Short Communication: A Novel Mutation (F227L) Arises in the Reverse Transcriptase of Human Immunodeficiency Virus Type 1 on Dose-Escalating Treatment of HIV Type 1-Infected Cell Cultures with the Nonnucleoside Reverse Transcriptase Inhibitor Thiocarboxanilide UC-781

1998 ◽  
Vol 14 (3) ◽  
pp. 255-260 ◽  
Author(s):  
JAN BALZARINI ◽  
HEIDI PELEMANS ◽  
ROBERT ESNOUF ◽  
ERIK DE CLERCQ
Keyword(s):  
Reverse Transcriptase ◽  
Short Communication ◽  
Novel Mutation ◽  
Transcriptase Inhibitor ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Immunodeficiency Virus ◽  
Hiv Type 1 ◽  
Reverse Transcriptase Inhibitor ◽  
Dose Escalating

Efavirenz Is a Potent Nonnucleoside Reverse Transcriptase Inhibitor of HIV Type 1 Replication in Microgliain Vitro

2000 ◽  
Vol 16 (15) ◽  
pp. 1527-1537 ◽  
Author(s):  
Andrew V. Albright ◽  
Susan Erickson-Viitanen ◽  
Michael O'Connor ◽  
Ian Frank ◽  
Marlene M. Rayner ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Hiv Type 1 ◽  
Reverse Transcriptase Inhibitor

scholarly journals In Vitro Cross-Resistance Profiles of Rilpivirine, Dapivirine, and MIV-150, Nonnucleoside Reverse Transcriptase Inhibitor Microbicides in Clinical Development for the Prevention of HIV-1 Infection

2017 ◽  
Vol 61 (7) ◽  
Author(s):  
Nicholas S. Giacobbi ◽  
Nicolas Sluis-Cremer
Keyword(s):  
Reverse Transcriptase ◽  
Genital Tract ◽  
Transcriptase Inhibitor ◽  
Cross Resistance ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACT Rilpivirine (RPV), dapivirine (DPV), and MIV-150 are in development as microbicides. It is not known whether they will block infection of circulating nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant human immunodeficiency virus type 1 (HIV-1) variants. Here, we demonstrate that the activity of DPV and MIV-150 is compromised by many resistant viruses containing single or double substitutions. High DPV genital tract concentrations from DPV ring use may block replication of resistant viruses. However, MIV-150 genital tract concentrations may be insufficient to inhibit many resistant viruses, including those harboring K103N or Y181C.

scholarly journals In Vitro Microbicidal Activity of the Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) UC781 against NNRTI-Resistant Human Immunodeficiency Virus Type 1

2006 ◽  
Vol 80 (9) ◽  
pp. 4440-4446 ◽  
Author(s):  
Mohammad M. Hossain ◽  
Michael A. Parniak
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Resistant Virus ◽  
Microbicidal Activity ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor ◽  
Hiv 1

ABSTRACT The nonnucleoside reverse transcriptase inhibitor (NNRTI) UC781 is under development as a microbicide to prevent sexual transmission of the human immunodeficiency virus type 1 (HIV-1). However, NNRTI-resistant HIV-1 is increasingly prevalent in the infected population, and one of the concerns for NNRTI-based microbicides is that they will be ineffective against drug-resistant virus and may in fact selectively transmit NNRTI-resistant virus. We evaluated the microbicidal activity of UC781 against UC781-resistant (UCR), efavirenz-resistant (EFVR), and nevirapine-resistant (NVPR) strains in a variety of microbicide-relevant tests, including inactivation of cell-free virus, inhibition of cell-to-cell HIV-1 transmission, and the ability of UC781 pretreatment to protect cells from subsequent infection in the absence of exogenous drug. UC781 was 10- to 100-fold less effective against NNRTI-resistant HIV-1 compared to wild-type (wt) virus in each of these tests, with UC781 microbicidal activity against the various virus strains being wt ≥ NVPR > UCR ≥ EFVR. Breakthrough experiments using UC781-pretreated cells and mixtures of wt and NNRTI-resistant HIV-1 showed that UC781-pretreatment selected for NNRTI-resistant HIV-1. However, the efficacy of UC781 was dose dependent, and 25 μM UC781 provided essentially equivalent microbicidal activity against NNRTI-resistant and wt virus. The amount of UC781 in topical microbicide formulations under current development is approximately 100-fold greater than this concentration, so transmission of NNRTI-resistant virus may not be an issue at these microbicide formulation levels of UC781. Nonetheless, the reduced microbicidal activity of UC781 against NNRTI-resistant HIV-1 suggests that additional antiviral agents should be included in NNRTI-based microbicide formulations.

scholarly journals The K101P and K103R/V179D Mutations in Human Immunodeficiency Virus Type 1 Reverse Transcriptase Confer Resistance to Nonnucleoside Reverse Transcriptase Inhibitors

2006 ◽  
Vol 50 (1) ◽  
pp. 351-354 ◽  
Author(s):  
Neil T. Parkin ◽  
Soumi Gupta ◽  
Colombe Chappey ◽  
Christos J. Petropoulos
Keyword(s):  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Site Directed Mutagenesis ◽  
Resistance Mutations ◽  
Nnrti Resistance ◽  
Nonnucleoside Reverse Transcriptase Inhibitors ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor

ABSTRACT Genotypic patterns associated with nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance in the absence of well-characterized resistance mutations were identified using a database (n > 47,000) of phenotype-genotype data. Among samples with no known NNRTI mutations, the most resistant samples contained K101P (n = 35) or a combination of K103R and V179D (n = 41). Site-directed mutagenesis confirmed the importance of these mutations.

scholarly journals Inhibition of Human Immunodeficiency Virus Type 1 Infection by the Candidate Microbicide Dapivirine, a Nonnucleoside Reverse Transcriptase Inhibitor

2008 ◽  
Vol 53 (2) ◽  
pp. 487-495 ◽  
Author(s):  
P. Fletcher ◽  
S. Harman ◽  
H. Azijn ◽  
N. Armanasco ◽  
P. Manlow ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Reverse Transcriptase ◽  
Transcriptase Inhibitor ◽  
Heterosexual Transmission ◽  
Inhibitory Effects ◽  
Nonnucleoside Reverse Transcriptase Inhibitor ◽  
Wide Range ◽  
Immunodeficiency Virus ◽  
Reverse Transcriptase Inhibitor

ABSTRACT Heterosexual transmission of human immunodeficiency virus (HIV) remains the major route of infection worldwide; thus, there is an urgent need for additional prevention strategies, particularly strategies that could be controlled by women, such as topical microbicides. Potential microbicide candidates must be both safe and effective. Using cellular and tissue explant models, we have evaluated the activity of the nonnucleoside reverse transcriptase inhibitor (NNRTI) dapivirine as a vaginal microbicide. In tissue compatibility studies, dapivirine was well tolerated by epithelial cells, T cells, macrophages, and cervical tissue explants. Dapivirine demonstrated potent dose-dependent inhibitory effects against a broad panel of HIV type 1 isolates from different clades. Furthermore, dapivirine demonstrated potent activity against a wide range of NNRTI-resistant isolates. In human cervical explant cultures, dapivirine was able not only to inhibit direct infection of mucosal tissue but also to prevent the dissemination of the virus by migratory cells. Activity was retained in the presence of semen or a cervical mucus simulant. Furthermore, dapivirine demonstrated prolonged inhibitory effects: it was able to prevent both localized and disseminated infection for as long as 6 days posttreatment. The prolonged protection observed following pretreatment of genital tissue and the lack of observable toxicity suggest that dapivirine has considerable promise as a potential microbicide candidate.

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