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 data correlations underlying HIV-1 drug resistance knowledge: (1) Correlations between the genetic sequences of the enzymatic targets of ARV therapy - PR, RT, and IN - with the ARV treatments of persons from whom sequenced HIV-1 variants are 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 improve the 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 regression methods and correlation network analyses to the study of HIV-1 drug resistance mutations;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.

National Institute of Health (NIH)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Petrakova, Eva
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Stanford University
Internal Medicine/Medicine
Schools of Medicine
United States
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Clutter, Dana S; Jordan, Michael R; Bertagnolio, Silvia et al. (2016) HIV-1 drug resistance and resistance testing. Infect Genet Evol 46:292-307
Clutter, Dana S; Rojas Sánchez, Patricia; Rhee, Soo-Yon et al. (2016) Genetic Variability of HIV-1 for Drug Resistance Assay Development. Viruses 8:
Clutter, Dana S; Fessel, W Jeffrey; Rhee, Soo-Yon et al. (2016) Response to Therapy in Antiretroviral Therapy-Naive Patients With Isolated Nonnucleoside Reverse Transcriptase Inhibitor-Associated Transmitted Drug Resistance. J Acquir Immune Defic Syndr 72:171-6
Feder, Alison F; Rhee, Soo-Yon; Holmes, Susan P et al. (2016) More effective drugs lead to harder selective sweeps in the evolution of drug resistance in HIV-1. Elife 5:
Collins, Sean E; Grant, Philip M; Shafer, Robert W (2016) Modifying Antiretroviral Therapy in Virologically Suppressed HIV-1-Infected Patients. Drugs 76:75-98
TenoRes Study Group (2016) Global epidemiology of drug resistance after failure of WHO recommended first-line regimens for adult HIV-1 infection: a multicentre retrospective cohort study. Lancet Infect Dis 16:565-75
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
Basson, Adriaan E; Rhee, Soo-Yon; Parry, Chris M et al. (2015) Impact of drug resistance-associated amino acid changes in HIV-1 subtype C on susceptibility to newer nonnucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 59:960-71
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

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