Recent studies show that HIV-1 replication can be dramatically curtailed, if not completely arrested, with potent, rationally-designed drug combinations. The benefits of combination therapy, however, are greatly diminished in patients who have received previous antiretroviral therapy. Although 13 antiretroviral drugs are available, there is considerable cross-resistance within each class of inhibitors. Preliminary data suggest that some of the current drug-resistant HIV-1 isolates are already cross-resistant to many of the drugs in clinical development. This proposal plans to identify patterns of RT and protease mutations developing in HIV-1 isolates from patients receiving treatment with the majority of available RT and protease inhibitors. This application will analyze (I) published HIV-1 RT and protease sequences, (II) RT and protease sequences obtained in ACTG trials, and (III) RT and protease sequences obtained during the clinical management of >500 HIV-1-infected patients in the San Francisco Bay area. Infectious biological and recombinant molecular clones will be created from these isolates; their susceptibility to available and experimental antiretroviral drugs will be assessed; and, the role of specific multidrug-resistance mutations in site-directed mutagenesis and virus passage experiments will be assessed. An understanding of the genetic changes responsible for multidrug-resistance is essential for the development of new antiretroviral drugs, for designing optimal drug combinations, and for the clinical management of individual patients. A set of well-characterized multidrug-resistance HIV-1 isolates will also be of the utmost value to researchers in the areas of antiretroviral drug development and drug resistance.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI046148-02
Application #
6170843
Study Section
Special Emphasis Panel (ZRG1-AARR-3 (01))
Program Officer
Bridges, Sandra H
Project Start
1999-08-01
Project End
2002-07-31
Budget Start
2000-08-01
Budget End
2001-07-31
Support Year
2
Fiscal Year
2000
Total Cost
$282,408
Indirect Cost
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Varghese, Vici; Mitsuya, Yumi; Fessel, W Jeffrey et al. (2013) Prototypical Recombinant Multi-Protease-Inhibitor-Resistant Infectious Molecular Clones of Human Immunodeficiency Virus Type 1. Antimicrob Agents Chemother 57:4290-4299
Balamane, Maya; Varghese, Vici; Melikian, George L et al. (2012) Panel of prototypical recombinant infectious molecular clones resistant to nevirapine, efavirenz, etravirine, and rilpivirine. Antimicrob Agents Chemother 56:4522-4
Blanco, Jose-Luis; Varghese, Vici; Rhee, Soo-Yon et al. (2011) HIV-1 integrase inhibitor resistance and its clinical implications. J Infect Dis 203:1204-14
Reuman, Elizabeth C; Margeridon-Thermet, Severine; Caudill, Harrison B et al. (2010) A classification model for G-to-A hypermutation in hepatitis B virus ultra-deep pyrosequencing reads. Bioinformatics 26:2929-32
Varghese, Vici; Wang, Elijah; Babrzadeh, Farbod et al. (2010) Nucleic acid template and the risk of a PCR-Induced HIV-1 drug resistance mutation. PLoS One 5:e10992
Reuman, Elizabeth C; Rhee, Soo-Yon; Holmes, Susan P et al. (2010) Constrained patterns of covariation and clustering of HIV-1 non-nucleoside reverse transcriptase inhibitor resistance mutations. J Antimicrob Chemother 65:1477-85
Reuman, Elizabeth C; Bachmann, Michael H; Varghese, Vici et al. (2010) Panel of prototypical raltegravir-resistant infectious molecular clones in a novel integrase-deleted cloning vector. Antimicrob Agents Chemother 54:934-6
Varghese, Vici; Liu, Tommy F; Rhee, Soo-Yon et al. (2010) HIV-1 integrase sequence variability in antiretroviral naïve patients and in triple-class experienced patients subsequently treated with raltegravir. AIDS Res Hum Retroviruses 26:1323-6
Varghese, Vici; Shahriar, Rajin; Rhee, Soo-Yon et al. (2009) Minority variants associated with transmitted and acquired HIV-1 nonnucleoside reverse transcriptase inhibitor resistance: implications for the use of second-generation nonnucleoside reverse transcriptase inhibitors. J Acquir Immune Defic Syndr 52:309-15
Shafer, Robert W (2009) Low-abundance drug-resistant HIV-1 variants: finding significance in an era of abundant diagnostic and therapeutic options. J Infect Dis 199:610-2

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