HIV-1 Drug Resistance in Different Subtypes

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DESCRIPTION (provided by applicant): The human immunodeficiency virus (HIV-1) pandemic is due to multiple subtypes and emerging recombinant viruses that are widely distributed around the world. An important response to the epidemic is the global scale-up of access to antiretroviral treatment (ART) programs, potentially delivering ART to millions of infected individuals. A barrier to successful long term treatment is the emergence of drug resistance, caused by mutations selected in viral genes, which are both a cause and a consequence of ART failure. Knowledge about drug resistance comes largely from the US and Europe, focused on one HIV-1 variant, subtype B. However, 90% of infections globally, are in resource limited settings in Africa and Asia, where other distinct, non-B HIV-1 subtypes predominate. There is strong preliminary evidence that pre-therapy genotypes differ among subtypes and that distinct mutations at positions related to resistance may occur, even before treatment, among non-B subtypes. Furthermore, distinct, new mutations are detected in non-B subtypes after drug-exposure. Information on susceptibility and resistance of non-B viruses is critical for strategies to sustain the benefit of ART. Prevalence and incidence of transmitted and acquired drug resistance will drive decisions about diagnostic testing, initial and second-line therapies in public health HIV treatment programs in resource limited settings. The focus of this proposal is to build the scientific infrastructure for surveillance and monitoring of drug resistance in three Resource-limited settings, where specific non- B subtypes predominate. Through these studies we will develop a robust sequence database of HIV-1 non-B variants for genotypic analyses and phenotypic validation of resistance mutations and patterns. We have designed a program to first develop quality assured, low cost drug resistance monitoring strategies using dried filter specimens for resistance testing. These strategies will be implemented in Thailand, India and china, to study differences between HIV-1 subtypes in drug resistance to current first-line, WHO- recommended treatment regimens. In collaboration with Monogram Biosciences we will assess the importance of mutations and patterns in these samples using an advanced method for phenotypic resistance testing. The goals of this proposal are to (i) validate low-cost resistance testing; (ii) determine frequency and patterns of virological failure and drug resistance after 1 and 2 years of ART; and (iii) conduct genotypic analyses and phenotypic validation of subtype-specific mutations and patterns. PUBLIC HEALTH RELEVANCE: The HIV-1 pandemic is a global emergency caused by multiple subtypes. Evolution of anti-HIV drug resistance is the main cause and consequence of drug treatment failure. Most knowledge about drug resistance stems from work in the US and Europe on the relatively uncommon subtype B HIV-1. In resource limited settings, where the majority of the pandemic prevails, non-B subtypes and circulating recombinant forms (CRF) predominate. Treatment access programs are rapidly increasing the numbers of AIDS patients, throughout the world, who are receiving combinations of antiretroviral therapies (ART). Our long-term goal is to determine the how different subtypes of HIV-1 respond to treatment with antiretroviral drugs and the significance of subtype in the selection and the evolution of drug resistance.