Research Interests Nicolas Sluis-Cremer is an Assistant Professor and a member of the Viral Diseases Unit. His research focuses on: Modulation of the dimeric structure of HIV-1 reverse transcriptase (RT) by nonnucleoside reverse transcriptase inhibitors (NNRTI): Recent studies have shown that NNRTI binding to HIV-1 RT impacts on the inter-subunit interactions between the p66 and p51 polypeptides of the enzyme. The objectives of this project are to (1) determine the mechanism by which NNRTI modulate HIV-1 RT inter-subunit interactions and intra-subunit conformational changes, and (2) to define the molecular interactions in the HIV-1 RT dimer interface and to evaluate the consequences of altering the intrinsic dimeric stability on enzymatic activity. Molecular mechanisms of HIV-1 RT resistance to nucleoside reverse transcriptase inhibitors (NRTI): Although NRTI is initially quite effective in reducing viral load in HIV-1 infected individuals, the viral burden inevitably rebounds despite continued therapy, due to the appearance of drug-resistant strains of HIV. The primary objectives of this project are to understand the molecular (phenotypic) mechanisms by which drug-resistant HIV-1 RT provides resistance to NRTI such as 3’-azido-3’deoxythymidine (AZT) by utilizing appropriate in vitro biochemical models and molecular modeling. Significant emphasis has also been placed in determining the underlying kinetic principles involved in AZT-resistant RT phosphorolytic excision of AZT-monophosphate from chain-terminated primer/templates, using modified AZT-triphosphate analogs (such as AZT-a-thiotriphosphate) and a transient kinetic approach.   Selected Publications Bonache MC, Quesada E, Sheen CW, Balzarini J, Sluis-Cremer N, Pérez-Pérez MJ, Camarasa MJ, San-Félix A. Novel N-3 Substituted TSAO-T Derivatives: Synthesis and Anti-HIV-Evaluation. Nucleosides Nucleotides Nucleic Acids. 2008 Apr;27(4):351-67. Sluis-Cremer N, Tachedjian G. Mechanisms of inhibition of HIV replication by non-nucleoside reverse transcriptase inhibitors. Virus Res. 2008 Mar 25. Figueiredo A, Zelina S, Sluis-Cremer N, Tachedjian G. Impact of residues in the nonnucleoside reverse transcriptase inhibitor binding pocket on HIV-1 reverse transcriptase heterodimer stability. Curr HIV Res. 2008 Mar;6(2):130-7. Yap SH, Sheen CW, Fahey J, Zanin M, Tyssen D, Lima VD, Wynhoven B, Kuiper M, Sluis-Cremer N, Harrigan PR, Tachedjian G. N348I in the connection domain of HIV-1 reverse transcriptase confers zidovudine and nevirapine resistance. PLoS Med. 2007 Dec;4(12):e335. Radzio J, Sluis-Cremer N. Efavirenz accelerates HIV-1 reverse transcriptase ribonuclease H cleavage, leading to diminished zidovudine excision. Mol Pharmacol. 2008 Feb;73(2):601-6. Epub 2007 Nov 16. Complete Publication Listing     Other Links Division of Infectious Diseases University of Pittsburgh

Nicolas Sluis-Cremer, Ph.D. Office:  808 and 810 Scaife Hall Lab: Pittsburgh, PA Phone: 412-648-8396 Fax: 412-648-8521 nps2@pitt.edu     Education 1993 B.Sc Biochemistry; Biology University of Witwatersrand Johannesburg, South Africa 1994 B.Sc. (Honors) Biochemistry University of Witwatersrand Johannesburg, South Africa 1997 Ph.D. Biochemistry University of Witwatersrand Johannesburg, South Africa   Lab Personnel Lab Manager: Chihwei Tina Sheen Graduate Student: Jessica Radzio