Comparative anti-HIV evaluation of diverse HIV-1-specific reverse transcriptase inhibitor-resistant virus isolates demonstrates the existence of distinct phenotypic subgroups

doi:10.1016/0166-3542(94)00069-K

Antiviral Research

Volume 26, Issue 2, March 1995, Pages 117-132

https://doi.org/10.1016/0166-3542(94)00069-K Get rights and content

Abstract

We have biologically and biochemically evaluated a structurally diverse group of HIV-1-specific reverse transcriptase (RT) inhibitors and determined that the members of this class share many common properties. These include reproducible and selective antiviral activity against a panel of biologically distinct laboratory and clinical strains of HIV-1, activity against HIV-1 in a wide variety of culture and fresh human cells, and potent inhibition of HIV-1 RT when evaluated using a heteropolymeric ribosomal RNA template assay. Each of the HIV-1-specific compounds was capable of inhibiting HIV replication when challenged at high m.o.i., further distinguishing them from the nucleoside analogs 3'-azido-3'-deoxythymidine (AZT) and 2',3'-dideoxycytidine (ddC). When tested in combination with AZT, each of the HIV-1-specific compounds synergistically inhibited the replication of HIV-1. HIV-1 isolates resistant to different HIV-1-specific inhibitors exhibited heterogeneous patterns of cross-resistance to other members of this pharmacologic class. Four distinct phenotypic classes have been defined through the use of drug-resistant virus isolates which derive from distinct mutations in the RT. These results indicate that the various subgroups of HIV-1-specific inhibitors interact differently with HIV-1 RT, suggesting important potential implications for drug combination therapeutic strategies.

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Research articleComparative anti-HIV evaluation of diverse HIV-1-specific reverse transcriptase inhibitor-resistant virus isolates demonstrates the existence of distinct phenotypic subgroups

Abstract

Biochem. Pharmacol.

Virology

Antiviral Res.

Antiviral Res.

Virology

J. Virol. Methods

Lancet

Oxathiin carboxanilide, a potent inhibitor of human immunodeficiency virus reproduction

Treatment of human immunodeficiency virus type 1 (HIV-1)-infected cells with combinations of HIV-1-specific inhibitors results in a different resistance pattern than does treatment with single drug therapy

J. Virol.

Human immunodeficiency virus type 1 drug-resistance patterns with different 1-[(2-hydroxyethoxy)methyl]-6-(phenylthio)thymine derivatives

Mol. Pharmacol.

Strategies for the identification of new agents for the treatment of AIDS: a national program to facilitate the discovery and preclinical development of new drug candidates for clinical evaluation

Analysis of nonnucleoside drug-resistant variants of human immunodeficiency virus type 1 reverse transcriptase

J. Virol.

HIV-heterogeneity: Characterization of HIV-1 isolates displaying an apparent absence of virion-associated reverse transcriptase activity

AIDS Res. Hum. Retroviruses

Differential antiviral activity of two TIBO derivatives against the human immunodeficiency and murine leukemia viruses alone and in combination with other anti-HIV agents

AIDS Res. Hum. Retroviruses

Cell based and biochemical analysis of the anti-HIV activity of combinations of 3'-azido-3'-deoxythymidine and analogs of TIBO

Antiviral Chem. Chemother.

Comprehensive mutant enzyme and viral variant assessment of human immunodeficiency virus type 1 reverse transcriptase resistance to nonnucleoside inhibitors

Antimicrob. Agents Chemother.

Susceptibilities of human immunodeficiency virus type 1 enzyme and viral variants expressing multiple resistance-engendering amino acid substitutions to reverse transcriptase inhibitors

Antimicrob. Agents Chemother.

Characterization of the binding site for nevirapine (BI-RG-587), a nonnucleoside inhibitor of human immunodeficiency virus type-I reverse transcriptase

J. Biol. Chem.

Identification of the human immunodeficiency virus reverse transcriptase residues that contribute to the activity of diverse nonnucleoside inhibitors

Antimicrob. Agents Chemother.

Antiretroviral therapy: Reverse transcriptase inhibition

Antimicrob. Agents Chemother.

A mutation in reverse transcriptase of bis(heteroaryl)piperazine-resistant human immunodeficiency virus type I that confers increased sensitivity to other nonnucleoside inhibitors

In vitro and in vivo derivation of HIV-1 variants resistant to inhibition by the nonnucleoside reverse transcriptase inhibitor L-697, 661

Pyridinone derivatives: specific human immunodeficiency virus type 1 reverse transcriptase inhibitors with antiviral activity

Nonnucleoside inhibitors of HIV-1 reverse transcriptase: nevirapine as a prototype drug

AIDS Res. Hum. Retroviruses.

Research article
Comparative anti-HIV evaluation of diverse HIV-1-specific reverse transcriptase inhibitor-resistant virus isolates demonstrates the existence of distinct phenotypic subgroups