Efavirenz therapy in rhesus macaques infected with a chimera of simian immunodeficiency virus containing reverse transcriptase from human immunodeficiency virus type 1

Michael J. Hofman, Joanne Higgins, Timothy B. Matthews, Niels C Pedersen, Chalet Tan, Raymond F. Schinazi, Thomas W. North

Research output: Contribution to journalArticle

36 Citations (Scopus)

Abstract

The specificity of nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) for the RT of human immunodeficiency virus type 1 (HIV-1) has prevented the use of simian immunodeficiency virus (SIV) in the study of NNRTIs and NNRTI-based highly active antiretroviral therapy. However, a SIV-HIV-1 chimera (RT-SHIV), in which the RT from SIVmac239 was replaced with the RT-encoding region from HIV-1, is susceptible to NNRTIs and is infectious to rhesus macaques. We have evaluated the antiviral activity of efavirenz against RT-SHIV and the emergence of efavirenz-resistant mutants in vitro and in vivo. RT-SHIV was susceptible to efavirenz with a mean effective concentration of 5,9 ± 4.5 nM, and RT-SHIV variants selected with efavirenz in cell culture displayed 600-fold-reduced susceptibility. The efavirenz-resistant mutants of RT-SHIV had mutations in RT similar to those of HIV-1 variants that were selected under similar conditions. Efavirenz monotherapy of RT-SHIV-infected macaques produced a 1.82-log-unit decrease in plasma viral-RNA levels after 1 week. The virus load rebounded within 3 weeks in one treated animal and more slowly in a second animal. Virus isolated from these two animals contained the K103N and Y188C or Y188L mutations. The RT-SHIV-rhesus macaque model may prove useful for studies of antiretroviral drug combinations that include efavirenz.

Original languageEnglish (US)
Pages (from-to)3483-3490
Number of pages8
JournalAntimicrobial Agents and Chemotherapy
Volume48
Issue number9
DOIs
StatePublished - Sep 2004

Fingerprint

efavirenz
Simian Immunodeficiency Virus
RNA-Directed DNA Polymerase
Macaca mulatta
HIV-1
Reverse Transcriptase Inhibitors
Therapeutics
Viruses
Human immunodeficiency virus 1 reverse transcriptase
Mutation
Highly Active Antiretroviral Therapy
Viral RNA
Macaca
Drug Combinations

ASJC Scopus subject areas

  • Pharmacology (medical)

Cite this

Efavirenz therapy in rhesus macaques infected with a chimera of simian immunodeficiency virus containing reverse transcriptase from human immunodeficiency virus type 1. / Hofman, Michael J.; Higgins, Joanne; Matthews, Timothy B.; Pedersen, Niels C; Tan, Chalet; Schinazi, Raymond F.; North, Thomas W.

In: Antimicrobial Agents and Chemotherapy, Vol. 48, No. 9, 09.2004, p. 3483-3490.

Research output: Contribution to journalArticle

Hofman, Michael J. ; Higgins, Joanne ; Matthews, Timothy B. ; Pedersen, Niels C ; Tan, Chalet ; Schinazi, Raymond F. ; North, Thomas W. / Efavirenz therapy in rhesus macaques infected with a chimera of simian immunodeficiency virus containing reverse transcriptase from human immunodeficiency virus type 1. In: Antimicrobial Agents and Chemotherapy. 2004 ; Vol. 48, No. 9. pp. 3483-3490.
@article{24de68665da544bcb45f40a641e31c1e,
title = "Efavirenz therapy in rhesus macaques infected with a chimera of simian immunodeficiency virus containing reverse transcriptase from human immunodeficiency virus type 1",
abstract = "The specificity of nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) for the RT of human immunodeficiency virus type 1 (HIV-1) has prevented the use of simian immunodeficiency virus (SIV) in the study of NNRTIs and NNRTI-based highly active antiretroviral therapy. However, a SIV-HIV-1 chimera (RT-SHIV), in which the RT from SIVmac239 was replaced with the RT-encoding region from HIV-1, is susceptible to NNRTIs and is infectious to rhesus macaques. We have evaluated the antiviral activity of efavirenz against RT-SHIV and the emergence of efavirenz-resistant mutants in vitro and in vivo. RT-SHIV was susceptible to efavirenz with a mean effective concentration of 5,9 ± 4.5 nM, and RT-SHIV variants selected with efavirenz in cell culture displayed 600-fold-reduced susceptibility. The efavirenz-resistant mutants of RT-SHIV had mutations in RT similar to those of HIV-1 variants that were selected under similar conditions. Efavirenz monotherapy of RT-SHIV-infected macaques produced a 1.82-log-unit decrease in plasma viral-RNA levels after 1 week. The virus load rebounded within 3 weeks in one treated animal and more slowly in a second animal. Virus isolated from these two animals contained the K103N and Y188C or Y188L mutations. The RT-SHIV-rhesus macaque model may prove useful for studies of antiretroviral drug combinations that include efavirenz.",
author = "Hofman, {Michael J.} and Joanne Higgins and Matthews, {Timothy B.} and Pedersen, {Niels C} and Chalet Tan and Schinazi, {Raymond F.} and North, {Thomas W.}",
year = "2004",
month = "9",
doi = "10.1128/AAC.48.9.3483-3490.2004",
language = "English (US)",
volume = "48",
pages = "3483--3490",
journal = "Antimicrobial Agents and Chemotherapy",
issn = "0066-4804",
publisher = "American Society for Microbiology",
number = "9",

}

TY - JOUR

T1 - Efavirenz therapy in rhesus macaques infected with a chimera of simian immunodeficiency virus containing reverse transcriptase from human immunodeficiency virus type 1

AU - Hofman, Michael J.

AU - Higgins, Joanne

AU - Matthews, Timothy B.

AU - Pedersen, Niels C

AU - Tan, Chalet

AU - Schinazi, Raymond F.

AU - North, Thomas W.

PY - 2004/9

Y1 - 2004/9

N2 - The specificity of nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) for the RT of human immunodeficiency virus type 1 (HIV-1) has prevented the use of simian immunodeficiency virus (SIV) in the study of NNRTIs and NNRTI-based highly active antiretroviral therapy. However, a SIV-HIV-1 chimera (RT-SHIV), in which the RT from SIVmac239 was replaced with the RT-encoding region from HIV-1, is susceptible to NNRTIs and is infectious to rhesus macaques. We have evaluated the antiviral activity of efavirenz against RT-SHIV and the emergence of efavirenz-resistant mutants in vitro and in vivo. RT-SHIV was susceptible to efavirenz with a mean effective concentration of 5,9 ± 4.5 nM, and RT-SHIV variants selected with efavirenz in cell culture displayed 600-fold-reduced susceptibility. The efavirenz-resistant mutants of RT-SHIV had mutations in RT similar to those of HIV-1 variants that were selected under similar conditions. Efavirenz monotherapy of RT-SHIV-infected macaques produced a 1.82-log-unit decrease in plasma viral-RNA levels after 1 week. The virus load rebounded within 3 weeks in one treated animal and more slowly in a second animal. Virus isolated from these two animals contained the K103N and Y188C or Y188L mutations. The RT-SHIV-rhesus macaque model may prove useful for studies of antiretroviral drug combinations that include efavirenz.

AB - The specificity of nonnucleoside reverse transcriptase (RT) inhibitors (NNRTIs) for the RT of human immunodeficiency virus type 1 (HIV-1) has prevented the use of simian immunodeficiency virus (SIV) in the study of NNRTIs and NNRTI-based highly active antiretroviral therapy. However, a SIV-HIV-1 chimera (RT-SHIV), in which the RT from SIVmac239 was replaced with the RT-encoding region from HIV-1, is susceptible to NNRTIs and is infectious to rhesus macaques. We have evaluated the antiviral activity of efavirenz against RT-SHIV and the emergence of efavirenz-resistant mutants in vitro and in vivo. RT-SHIV was susceptible to efavirenz with a mean effective concentration of 5,9 ± 4.5 nM, and RT-SHIV variants selected with efavirenz in cell culture displayed 600-fold-reduced susceptibility. The efavirenz-resistant mutants of RT-SHIV had mutations in RT similar to those of HIV-1 variants that were selected under similar conditions. Efavirenz monotherapy of RT-SHIV-infected macaques produced a 1.82-log-unit decrease in plasma viral-RNA levels after 1 week. The virus load rebounded within 3 weeks in one treated animal and more slowly in a second animal. Virus isolated from these two animals contained the K103N and Y188C or Y188L mutations. The RT-SHIV-rhesus macaque model may prove useful for studies of antiretroviral drug combinations that include efavirenz.

UR - http://www.scopus.com/inward/record.url?scp=4344667399&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=4344667399&partnerID=8YFLogxK

U2 - 10.1128/AAC.48.9.3483-3490.2004

DO - 10.1128/AAC.48.9.3483-3490.2004

M3 - Article

VL - 48

SP - 3483

EP - 3490

JO - Antimicrobial Agents and Chemotherapy

JF - Antimicrobial Agents and Chemotherapy

SN - 0066-4804

IS - 9

ER -