Sustained profile of transmitted drug resistance mutations for more than 10 years in an HIV type 1-infected patient.
ABSTRACT We present an HIV-1-infected patient with a profile of transmitted drug resistance (RT M41L, E44D, V118I, L210W, T215D) sustained during more than 10 years in the absence of treatment. Clonal analysis of different plasma and cellular samples within this period did not reveal any reversion to the wild-type genotype.
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ABSTRACT: The precise identification of the HIV-1 envelope glycoprotein (Env) responsible for productive clinical infection could be instrumental in elucidating the molecular basis of HIV-1 transmission and in designing effective vaccines. Here, we developed a mathematical model of random viral evolution and, together with phylogenetic tree construction, used it to analyze 3,449 complete env sequences derived by single genome amplification from 102 subjects with acute HIV-1 (clade B) infection. Viral env genes evolving from individual transmitted or founder viruses generally exhibited a Poisson distribution of mutations and star-like phylogeny, which coalesced to an inferred consensus sequence at or near the estimated time of virus transmission. Overall, 78 of 102 subjects had evidence of productive clinical infection by a single virus, and 24 others had evidence of productive clinical infection by a minimum of two to five viruses. Phenotypic analysis of transmitted or early founder Envs revealed a consistent pattern of CCR5 dependence, masking of coreceptor binding regions, and equivalent or modestly enhanced resistance to the fusion inhibitor T1249 and broadly neutralizing antibodies compared with Envs from chronically infected subjects. Low multiplicity infection and limited viral evolution preceding peak viremia suggest a finite window of potential vulnerability of HIV-1 to vaccine-elicited immune responses, although phenotypic properties of transmitted Envs pose a formidable defense.Proceedings of the National Academy of Sciences 06/2008; 105(21):7552-7. · 9.74 Impact Factor
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ABSTRACT: Following interruption of antiretroviral therapy among individuals with acquired drug resistance, preexisting drug-sensitive virus emerges relatively rapidly. In contrast, wild-type virus is not archived in individuals infected with drug-resistant human immunodeficiency virus (HIV) and thus cannot emerge rapidly in the absence of selective drug pressure. Fourteen recently HIV-infected patients with transmitted drug-resistant virus were followed for a median of 2.1 years after the estimated date of infection (EDI) without receiving antiretroviral therapy. HIV drug resistance and pol replication capacity (RC) in longitudinal plasma samples were assayed. Resistance mutations were characterized as pure populations or mixtures. The mean time to first detection of a mixture of wild-type and drug-resistant viruses was 96 weeks (1.8 years) (95% confidence interval, 48 to 192 weeks) after the EDI. The median time to loss of detectable drug resistance using population-based assays ranged from 4.1 years (conservative estimate) to longer than the lifetime of the individual (less conservative estimate). The transmission of drug-resistant virus was not associated with virus with reduced RC. Sexual transmission of HIV selects for highly fit drug-resistant variants that persist for years. The prolonged persistence of transmitted drug resistance strongly supports the routine use of HIV resistance genotyping for all newly diagnosed individuals.Journal of Virology 07/2008; 82(11):5510-8. · 5.08 Impact Factor
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ABSTRACT: Genetic diversity plays a key role in human immunodeficiency virus (HIV) adaptation, providing a mechanism to escape host immune responses and develop resistance to antiretroviral drugs. This process is driven by the high-mutation rate during DNA synthesis by reverse transcriptase (RT), by the large viral populations, by rapid viral turnover, and by the high-recombination rate. Drugs targeting HIV RT are included in all regimens of highly active antiretroviral therapy (HAART), which helps to reduce the morbidity and mortality of HIV-infected patients. However, the emergence of resistant viruses is a significant obstacle to effective long-term management of HIV infection and AIDS. The increasing complexity of antiretroviral regimens has favored selection of HIV variants harboring multiple drug resistance mutations. Evolution of drug resistance is characterized by severe fitness losses when the drug is not present, which can be partially overcome by compensatory mutations or other adaptive changes that restore replication capacity. Here, we review the impact of mutations conferring resistance to nucleoside and nonnucleoside RT inhibitors on in vitro and in vivo fitness, their involvement in pathogenesis, persistence upon withdrawal of treatment, and transmission. We describe the techniques used to estimate viral fitness, the molecular mechanisms that help to improve the viral fitness of drug-resistant variants, and the clinical implications of viral fitness data, by exploring the potential relationship between plasma viral load, drug resistance, and disease progression.Virus Research 07/2008; 134(1-2):104-23. · 2.75 Impact Factor