Daniel R. Kuritzkes, M.D.
Professor of Medicine
Brigham & Women's Hospital
Infectious Disease/Partners AIDS Research Ctr.
65 Landsdowne Street, Rm. 449
Cambridge, MA 02139
Tel: 617-768-8371
Fax: 617-768-8738
e-mail:dkuritzkes@partners.org
1. Resistance to HIV-1 entry inhibitors
HIV-1 entry is a complex, multi-step process that affords multiple targets for viral inhibition. A variety of molecules that inhibit viral attachment, co-receptor binding, and/or fusion are in clinical development; one (enfuvirtide) is approved for clinical use. The mechanisms of resistance to these novel compounds is not yet well-understood. Our laboratory has been studying resistance to the chemokine receptor antagonists maraviroc and vicriviroc, as well as other investigational entry inhibitors. Approaches include novel sequencing strategies using ultra-deep sequencing in femtoliter microreactors; construction and testing of recombinant viruses expressing patient-derived env sequences; site-directed mutagenesis; and studies of viral entry kinetics and fusogenicity. We are also characterizing co-receptor usage in HIV-1 subtype C viruses from Botswana.
2. Viral fitness
Considerable attention has been focused recently on the relationship between drug resistance and viral fitness. The reduced replicative capacity of highly drug-resistant variants of HIV-1 may contribute to the persistent immunological benefits in patients considered to be “failing” antiretroviral therapy. The relatively rapid replacement of drug-resistant virus by wild-type virus upon interruption of therapy provides evidence that wild-type virus has a significant fitness advantage over drug-resistant variants in the absence of drug pressure. Despite progress to date, our understanding of the effect of various polymorphisms in RT on viral fitness is incomplete. We are using a novel recombinant marker virus assay developed in my laboratory to determine the fitness of drug-resistant HIV-1 and study the effect of viral fitness in the evolution of antiretroviral drug resistance.
We have also adapted this assay to study the relative fitness of HIV-1 strains that carry env mutations conferring resistance to viral entry inhibitors. Results of fitness assays will be correlated to results of receptor binding assays to determine the relationship between envelope functionality and viral fitness. Future plans include studying the fitness of HIV-1 isolates resistant to the novel HIV-1 integrase inhibitors now in clinical development.
References:
- Lu J, Whitcomb J, Kuritzkes DR. Effect of the Q207D mutation in human immunodeficiency virus type 1 reverse transcriptase on zidovudine susceptibility and replicative fitness. J Acquir Immune Defic Syndr 2005; 40:20-3.
- Hu Z, Giguel F, Hatano H, Reid P, Lu J, Kuritzkes DR. Fitness comparison of thymidine analog resistance pathways in human immunodeficiency virus type 1. J Virol 2006; 80:7020-70.
- Lu J, Deeks SG, Ho R, Beatty G, Kuritzkes BA, Martin NJ, Kuritzkes DR. Rapid emergence of enfuvirtide resistance in HIV-1-infected patients: Results of a clonal analysis. JAIDS 2006; 43:60-4.
- Kitchen CMR, Lu J, Suchard M, Hoh R, Martin JN, Kuritzkes DR, Deeks SG. Continued evolution in gp41 after interruption of enfuvirtide in subjects with advanced HIV disease. AIDS Res Hum Retrovir 2006;22:1260-6.
- Paredes R, Marconi VC, Campbell TB, Kuritzkes DR. Systematic evaluation of allele-specific real time PCR for the detection of minor HIV-1 variants with pol and env resistance mutations. J Virol Methods; 146:136-46.
- Hu Z, Hatano H, Hammon SP, Smith D, Wild M, Goupta S, Whitcomb J, Kalayjian RC, Gripshover B, Kuritzkes DR. Virologic characterization of human immunodeficiency type 1 virus with a codon 70 deletion in reverse transcriptase. JAIDS 2007; [Kuritzkes, Daniel R.,M.D.]45:494-500.
- Marconi VC, Bonhoeffer S, Paredes R, Lu J, Hoh R, Martin JN, Deeks SG, Kuritzkes DR. Viral dynamics and in vivo fitness of HIV-1 in the presence and absence of enfuvirtide. JAIDS 2008; in press.
- Tsibris AMN, Sagar M, Gulick RM, Su Z, Hughes M, Greaves W, Subramanian M, Flexner C, Giguel F, Leopold KE, Coakley E, Kuritzkes DR. In vivo emergence of vicriviroc resistance in an HIV-1 subtype C-infected subject. J Virol 2008; epublished ahead of print.
Virology webpage updated 12/02/2009