Transcript No Slide Title

RESEARCH PROGRAM
John W. Mellors, M.D.
Professor of Medicine
Chief, Division of Infectious Diseases
Director, HIV/AIDS Program, UPMC
[email protected]
www.pitt.edu/~disease
Basic Research
Translational Research
Clinical Research
Understand Drug Resistance
Discover New Drugs
Better Treatment and Prevention
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
Past/Current Doctoral Trainees
C. Shi, PhD
19911997
Development of recombinant retroviral
systems for analysis of HIV-1 drug resistance
J. Hammond, PhD
19962002
Structural determinants of HIV resistance to
nucleoside analogs
U. Parikh, PhD
19992005
Antagonistic evolutionary pathways of HIV-1
resistance to NRTI
E. Halvas, PhD
2000Present
Role of low frequency drug-resistant variants
in antiretroviral treatment failure
S. Clark, PhD
2002Present
Genetic, biochemical, and structural
mechanisms of NNRTI hypersusceptibility
J. Brehm
2005Present
The influence of mutations in the polymerase
and RNase H domains on resistance to
reverse transcriptase inhibitors
J. Meeter
2007Present
Structural basis of nucleoside activity,
resistance and toxicity
PEER-REVIEWED PUBLICATION
1. Brehm JH, Koontz D, Meteer JD, Pithak V,
Sluis-Cremer N, Mellors JW. Selection of Mutations
in the Connection and RNase H Domains of Human
Immunodeficiency Virus Type 1 Reverse
Transcriptase that Increase Resistance to 3'-Azido3'-Dideoxythymidine. J Virol 2007;81:7852-9
ABSTRACTS Presented at Conferences 2007-08
Jessica Brehm
Pre-doctoral Student
IDM Department - GSPH
And member of
Mellors Lab since 2004
BS Biochemistry and Chemistry 2003
College of Charleston
South Carolina
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 Training
Fellow (PART) – 2007-08
PEER-REVIEWED PUBLICATION
Jeff Meteer
Pre-doctoral Student
Molecular Virology and
Microbiology Graduate Program MVM
BS Biochemistry 2006
St. John Fisher College,
Rochester NY
Member of
Mellors Lab since 2007
Brehm JH, Koontz D, Meteer JD, Pithak V,
Sluis-Cremer N, Mellors JW. Selection of
Mutations in 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.
ABSTRACT Presented at Conference:
Meteer J, Koontz D, Rapp KL, Detorio M,
Ruckstuhl M, Schinazi RF, Mellors JW.
Novel resistance profile of the potent
Nucleoside analogue reverse transcriptase
Inhibitor 3’-azido-2’,3’-dideoxyguanosine.
ORAL PRESENTATION at the XVII International
HIV Drug Resistance Workshop. June 2008
Sitges, Spain.
Urvi’s Carrer Path
after Mellors Lab….(5 publications, 4 first author)
2006 to 2008
Emerging Infectious Disease Research Fellow
Centers for Disease Control and Prevention
Laboratory of Walid Heneine, PhD, Division of
HIV/AIDS Prevention Laboratory Branch.
Urvi Parikh, PhD
University of Pittsburgh
Assistant Professor of Medicine
Associate Director
Microbial Trials Network Lab
Doctoral student in
MELLORS LAB
1999-2005
PhD – IDM GSPH 2006
BS Biochemistry and
Molecular Biology - 1998
Pennsylvania State University
Conducted in vitro evaluations of nucleoside reverse
transcriptase 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 2008
To serve as Associate Director of Microbial Trials
Network and to enhance ID Division global health
Initiatives
Nicolas Sluis-Cremer, PhD
University of Pittsburgh
Assistant Professor
Director, Basic Education
ID Division
PEER-REVIEWED PUBLICATIONS 2007-08
1. Radzio J, Sluis-Cremer N. Efavirenz accelerates
HIV-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 and
Sluis-Cremer N. Mechanisms by which the G333D
Mutation in human immunodeficiency virus type 1
Reverse transcriptase facilitates dual resistance
Protein Sci 2007;16(8) 1728-37.
Jessica Radzio
Pre-doctoral Student
IDM Department of GSPH
Sluis-Cremer Lab since 2007
BS Biology - 2001
MS Life Sciences - 2003
Virginia Polytechnic & State
University, Blacksburg, VA
3. Xia Q, Radzio J and Sluis-Cremer N. Probing
Non-nucleoside inhibitor-induced active-site
distortion in HIV-1 reverse transcriptase by
transient kinetic analyses. Protein Sci 2007(16)
(8);1728-37
4. Nissley DV, Radzio J, Anderson KS, SluisCremer N. Characterization of novel nonNucleoside inhibitor-induced active-site distortion
In HIV-1 reverse transcriptase by RT. Biochem J
2007;404(1) 151-7.
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. A
Mouse-adapted SARS-coronavirus causes disease
and mortality in BALB/cmice. PLoS Pathog
2007;3(1):e5 T.
PhD Thesis: Structure-activity-resistance
Brian Herman
Pre-doctoral Student
Molecular Virology and
Microbiology Graduate Program
BS Biology/Biochemistry
Allegheny College 2005
Sluis-Cremer Lab
2007
Relationships and biochemical
Pharmacology of novel nucleoside and
Nucleotide HIV-1 reverse transcriptase
inhibitors
Past MD Fellow Trainees
S. Riddler, MD
1991-1994
Antiretroviral activity of stavudine (2’,3’didehydro’3’-depxythymiding, d4T)
H. Nguyen, MD
1991-1995
Molecular basis of HIV resistance to
NNRTI
N. Connolly, MD
2002-2005
Immune based therapies for HIV infection
J. McKinnon, MD
2003-2005
Simplified maintenance antiretroviral
therapy: Virologic predictors of outcome
S. Patel, DO
2003-2005
Persistence of multidrug resistant HIV
after structured treatment interruptions
J. Chow, BS
2007-Present
Role of minor drug-resistant variants in
treatment failure
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 Lab
University of Pittsburgh
Division
Infections Diseases