interests: human immunodeficiency virus (HIV), Hepatitis C virus (HCV)
Our laboratory has a longstanding interest in the pathogenesis and molecular biology of viruses that cause chronic human infections, in particular, human immunodeficiency virus (HIV) and Hepatitis C virus (HCV). More recently,
we have become fascinated by how humans live in symbiosis with a diverse community of commensal organisms, and by how perturbation of this fine balance can lead to devastating infections. Building on our expertise in genomics and infectious diseases, our laboratory has embarked on a new area of investigation to understand the role of indigenous microbial communities in human infections. Thus, our current research falls within the general themes of host-pathogen interactions, and is divided into two major areas: (1) Molecular studies of HIV and HCV pathogenesis and drug resistance; and (2) Ecology of indigenous microbial communities associated with human infections. Our studies in microbial ecology include investigations of gut microbiota during Clostridium difficile infection, chronic periodontal disease in HIV, lung microbiota in cystic fibrosis, and microbial ecology during febrile neutropenia. We use a variety of techniques ranging from next-generation sequencing, bioinformatics and traditional methods of molecular biology.
Molecular studies of HCV pathogenesis and drug resistance
Hepatitis C virus infects over 170 million individuals worldwide. Therapy using pegylated-interferon and ribavirin is curative in only up to 50% of individuals with genotype 1 virus infection, but treatment outcome has substantially improved with newer small molecular inhibitors that specifically target HCV-encoded protein. However, resistance to these new drugs is an important consideration in HCV therapy. We are currently investigating the prevalence, frequency, and the dynamics of naturally occurring mutations associated with NS3 protease resistance, including those that circulate at very low frequencies. These studies will provide an important framework for analyzing the emergence and dynamics of resistance during viral breakthrough or relapse after therapy with new therapeutic agents. Our long-term goal is to determine the most effective therapeutic strategies for the treatment of chronic HCV infection using the new generation of small molecule inhibitors.
Ecology of indigenous microbial communities
Some 100 trillion microorganisms inhabit and colonize our human body. These commensal organisms, collectively known as human microbiota, serve a wide range of functions increasingly recognized as mutualistic and indispensable for the health of the host, including proper digestion, metabolism, and, importantly, colonization resistance against pathogens. Alterations of human microbiota have been linked to asthma, allergic diseases, immune system development, and inflammatory bowel diseases. Our research focuses on understanding the ecology and variations of indigenous microbial communities in relation to infectious diseases. For example, in one recent study, we identified several essential butyrate and short-chain fatty acid producing bacteria that were markedly depleted in Clostridium difficile infection (CDI), a health care associated infection that is responsible for 3 million cases of diarrhea in the US annually. Our results implicate butyric acid-producing anaerobic bacteria in C. difficile pathogenesis and suggest a potential role in colonization resistance against C. difficile. The discovery of potential protective organisms in the gut will greatly increase the understanding of C. difficile pathogenesis, and may lead to the development of novel approaches for the prevention and treatment of CDI based on probiotics.
- The subgingival microbiome in patients with established rheumatoid arthritis. Mikuls TR, Walker C, Qiu F, Yu F, Thiele GM, Alfant B, Li EC, Zhao LY, Wang GP, Datta S, Payne JB. Rheumatology (Oxford, England). 2018; PubMed [journal] PMID: 29562298
- Prevalence and impact of baseline resistance-associated substitutions on the efficacy of ledipasvir/sofosbuvir or simeprevir/sofosbuvir against GT1 HCV infection. Wang GP, Terrault N, Reeves JD, Liu L, Li E, Zhao L, Lim JK, Morelli G, Kuo A, Levitsky J, Sherman KE, Frazier LM, Ramani A, Peter J, Akuskevich L, Fried MW, Nelson DR. Scientific reports. 2018; 8(1):3199. PubMed [journal] PMID: 29453451 PMCID: PMC5816647
- Molecular Identification of Bacteria in Intra-abdominal Abscesses Using Deep Sequencing. Kozlov A, Bean L, Hill EV, Zhao L, Li E, Wang GP. Open forum infectious diseases. 2018; 5(2):ofy025. PubMed [journal] PMID: 29479554 PMCID: PMC5817941
- Sofosbuvir (SOF) Suppresses Ledipasvir (LDV)-resistant Mutants during SOF/LDV Combination Therapy against Genotype 1b Hepatitis C Virus (HCV). Brown AN, Liu L, Rodriquez JL, Zhao L, Schuster L, Li E, Wang GP, Neely MN, Yamada W, Drusano GL.Scientific reports. 2017; 7(1):14421. PubMed [journal] PMID: 29089577 PMCID: PMC5663921
- Sequencing of hepatitis C virus for detection of resistance to direct-acting antiviral therapy: A systematic review. Bartlett SR, Grebely J, Eltahla AA, Reeves JD, Howe AYM, Miller V, Ceccherini-Silberstein F, Bull RA, Douglas MW, Dore GJ, Harrington P, Lloyd AR, Jacka B, Matthews GV, Wang GP, Pawlctsky JM, Feld JJ, Schinkel J, Garcia F, Lennerstrand J, Applegate TL. Hepatology communications. 2017; 1(5):379-390. PubMed [journal] PMID: 29404466 PMCID: PMC5721421
- Butyrogenic bacteria as probiotics to treat Clostridium difficile. Wang GP. University of Florida Research Foundation, Incorporated (Gainesville, FL, US) , assignee. US 9,669,059. [patent]
- Locoregional Effects of Microbiota in a Preclinical Model of Colon Carcinogenesis. Tomkovich S, Yang Y, Winglee K, Gauthier J, Mühlbauer M, Sun X, Mohamadzadeh M, Liu X, Martin P, Wang GP, Oswald E, Fodor AA, Jobin C. Cancer research. 2017; 77(10):2620-2632. NIHMSID: NIHMS862411. PubMed [journal] PMID: 28416491 PMCID: PMC5468752
- Shifts in the Gut Microbiota Composition Due to Depleted Bone Marrow Beta Adrenergic Signaling Are Associated with Suppressed Inflammatory Transcriptional Networks in the Mouse Colon. Yang T, Ahmari N, Schmidt JT, Redler T, Arocha R, Pacholec K, Magee KL, Malphurs W, Owen JL, Krane GA, Li E, Wang GP, Vickroy TW, Raizada MK, Martyniuk CJ, Zubcevic J. Frontiers in physiology. 2017; 8:220. PubMed [journal] PMID: 28446880 PMCID: PMC5388758
- Biofilm Formation by Mycobacterium abscessus in a Lung Cavity. Fennelly KP, Ojano-Dirain C, Yang Q, Liu L, Lu L, Progulske-Fox A, Wang GP, Antonelli P, Schultz G. American journal of respiratory and critical care medicine. 2016; 193(6):692-3. PubMed [journal] PMID: 26731090
- CD4+ T-cell recovery with suppressive ART-induced rapid sequence evolution in hepatitis C virus envelope but not NS3. Liu L, Nardo D, Li E, Wang GP. AIDS (London, England). 2016; 30(5):691-700. NIHMSID: NIHMS744422. PubMed [journal] PMID: 26645605 PMCID: PMC4767613
- An Integrated Metabolomic and Microbiome Analysis Identified Specific Gut Microbiota Associated with Fecal Cholesterol and Coprostanol in Clostridium difficile Infection. Antharam VC, McEwen DC, Garrett TJ, Dossey AT, Li EC, Kozlov AN, Mesbah Z, Wang GP. PloS one. 2016; 11(2):e0148824. PubMed [journal] PMID: 26871580 PMCID: PMC4752508
- Defining functional signatures of dysbiosis in periodontitis progression. Wang GP. Genome medicine. 2015; 7(1):40. PubMed [journal] PMID: 25926890 PMCID: PMC4414443
- Dysbiosis and alterations in predicted functions of the subgingival microbiome in chronic periodontitis. Kirst ME, Li EC, Alfant B, Chi YY, Walker C, Magnusson I, Wang GP. Applied and environmental microbiology. 2015; 81(2):783-93. PubMed [journal] PMID: 25398868 PMCID: PMC4277562
- Epithelial CaSR deficiency alters intestinal integrity and promotes pro inflammatory immune responses. Cheng SX, Lightfoot YL, Yang T, Zadeh M, Tang L, Sahay B, Wang GP, Owen JL, Mohamadzadeh M. FEBS letters. 2014; 588(22):4158-66. NIHMSID: NIHMS600475. PubMed [journal] PMID: 24842610 PMCID: PMC4234694
- Use of Truvada as prophylaxis against HIV infection. Wang GP. [Audio]. AMA Journal of Ethics2014 April. Available from: http://virtualmentor.ama-assn.org/site/ethicstalk.html.
- Colonic immune suppression, barrier dysfunction, and dysbiosis by gastrointestinal bacillus anthracis Infection. Lightfoot YL, Yang T, Sahay B, Zadeh M, Cheng SX, Wang GP, Owen JL, Mohamadzadeh M. PloS one. 2014; 9(6):e100532. PubMed [journal] PMID: 24945934 PMCID: PMC4063899
- Intestinal dysbiosis and depletion of butyrogenic bacteria in Clostridium difficile infection and nosocomial diarrhea. Antharam VC, Li EC, Ishmael A, Sharma A, Mai V, Rand KH, Wang GP. Journal of clinical microbiology. 2013; 51(9):2884-92.PubMed [journal] PMID: 23804381 PMCID: PMC3754663
- Deep sequencing analysis of HCV NS3 resistance-associated variants and mutation linkage in liver transplant recipients. Kirst ME, Li EC, Wang CX, Dong HJ, Liu C, Fried MW, Nelson DR, Wang GP. PloS one. 2013; 8(7):e69698. PubMed [journal] PMID: 23922778 PMCID: PMC3726766
- Loop residues and catalysis in OMP synthase. Wang GP, Hansen MR, Grubmeyer C. Biochemistry. 2012; 51(22):4406-15. NIHMSID: NIHMS380028. PubMed [journal] PMID: 22531099 PMCID: PMC3436960
- Loss of p19Arf in a Rag1(-/-) B-cell precursor population initiates acute B-lymphoblastic leukemia. Hauer J, Mullighan C, Morillon E, Wang G, Bruneau J, Brousse N, Lelorc’h M, Romana S, Boudil A, Tiedau D, Kracker S, Bushmann FD, Borkhardt A, Fischer A, Hacein-Bey-Abina S, Cavazzana-Calvo M. Blood. 2011; 118(3):544-53. PubMed [journal] PMID: 21622646 PMCID: PMC3142899.
- A method to sequence and quantify DNA integration for monitoring outcome in gene therapy. Brady T, Roth SL, Malani N, Wang GP, Berry CC, Leboulch P, Hacein-Bey-Abina S, Cavazzana-Calvo M, Papapetrou EP, Sadelain M, Savilahti H, Bushman FD.Nucleic acids research. 2011; 39(11):e72. PubMed [journal] PMID: 21415009 PMCID: PMC3113588
- Transfusion independence and HMGA2 activation after gene therapy of human β-thalassaemia. Cavazzana-Calvo M, Payen E, Negre O, Wang G, Hehir K, Fusil F, Down J, Denaro M, Brady T, Westerman K, Cavallesco R, Gillet-Legrand B, Caccavelli L, Sgarra R, Maouche-Chrétien L, Bernaudin F, Girot R, Dorazio R, Mulder GJ, Polack A, Bank A, Soulier J, Larghero J, Kabbara N, Dalle B, Gourmel B, Socie G, Chrétien S, Cartier N, Aubourg P, Fischer A, Cornetta K, Galacteros F, Beuzard Y, Gluckman E, Bushman F, Hacein-Bey-Abina S, Leboulch P. Nature. 2010; 467(7313):318-22. NIHMSID: NIHMS376529. PubMed [journal] PMID: 20844535 PMCID: PMC3355472
- Efficacy of gene therapy for X-linked severe combined immunodeficiency. Hacein-Bey-Abina S, Hauer J, Lim A, Picard C, Wang GP, Berry CC, Martinache C, Rieux-Laucat F, Latour S, Belohradsky BH, Leiva L, Sorensen R, Debré M, Casanova JL, Blanche S, Durandy A, Bushman FD, Fischer A, Cavazzana-Calvo M. The New England journal of medicine. 2010; 363(4):355-64. NIHMSID: NIHMS228632. PubMed [journal] PMID: 20660403 PMCID: PMC2957288
- Dynamics of gene-modified progenitor cells analyzed by tracking retroviral integration sites in a human SCID-X1 gene therapy trial. Wang GP, Berry CC, Malani N, Leboulch P, Fischer A, Hacein-Bey-Abina S, Cavazzana-Calvo M, Bushman FD. Blood. 2010; 115(22):4356-66. PubMed [journal] PMID: 20228274 PMCID: PMC2881494
- Hepatitis C virus transmission bottlenecks analyzed by deep sequencing. Wang GP, Sherrill-Mix SA, Chang KM, Quince C, Bushman FD. Journal of virology. 2010; 84(12):6218-28. PubMed [journal] PMID: 20375170 PMCID: PMC2876626
- Analysis of lentiviral vector integration in HIV+ study subjects receiving autologous infusions of gene modified CD4+ T cells. Wang GP, Levine BL, Binder GK, Berry CC, Malani N, McGarrity G, Tebas P, June CH, Bushman FD. Molecular therapy : the journal of the American Society of Gene Therapy. 2009; 17(5):844-50. PubMed [journal] PMID: 19259065 PMCID: PMC2835137
- Methods for integration site distribution analyses in animal cell genomes. Ciuffi A, Ronen K, Brady T, Malani N, Wang G, Berry CC, Bushman FD. Methods (San Diego, Calif.). 2009; 47(4):261-8. NIHMSID: NIHMS601439. PubMed [journal] PMID: 19038346 PMCID: PMC4104535
- Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. Hacein-Bey-Abina S, Garrigue A, Wang GP, Soulier J, Lim A, Morillon E, Clappier E, Caccavelli L, Delabesse E, Beldjord K, Asnafi V, MacIntyre E, Dal Cortivo L, Radford I, Brousse N, Sigaux F, Moshous D, Hauer J, Borkhardt A, Belohradsky BH, Wintergerst U, Velez MC, Leiva L, Sorensen R, Wulffraat N, Blanche S, Bushman FD, Fischer A, Cavazzana-Calvo M. The Journal of clinical investigation. 2008; 118(9):3132-42. PubMed [journal] PMID: 18688285 PMCID: PMC2496963
- Massively parallel pyrosequencing in HIV research. Bushman FD, Hoffmann C, Ronen K, Malani N, Minkah N, Rose HM, Tebas P, Wang GP. AIDS (London, England). 2008; 22(12):1411-5. NIHMSID: NIHMS60849. PubMed [journal] PMID: 18614863 PMCID: PMC4221253
- DNA bar coding and pyrosequencing to analyze adverse events in therapeutic gene transfer. Wang GP, Garrigue A, Ciuffi A, Ronen K, Leipzig J, Berry C, Lagresle-Peyrou C, Benjelloun F, Hacein-Bey-Abina S, Fischer A, Cavazzana-Calvo M, Bushman FD. Nucleic acids research. 2008; 36(9):e49. PubMed [journal] PMID: 18411205 PMCID: PMC2396413
- HIV integration site selection: analysis by massively parallel pyrosequencing reveals association with epigenetic modifications. Wang GP, Ciuffi A, Leipzig J, Berry CC, Bushman FD. Genome research. 2007; 17(8):1186-94. PubMed [journal] PMID: 17545577 PMCID: PMC1933515
- DNA bar coding and pyrosequencing to identify rare HIV drug resistance mutations. Hoffmann C, Minkah N, Leipzig J, Wang G, Arens MQ, Tebas P, Bushman FD. Nucleic acids research. 2007; 35(13):e91. PubMed [journal] PMID: 17576693 PMCID: PMC1934997
- A statistical method for comparing viral growth curves. Wang GP, Bushman FD. Journal of virological methods. 2006; 135(1):118-23. PubMed [journal] PMID: 16564579
- Motional dynamics of the catalytic loop in OMP synthase. Wang GP, Cahill SM, Liu X, Girvin ME, Grubmeyer C. Biochemistry. 1999; 38(1):284-95. PubMed [journal] PMID: 9890909
- Kinetic mechanism of OMP synthase: a slow physical step following group transfer limits catalytic rate. Wang GP, Lundegaard C, Jensen KF, Grubmeyer C. Biochemistry. 1999; 38(1):275-83. PubMed [journal] PMID: 9890908
- Making a nucleotide: structure and function of rotate phosphoribosyltransferase. Wang GP, Grubmeyer CT. Paths to Pyrimidines. 1998; 6:1-11.
- Local effect of glycine substitution in a model helical peptide. Lyu PC, Wang GP, Liff M, Kallenbach NR. Journal of the American Chemical Society. 1991; 113:3568-3572.
For a complete list of publications, please click here.