Comprehensive, accurate, and publicly available HIV-1 antiretroviral (ARV) drug resistance data is essential for population-based monitoring of acquired and transmitted drug resistance in resource-limited regions, for guiding salvage ARV therapy in well-resourced regions, and for identifying overall ARV- development needs. However, the variability of viruses that comprise the HIV-1 pandemic and the high mutation rate of HIV-1 make it difficult to quantify transmitted and acquired drug resistance, to optimally interpret HIV-1 genotypic resistance tests, and to identify those ARV-resistant variants most relevant to the development of future ARVs. The Stanford HIV Drug Resistance Database (HIVDB) is the only publicly available source for three main data correlations underlying HIV-1 drug resistance knowledge: (1) Correlations between genotypic data for the enzymatic targets of ARV therapy - PR, RT, and IN - with the ARV treatments of persons from whom the sequenced HIV-1 isolates were obtained;(2) Correlations between genotype and in vitro drug susceptibility;and (3) Correlations between genotype and the virological response to a new ARV treatment regimen. By emphasizing the collection, annotation, dissemination, and analysis of three main types of data, HIVDB facilitates meta-analyses in which data from many published studies and clinical trials can be effectively synthesized.
The specific aims of this competing renewal for funding HIVDB are (1) To develop standardized genotypic methods to monitor the extent of transmitted and acquired drug resistance and to determine whether these methods can be applied across all HIV-1 subtypes;(2) To expand HIVDB by collecting, annotating, and disseminating the genotype-treatment, genotype-phenotype, and genotype-virological response data that inform genotypic resistance test interpretation. Coupled with this aim, we will create an online framework for representing and describing the evidence basis associated with each genotypic resistance interpretation;and (3) To identify and preliminarily characterize representative and novel ARV-resistant variants that may help guide the development of future ARVs. Innovative aspects of this proposal include (1) the development of widely available and widely used online programs to facilitate data sharing and consistent analytic approaches across laboratories in many countries;(2) the development and implementation of novel applied regression methods and correlation network analyses;and (3) the use of data recruitment and curation methods adopted from model organism databases to create a sustainable model for the continuation and expansion of HIVDB. !

Public Health Relevance

The development of drug regimens and national programs for treating HIV has saved hundreds of thousands of lives and provided hope to millions of others. However, acquired and transmitted HIV drug resistance present continuing obstacles to this success. This proposal addresses ongoing major challenges in HIV drug research by expanding a publicly available HIV drug resistance database through experimental, analytical, and collaborative projects.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
High Priority, Short Term Project Award (R56)
Project #
2R56AI068581-06
Application #
8649106
Study Section
AIDS Clinical Studies and Epidemiology Study Section (ACE)
Program Officer
Fitzgibbon, Joseph E
Project Start
2005-12-01
Project End
2014-04-30
Budget Start
2013-05-15
Budget End
2014-04-30
Support Year
6
Fiscal Year
2013
Total Cost
$729,327
Indirect Cost
$259,327
Name
Stanford University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Clutter, Dana S; Rojas Sánchez, Patricia; Rhee, Soo-Yon et al. (2016) Genetic Variability of HIV-1 for Drug Resistance Assay Development. Viruses 8:
Collins, Sean E; Grant, Philip M; Shafer, Robert W (2016) Modifying Antiretroviral Therapy in Virologically Suppressed HIV-1-Infected Patients. Drugs 76:75-98
Rhee, Soo-Yon; Blanco, Jose Luis; Jordan, Michael R et al. (2015) Geographic and temporal trends in the molecular epidemiology and genetic mechanisms of transmitted HIV-1 drug resistance: an individual-patient- and sequence-level meta-analysis. PLoS Med 12:e1001810
Rhee, Soo-Yon; Jordan, Michael R; Raizes, Elliot et al. (2015) HIV-1 Drug Resistance Mutations: Potential Applications for Point-of-Care Genotypic Resistance Testing. PLoS One 10:e0145772
Kolomeets, Anna N; Varghese, Vici; Lemey, Philippe et al. (2014) A uniquely prevalent nonnucleoside reverse transcriptase inhibitor resistance mutation in Russian subtype A HIV-1 viruses. AIDS 28:F1-8
Pennings, Pleuni S; Holmes, Susan P; Shafer, Robert W (2014) HIV-1 transmission networks in a small world. J Infect Dis 209:180-2
Melikian, George L; Rhee, Soo-Yon; Varghese, Vici et al. (2014) Non-nucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance: implications for preclinical evaluation of novel NNRTIs and clinical genotypic resistance testing. J Antimicrob Chemother 69:12-20
Van Zyl, Gert U; Liu, Tommy F; Claassen, Mathilda et al. (2013) Trends in Genotypic HIV-1 Antiretroviral Resistance between 2006 and 2012 in South African Patients Receiving First- and Second-Line Antiretroviral Treatment Regimens. PLoS One 8:e67188
Babrzadeh, Farbod; Varghese, Vici; Pacold, Mary et al. (2013) Collinearity of protease mutations in HIV-1 samples with high-level protease inhibitor class resistance. J Antimicrob Chemother 68:414-8
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

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