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Stephen H. Hughes, Ph.D.

Stephen H. Hughes, Ph.D.

  • Center for Cancer Research
  • National Cancer Institute
HIV Dynamics and Replication Program

RESEARCH SUMMARY

Dr. Hughes is internationally renowned for his work on the roles of reverse transcriptase (RT) and integrase (IN).  He is interested in how HIV becomes resistant to RT and IN inhibitors, in developing drugs that are more effective against the known resistance mutations, and in how the clonal expansion of HIV infected cells contributes to the formation and persistence of the reservoir that has made it impossible to cure HIV infections with the available drugs.  In his role as NIH Scientist Emeritus, Dr. Hughes interacts with scientists inside and outside of the HIV-DRP, providing advice and mentoring.

Areas of Expertise

1) HIV replication 2) retroviruses 3) antivirals 4) reverse transcription 5) integration

Publications

Selected Key Publications

Specific HIV integration sites are linked to clonal expansion and persistence of infected cells

Maldarelli F, Wu X, Su L, Simonetti FR, Shao W, Hill S, Spindler J, Ferris AL, Mellors JW, Kearney MF, Coffin JM, Hughes SH
Science. 345: 179-183, 2014. [ Journal Article ]

Lens epithelium-derived growth factor fusion proteins redirect HIV-1 DNA integration

Ferris AL, Wu X, Hughes CM, Stewart C, Smith SJ, Milne TA, Wang GG, Shun MC, Allis CD, Engelman A, Hughes SH
Proc Natl Acad Sci U S A. 107: 3135-3140, 2010. [ Journal Article ]

Selective excision of AZTMP by drug-resistant human immunodeficiency virus reverse transcriptase

Boyer PL, Sarafianos SG, Arnold E, Hughes SH
J Virol. 75: 4832-4842, 2001.

A system for tissue-specific gene targeting: transgenic mice susceptible to subgroup A avian leukosis virus-based retroviral vectors

Federspiel MJ, Bates P, Young JA, Varmus HE, Hughes SH
Proc Natl Acad Sci U S A. 91: 11241-11245, 1994. [ Journal Article ]

Crystal structure of human immunodeficiency virus type 1 reverse transcriptase complexed with double-stranded DNA at 3.0 Å resolution shows bent DNA

Jacobo-Molina A, Ding J, Nanni RG, Clark AD Jr, Lu X, Tantillo C, Williams RL, Kamer G, Ferris AL, Clark P, Hizi A, Hughes SH, Arnold E
Proc Natl Acad Sci U S A. 90: 6320-6324, 1993.

Alumni

Michael Abram, Ph.D.
Michael Abram, Ph.D.
2005-2010
Postdoctoral Fellow
Aamir Akram, M.D.
Aamir Akram, M.D.
2013-2015
Postbaccalaureate Fellow
Eugene Barsov, Ph.D.
Eugene Barsov, Ph.D.
1999-2001
Research Fellow
Paul Boyer, Ph.D.
Paul Boyer, Ph.D.
1994-2021
Staff Scientist
Kevin Chang, Ph.D.
Kevin Chang, Ph.D.
2001-2007
Postdoctoral Fellow
Carolyn Crisp, B.S.
Carolyn Crisp, B.S.
2012-2013
Postbaccalaureate Fellow
Caroline Davis, Ph.D.
Caroline Davis, Ph.D.
2007-2012
Postdoctoral Fellow
Mark Driscoll, Ph.D.
Mark Driscoll, Ph.D.
1999-2000
Research Fellow
Hong-Qiang Gao, Ph.D.
Hong-Qiang Gao, Ph.D.
1999-2000
Research Fellow
Marie-Pierre Golinelli, Ph.D.
Marie-Pierre Golinelli, Ph.D.
1999-2001
Staff Scientist
Gunnar Gunnarsson, Ph.D.
Gunnar Gunnarsson, Ph.D.
2005-2007
Postdoctoral Fellow
Barry Johnson, Ph.D.
Barry Johnson, Ph.D.
2007-2013
Postdoctoral Fellow
Fatima Jones, Ph.D.
Fatima Jones, Ph.D.
2003-2004
Postdoctoral Fellow
John Julias, Ph.D.
John Julias, Ph.D.
1999-2006
Research Fellow
 Stanislaw Kaczmarczyk, Ph.D.
Stanislaw Kaczmarczyk, Ph.D.
2001-2008
Research Fellow
Mary Jane McWilliams, B.A.
Mary Jane McWilliams, B.A.
1999-2015
Research Biologist
Jangsuk Oh, Ph.D.
Jangsuk Oh, Ph.D.
2000-2007
Research Fellow
Elena Peletskaya, Ph.D.
Elena Peletskaya, Ph.D.
1999-2010
Research Fellow, Guest Scientist
Valerian Pinto, Ph.D.
Valerian Pinto, Ph.D.
1999-2001
Research Fellow
Carolyn Rinke, Ph.D.
Carolyn Rinke, Ph.D.
2002
Predoctoral Fellow
Steven Smith, Ph.D.
Steven Smith, Ph.D.
2008-2021
Research Biologist
Amber Steele, Ph.D.
Amber Steele, Ph.D.
2002-2003
Postdoctoral Fellow
B. Christie Vu, Ph.D.
B. Christie Vu, Ph.D.
2004-2010
Postdoctoral Fellow
Janani Varadarajan, Ph.D.
Janani Varadarajan, Ph.D.
2007-2013
Postdoctoral Fellow
Daria Wells, M.S.
Daria Wells, M.S.
2014-2021
Bioinformatics Analyst (Contr)
Rafal Wierzchoslawski, Ph.D.
Rafal Wierzchoslawski, Ph.D.
2005-2008
Research Fellow
Edward Chia-Kuei Wu, Ph.D.
Edward Chia-Kuei Wu, Ph.D.
2000-2007
Research Fellow

Covers

Inside cover graphic of ACS Infectious Disease Volume 7 Issue 6 June 2021

HIV-1 Integrase Inhibitors with Modifications That Affect Their Potencies against Drug Resistant Integrase Mutants

Published Date

Abstract:

Integrase strand transfer inhibitors (INSTIs) block the integration step of the retroviral lifecycle and are first-line drugs used for the treatment of HIV-1/AIDS.  INSTIs have a polycyclic core with heteroatom triads, chelate the metal ions at the active site, and have a halobenzyl group that interacts with viral DNA attached to the core by a flexible linker.  The most broadly effective INSTIs inhibit both wild-type (WT) integrase (IN) and a variety of well-known mutants.  However, because there are mutations that reduce the potency of all of the available INSTIs, new and better compounds are needed.  Models based on recent structures of HIV-1 and red-capped mangabey SIV INs suggest modifications in the INSTI structures that could enhance interactions with the 3'-terminal adenosine of the viral DNA, which could improve performance against INSTI resistant mutants.  We designed and tested a series of INSTIs having modifications to their naphthyridine scaffold.  One of the new compounds retained good potency against an expanded panel of HIV-1 IN mutants that we tested.  Our results suggest the possibility of designing inhibitors that combine the best features of the existing compounds, which could provide additional efficacy against known HIV-1 IN mutants.

On the cover:

INSTIs bound to HIV-1 IN.  Compound 5j (magenta) was docked onto the structures of 4d (yellow) and BIC (green) bound to the active site of HIV-1 IN; the surface of IN is shown in white.  The surface envelope of the unprocessed 3′ end of the vDNA is shown as brown mesh.  Ordered water molecules bound to the active site of IN in the absence of a bound INSTI are shown in cyan.

Cover graphic of Journal of Medicinal Chemistry Volume 60 Issue 17 September 14, 2017

Structure-Guided Optimization of HIV Integrase Strand Transfer Inhibitors

Published Date

Abstract:

Integrase mutations can reduce the effectiveness of the first-generation FDA-approved integrase strand transfer inhibitors (INSTIs), raltegravir (RAL) and elvitegravir (EVG).  The second-generation agent, dolutegravir (DTG), has enjoyed considerable clinical success; however, resistance-causing mutations that diminish the efficacy of DTG have appeared.  Our current findings support and extend the substrate envelope concept that broadly effective INSTIs can be designed by filling the envelope defined by the DNA substrates.  Previously, we explored 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides as an INSTI scaffold, making a limited set of derivatives, and concluded that broadly effective INSTIs can be developed using this scaffold.  Herein, we report an extended investigation of 6-substituents as well the first examples of 7-substituted analogues of this scaffold.  While 7-substituents are not well-tolerated, we have identified novel substituents at the 6-position that are highly effective, with the best compound (6p) retaining better efficacy against a broad panel of known INSTI resistant mutants than any analogues we have previously described.

On the cover:

Shown is an HIV integrase strand transfer inhibitor possessing a good mutant profile, bound at the catalytic site of the prototype foamy virus intasome including metal cofactors and viral DNA.

Cover design by Joseph Myer

Cover graphic of ACS Chemical Biology Volume 11 Issue 4 April 1, 2016

HIV‑1 Integrase Strand Transfer Inhibitors with Reduced Susceptibility to Drug Resistant Mutant Integrases

Published Date

Abstract:

HIV integrase (IN) strand transfer inhibitors (INSTIs) are among the newest anti-AIDS drugs; however, mutant forms of IN can confer resistance.  We developed noncytotoxic naphthyridine-containing INSTIs that retain low nanomolar IC50 values against HIV-1 variants harboring all of the major INSTI-resistant mutations.  We found by analyzing crystal structures of inhibitors bound to the IN from the prototype foamy virus (PFV) that the most successful inhibitors show striking mimicry of the bound viral DNA prior to 3'-processing and the bound host DNA prior to strand transfer.  Using this concept of "bi-substrate mimicry," we developed a new broadly effective inhibitor that not only mimics aspects of both the bound target and viral DNA but also more completely fills the space they would normally occupy.  Maximizing shape complementarity and recapitulating structural components encompassing both of the IN DNA substrates could serve as a guiding principle for the development of new INSTIs.

On the cover:

Mutant forms of HIV-1 IN reduce the therapeutic effectiveness of integrase strand transfer inhibitors (INSTIs).  The cover figure shows the IN of prototype foamy virus complexed to a novel INSTI (gold) that retains potency against resistant mutants of HIV-1 IN.  Overlain are the host and viral DNA substrates (blue and green, respectively), showing substrate mimicry by the inhibitor.

Cover design by Joseph Myer