Highly drug-resistant HIV-1 clinical isolates are cross-resistant to many antiretroviral compounds in current clinical development

Abstract

Objectives-To assess the in-vitro drug susceptibility of a panel of five well-characterized drugresistant HIV variants to recently developed anti-HIV compounds including seven reverse transcriptase (RT) inhibitors and seven protease inhibitors.Methods-Drug-resistant viral strains were selected on the basis of the prevalence of these mutants in patient samples from local area HIV clinics. The isolates included one multinucleoside-resistant virus containing the Q151M mutation, and four clinical isolates containing multiple RT and protease resistance mutations. The activity of the experimental compounds against these isolates was determined using drug susceptibility assays and measuring the viral antigen p24 end-point.Results-These clinically relevant highly drug-resistant viruses were resistant to many of the new compounds in clinical development. In most cases the resistance mutations of the clinical isolate were different from those selected in vitro for the particular experimental compound.Conclusions-It is critical to expand the preclinical development of new drugs to include the assessment of their activity against currently circulating highly drug-resistant clinical strains, in order to develop appropriate salvage therapies for patients harboring resistant strains.

Rapid Enzymatic Test for Phenotypic HIV Protease Drug Resistance

“…Cross-resistance is an important problem particularly in therapy with PI, leading to resistance toward antiretroviral drugs before their approval. Thus several authors (Palmer et al, 1999;Harrigan and Cote, 2000) recommend testing newly developed inhibitors against highly resistant clinical isolates. For this purpose our test might be useful, because it is easily standardized and suited for high-throughput screening.…”

A Novel Assay Allows Genotyping of the Latent Reservoir for Human Immunodeficiency Virus Type 1 in the Resting CD4+T Cells of Viremic Patients

“…The patient had taken zidovudine (AZT) and 3TC initially after being diagnosed with HIV-1 infection but had been off 3TC for 65 months prior to sampling. This mutation makes the virus less fit than wild-type virus in the absence of 3TC (1,21) and hypersensitive to other NRTIs, including tenofovir in the current HAART regimen (39,42,46,64,68). Not surprisingly, the M184V mutation was absent from actively replicating plasma virus.…”

Antiretroviral Drug Resistance Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Increase Template-Switching Frequency

“…The Y115F substitution occurs predominantly in patients treated with abacavir (44). In addition, the F116Y substitution arises in association with the Q151M substitution and is associated with a high level of resistance to several nucleoside RT inhibitors (NRTI) (43,52). We generated RT mutants Y115F, F116Y, and F116W and determined the effects of these mutations on RT template switching.…”