RESEARCH PROGRAM John W. Mellors, M.D. Professor of Medicine Chief, Division of Infectious Diseases...
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Transcript of RESEARCH PROGRAM John W. Mellors, M.D. Professor of Medicine Chief, Division of Infectious Diseases...
RESEARCH PROGRAM
John W. Mellors, M.D.Professor of Medicine
Chief, Division of Infectious DiseasesDirector, HIV/AIDS Program, UPMC
[email protected]/~disease
Basic Research
Translational Research
Clinical Research
Better Treatment and Prevention
Understand Drug ResistanceDiscover New Drugs
Major Projects
• Discovery of novel nucleoside analogs with activity against drug-resistant HIV
• New mechanisms of HIV drug resistance
• Role of low frequency drug-resistant variants in treatment failure
• Mechanisms of HIV persistence on antiretroviral therapy and strategies for eradication
• HIV prevention with antiretrovirals
Doctoral Student Training Model
Important Clinically Relevant Question?
Genetic, Virologic, Biochemical,
Structural Studies
C. Shi, PhD1991-1997
Development of recombinant retroviral systems for analysis of HIV-1 drug resistance
J. Hammond, PhD1996-2002
Structural determinants of HIV resistance to nucleoside analogs
U. Parikh, PhD1999-2005
Antagonistic evolutionary pathways of HIV-1 resistance to NRTI
E. Halvas, PhD2000-Present
Role of low frequency drug-resistant variants in antiretroviral treatment failure
S. Clark, PhD2002-Present
Genetic, biochemical, and structural mechanisms of NNRTI hypersusceptibility
J. Brehm2005-Present
The influence of mutations in the polymerase and RNase H domains on resistance to reverse transcriptase inhibitors
J. Meeter2007-
PresentStructural basis of nucleoside activity, resistance and toxicity
Past/Current Doctoral Trainees
Jessica BrehmPre-doctoral Student
IDM Department - GSPHAnd member of
Mellors Lab since 2004
BS Biochemistry and Chemistry 2003College of Charleston
South Carolina
PEER-REVIEWED PUBLICATION
1. Brehm JH, Koontz D, Meteer JD, Pithak V, Sluis-Cremer N, Mellors JW. Selection of Mutationsin the Connection and RNase H Domains of Human Immunodeficiency Virus Type 1 Reverse Transcriptase that Increase Resistance to 3'-Azido-3'-Dideoxythymidine. J Virol 2007;81:7852-9
ABSTRACTS Presented at Conferences 2007-08 1. 14th Annual Conference on Retroviruses and Opportunistic Infections (CROI). Feb 2007, Los Angeles, CA. (Oral presentation)2. XVI International HIV Drug Resistance Workshop June 2007, Barbados.3. 15th Annual CROI conference, February 2008, Boston, MA (Oral presentation)4. XVII International HIV Drug Resistance Workshop, June 2008, Sitges, Spain (Oral)
Fellowship: Pittsburgh AIDS Research TrainingFellow (PART) – 2007-08
Jeff MeteerPre-doctoral Student
Molecular Virology and Microbiology Graduate Program MVM
BS Biochemistry 2006St. John Fisher College,
Rochester NY
Member of
Mellors Lab since 2007
PEER-REVIEWED PUBLICATION
Brehm JH, Koontz D, Meteer JD, Pithak V, Sluis-Cremer N, Mellors JW. Selection ofMutations in the connection and RNase Hdomains of human immunodeficiency virusType 1 reverse transcriptase thatIncrease resistance to 3’-azido-3’-Dideoxythymidine. J Virol 2007;81:7852-9.
ABSTRACT Presented at Conference:
Meteer J, Koontz D, Rapp KL, Detorio M, Ruckstuhl M, Schinazi RF, Mellors JW.Novel resistance profile of the potentNucleoside analogue reverse transcriptase Inhibitor 3’-azido-2’,3’-dideoxyguanosine. ORAL PRESENTATION at the XVII InternationalHIV Drug Resistance Workshop. June 2008Sitges, Spain.
Urvi Parikh, PhDUniversity of Pittsburgh
Assistant Professor of MedicineAssociate Director
Microbial Trials Network Lab
Doctoral student inMELLORS LAB
1999-2005PhD – IDM GSPH 2006BS Biochemistry and
Molecular Biology - 1998Pennsylvania State University
Urvi’s Carrer Pathafter Mellors Lab….(5 publications, 4 first author)
2006 to 2008Emerging Infectious Disease Research Fellow
Centers for Disease Control and PreventionLaboratory of Walid Heneine, PhD, Division of
HIV/AIDS Prevention Laboratory Branch.
Conducted in vitro evaluations of nucleoside reversetranscriptase inhibitors for use as a microbicide gel for the prevention of HIV transmission. Also involved
In design and implementation of candidate Microbicide safety and efficacy studies in non-human
primates.
RECRUITED TO PITT FACULTY IN 2008To serve as Associate Director of Microbial TrialsNetwork and to enhance ID Division global health
Initiatives
Nicolas Sluis-Cremer, PhDUniversity of Pittsburgh
Assistant Professor
Director, Basic EducationID Division
Jessica RadzioPre-doctoral Student
IDM Department of GSPHSluis-Cremer Lab since 2007
BS Biology - 2001MS Life Sciences - 2003
Virginia Polytechnic & StateUniversity, Blacksburg, VA
PEER-REVIEWED PUBLICATIONS 2007-081. Radzio J, Sluis-Cremer N. Efavirenz acceleratesHIV-1 reverse transcriptase ribonuclease H cleavage, leading to diminished zidovudine excision. Mol Pharmacol 2008;73(2)601-6.
2. Zelina S, Sheen CW, Radzio J, Mellors JW andSluis-Cremer N. Mechanisms by which the G333DMutation in human immunodeficiency virus type 1Reverse transcriptase facilitates dual resistanceProtein Sci 2007;16(8) 1728-37.
3. Xia Q, Radzio J and Sluis-Cremer N. Probing Non-nucleoside inhibitor-induced active-site distortion in HIV-1 reverse transcriptase bytransient kinetic analyses. Protein Sci 2007(16)(8);1728-37
4. Nissley DV, Radzio J, Anderson KS, Sluis-Cremer N. Characterization of novel non-Nucleoside inhibitor-induced active-site distortionIn HIV-1 reverse transcriptase by RT. Biochem J2007;404(1) 151-7.
Brian HermanPre-doctoral Student
Molecular Virology andMicrobiology Graduate Program
BS Biology/BiochemistryAllegheny College 2005
Sluis-Cremer Lab2007
PEER REVIEWED PUBLICATION:
Roberts A, Deming D, Paddock CD, Cheng A, Yount B, Vogel L, Herman BD, Sheahan T, Heise M, Genrich GL, Zaki SR, Baric R, Subbarao K. AMouse-adapted SARS-coronavirus causes diseaseand mortality in BALB/cmice. PLoS Pathog 2007;3(1):e5 T.
PhD Thesis: Structure-activity-resistance Relationships and biochemicalPharmacology of novel nucleoside andNucleotide HIV-1 reverse transcriptaseinhibitors
S. Riddler, MD 1991-1994 Antiretroviral activity of stavudine (2’,3’-didehydro’3’-depxythymiding, d4T)
H. Nguyen, MD 1991-1995Molecular basis of HIV resistance to NNRTI
N. Connolly, MD 2002-2005 Immune based therapies for HIV infection
J. McKinnon, MD 2003-2005Simplified maintenance antiretroviral therapy: Virologic predictors of outcome
S. Patel, DO 2003-2005Persistence of multidrug resistant HIV after structured treatment interruptions
J. Chow, BS 2007-PresentRole of minor drug-resistant variants in treatment failure
Past MD Fellow Trainees
Laboratory Techniques
• Experimental design!
• Cell culture and virology
• Antiviral susceptibility/cytotoxicity assays− drug assessments
• Biochemistry of RT and other enzymes
• Molecular biology− Cloning, PCR, site-specific mutagenesis, DNA
sequencing, single genome sequencing
• Structural biology
• Application of above to human samples
Expectations
• Hard work and commitment to science
• Weekly meetings with supervisor
• 2 or 3 first author publications (for Ph.D)
• Scientific presentations at national meetings
Mellors LabUniversity of Pittsburgh
Division Infections Diseases