Virology Faculty Member - Daniel Kuritzkes

Daniel Kuritzkes

Professor of Medicine

Brigham & Women's Hospital
Infectious Disease, Room 449
65 Landsdowne Street
Cambridge, MA 2139
Tel: 617-768-8371
Fax: 617-768-8738
Email: dkuritzkes@partners.org



1. Resistance to antiretroviral drugs

For many HIV-infected patients, the potential benefits of antiretroviral therapy are limited by emergence of drug-resistant virus. Work in my laboratory is directed towards understanding mechanisms of resistance to novel entry inhibitors. Using viruses and virus sequences obtained from patients participating in clinical trials, we are also exploring the mechanisms of resistance to novel agents including CCR5 antagonists and integrase inhibitors. We are also using quantitative allele-specific PCR and other molecular diagnostic tools to quantify drug-resistant variants that are present as minority members of the viral quasispecies in order to characterize the population dynamics of drug-resistant virus in response to changing selective pressures. Better understanding of the virologic, genetic, and biochemical aspects of resistance to these agents will help direct therapy and may lead to better therapeutic strategies in the future.

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. 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. Ongoing and planned future studies include exploring the fitness of different NRTI-resistant mutants, as well as the fitness of mutants resistant to novel entry inhibitors.

3. Viral tropism

Early in the course of disease, most patients infected with HIV-1 harbor virus that uses CCR5 as the co-receptor for virus entry. In half of patients, CXCR4-using (X4) virus emerges over time, and appears correlated with advancing immune suppression. Patients with X4 virus are at greater risk of disease progression, but whether X4 viruses are the cause or consequence of disease progression remains unclear. We are using a variety of techniques, including ultra-deep pyrosequencing and GWAS, to identify factors that drive the emergence of X4 virus.

4. HIV-1 persistence and eradication

The apparent achievement of “functional” cure in at least one HIV-1-infected patient through allogeneic stem cell transplantation of CCR5-negative donor cells has stimulated interest in research towards a cure for HIV infection. My laboratory is engaged in a variety of studies to identify, characterize and quantify the reservoir of cells harboring latent HIV-1, and to determine the impact of ablative and non-ablative chemotherapy, autologous and allogeneic stem cell transplantation on the viral reservoir.



Last Update: 10/22/2013



Publications

1. Li JZ, Paredes R, Ribaudo H, Svarovskaia ES, Metzner KJ, Kozal MJ, Huppler Hulsiek K, Balduin M, Jakobsen MR, Geretti AM, Thiebaut R, Ostergaard L, Masquelier B, Johnson JA, Miller MD, Kuritzkes DR. Minority HIV-1 Drug Resistance Mutations and the Risk of NNRTI-based Antiretroviral Treatment Failure: A Systematic Review and Pooled Analysis. JAMA 2011, 305:1327-35.

2. Hu X, Kuritzkes DR. Interaction of reverse transcriptase (RT) mutations conferring resistance to lamivudine and etravirine: effects on fitness and RT activity of human immunodeficiency virus type 1. J Virol 2011; 85:11309-14.

3. Putcharoen O, Lee SH, Henrich TJ, Hu Z, Vanichanan J, Coakley E, Greaves W, Kuritzkes DR, Tsibris AMN. HIV-1 clinical isolates resistant to CCR5 antagonists exhibit delayed entry kinetics that correct in the presence of drug. J Virol 2012; 86:1119-28.

4. Tsibris AMN, Hu Z, Paredes R, Leopold KE, Putcharoen O, Schure AL, Mazur N, Coakley E, Su Z, Gulick RM, Kuritzkes DR. Vicriviroc resistance decay and relative replicative fitness in HIV-1 clinical isolates under sequential drug selection pressures. J Virol 2012; 86:6416-26.

5. Lin NH, Becerril C, Giguel F, Novitsky V, Moyo S, Makhema J, Essex M, Lockman S, Kuritzkes DR, Sagar M. Env sequence determinants in CXCR4-using human immunodeficiency virus type-1 subtype C. Virology 2012; 433:296-307.

6. Henrich TJ, Gallien S, Li JZ, Pereyra F, Kuritzkes DR. Low-level detection and quantitation of cellular HIV-1 DNA and 2-LTR circles using droplet digital PCR. J Virol Methods 2012; 186:68-72.

7. Henrich TJ, Hu Z, Li JZ, Sciaranghella G, Busch MP, Keating SM, Gallien S, Lin NH, Giguel F, Lavoie L, Ho VT, Armand P, Soiffer RJ, Sagar M, LaCasce AS, Kuritzkes DR. Long-term reduction in peripheral blood HIV-1 reservoirs following reduced-intensity conditioning allogeneic stem cell transplantation. J Infect Dis 2013 Mar 4 [Epub ahead of print].



© 2013 by the President and Fellows of Harvard College