scholarly journals Susceptibility of Human Immunodeficiency Virus Type 1 to the Maturation Inhibitor Bevirimat Is Modulated by Baseline Polymorphisms in Gag Spacer Peptide 1

2009 ◽  
Vol 53 (5) ◽  
pp. 2185-2188 ◽  
Author(s):  
Kurt Van Baelen ◽  
Karl Salzwedel ◽  
Evelien Rondelez ◽  
Veerle Van Eygen ◽  
Stephanie De Vos ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Antiretroviral Agents ◽  
New Class ◽  
Naturally Occurring ◽  
Immunodeficiency Virus ◽  
Maturation Inhibitor

ABSTRACT In this study, we evaluated baseline susceptibility to bevirimat (BVM), the first in a new class of antiretroviral agents, maturation inhibitors. We evaluated susceptibility to BVM by complete gag genotypic and phenotypic testing of 20 patient-derived human immunodeficiency virus type 1 isolates and 20 site-directed mutants. We found that reduced BVM susceptibility was associated with naturally occurring polymorphisms at positions 6, 7, and 8 in Gag spacer peptide 1.

scholarly journals In Vitro Resistance to the Human Immunodeficiency Virus Type 1 Maturation Inhibitor PA-457 (Bevirimat)

2006 ◽  
Vol 80 (22) ◽  
pp. 10957-10971 ◽  
Author(s):  
Catherine S. Adamson ◽  
Sherimay D. Ablan ◽  
Ioana Boeras ◽  
Ritu Goila-Gaur ◽  
Ferri Soheilian ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Single Amino Acid ◽  
Compensatory Mutation ◽  
C Terminus ◽  
Immunodeficiency Virus ◽  
Maturation Inhibitor ◽  
Hiv 1

ABSTRACT 3-O-(3′,3′-dimethylsuccinyl)betulinic acid (PA-457 or bevirimat) potently inhibits human immunodeficiency virus type 1 (HIV-1) maturation by blocking a late step in the Gag processing pathway, specifically the cleavage of SP1 from the C terminus of capsid (CA). To gain insights into the mechanism(s) by which HIV-1 could evolve resistance to PA-457 and to evaluate the likelihood of such resistance arising in PA-457-treated patients, we sought to identify and characterize a broad spectrum of HIV-1 variants capable of conferring resistance to this compound. Numerous independent rounds of selection repeatedly identified six single-amino-acid substitutions that independently confer PA-457 resistance: three at or near the C terminus of CA (CA-H226Y, -L231F, and -L231M) and three at the first and third residues of SP1 (SP1-A1V, -A3T, and -A3V). We determined that mutations CA-H226Y, CA-L231F, CA-L231M, and SP1-A1V do not impose a significant replication defect on HIV-1 in culture. In contrast, mutations SP1-A3V and -A3T severely impaired virus replication and inhibited virion core condensation. The replication defect imposed by SP1-A3V was reversed by a second-site compensatory mutation in CA (CA-G225S). Intriguingly, high concentrations of PA-457 enhanced the maturation of SP1 residue 3 mutants. The different phenotypes associated with mutations that confer PA-457 resistance suggest the existence of multiple mechanisms by which HIV-1 can evolve resistance to this maturation inhibitor. These findings have implications for the ongoing development of PA-457 to treat HIV-1 infection in vivo.

scholarly journals Naturally Occurring Human Immunodeficiency Virus Type 1 Long Terminal Repeats Have a Frequently Observed Duplication That Binds RBF-2 and Represses Transcription

1998 ◽  
Vol 72 (8) ◽  
pp. 6465-6474 ◽  
Author(s):  
Mario Clemente Estable ◽  
Brendan Bell ◽  
Martin Hirst ◽  
Ivan Sadowski
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Binding Sites ◽  
Naturally Occurring ◽  
Immunodeficiency Virus ◽  
Aids Study ◽  
Hiv 1 ◽  
In Cells

ABSTRACT Approximately 38% of human immunodeficiency virus type 1 (HIV-1)-infected patients within the Vancouver Lymphadenopathy-AIDS Study have proviruses bearing partial 15- to 34-nucleotide duplications upstream of the NF-κB binding sites within the 5′ long terminal repeat (LTR). This most frequent naturally occurring length polymorphism (MFNLP) of the HIV-1 5′ LTR encompasses potential binding sites for several candidate transcription factors, including TCF-1α/hLEF, c-Ets, AP-4, and Ras-responsive binding factor 2 (RBF-2) (M. C. Estable et al., J. Virol. 70:4053–4062, 1996). RBF-2 and an apparently related factor, RBF-1, bind to at least fourcis elements within the LTR which are required for full transcriptional responsiveness to protein-tyrosine kinases and v-Ras (B. Bell and I. Sadowski, Oncogene 13:2687–2697, 1996). Here we demonstrate that representative MFNLPs from two patients specifically bind RBF-2. In both cases, deletion of the MFNLP caused elevated LTR-directed transcription in cells expressing RBF-2 but not in cells with undetectable RBF-2. RBF-1, but not RBF-2, appears to contain the Ets transcription factor family member GABPα/GABPβ1. Taken together with the fact that every MFNLP from a comparative study of over 500 LTR sequences from 42 patients contains a predicted binding site for RBF-2, our data suggest that the MFNLP is selected in vivo because it provides a duplicated RBF-2 cis element, which may limit transcription in monocytes and activated T cells.

scholarly journals Inhibition of Human Immunodeficiency Virus Type 1 Replication by Combination of Transcription Inhibitor K-12 and Other Antiretroviral Agents in Acutely and Chronically Infected Cells

1999 ◽  
Vol 43 (3) ◽  
pp. 492-497 ◽  
Author(s):  
Mika Okamoto ◽  
Takashi Okamoto ◽  
Masanori Baba
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Mononuclear Cells ◽  
Peripheral Blood Mononuclear ◽  
Antiretroviral Agents ◽  
Immunodeficiency Virus ◽  
K 12 ◽  
Hiv 1

ABSTRACT 8 - Difluoromethoxy - 1 - ethyl - 6 - fluoro - 1,4 - dihydro - 7 - [4 - (2 - methoxyphenyl) - 1 - piperazinyl] - 4 - oxoquinoline - 3 - carboxylic acid (K-12) has recently been identified as a potent and selective inhibitor of human immunodeficiency virus type 1 (HIV-1) transcription. In this study, we examined several combinations of K-12 and other antiretroviral agents for their inhibitory effects on HIV-1 replication in acutely and chronically infected cell cultures. Combinations of K-12 and a reverse transcriptase (RT) inhibitor, either zidovudine, lamivudine, or nevirapine, synergistically inhibited HIV-1 replication in acutely infected MT-4 cells. The combination of K-12 and the protease inhibitor nelfinavir (NFV) also synergistically inhibited HIV-1, whereas the synergism of this combination was weaker than that of the combinations with the RT inhibitors. K-12 did not enhance the cytotoxicities of RT and protease inhibitors. Synergism of the combinations was also observed in acutely infected peripheral blood mononuclear cells. The combination of K-12 and cepharanthine, a nuclear factor κB inhibitor, synergistically inhibited HIV-1 production in tumor necrosis factor alpha-stimulated U1 cells, a promonocytic cell line chronically infected with the virus. In contrast, additive inhibition was observed for the combination of K-12 and NFV. These results indicate that the combinations of K-12 and clinically available antiretroviral agents may have potential as chemotherapeutic modalities for the treatment of HIV-1 infection.

scholarly journals Extent of Cross-Resistance between Agents Used To Treat Human Immunodeficiency Virus Type 1 Infection in Clinically Derived Isolates

2002 ◽  
Vol 46 (3) ◽  
pp. 909-912 ◽  
Author(s):  
P. Richard Harrigan ◽  
Brendan A. Larder
Keyword(s):  
United States ◽  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
The United States ◽  
Cross Resistance ◽  
Antiretroviral Agents ◽  
Immunodeficiency Virus

ABSTRACT The phenomenon of cross-resistance to antiretroviral agents used to treat human immunodeficiency virus type 1 infection is well known but so far has been only qualitatively described. Here, we quantitate the degree of cross-resistance among all commonly prescribed antiretroviral agents in almost 5,000 clinically derived recombinant isolates collected in the United States since January 2000.

A Phase IIa Study Evaluating Safety, Pharmacokinetics, and Antiviral Activity of GSK2838232, a Novel, Second-generation Maturation Inhibitor, in Participants With Human Immunodeficiency Virus Type 1 Infection

2019 ◽  
Vol 71 (5) ◽  
pp. 1255-1262 ◽  
Author(s):  
Edwin DeJesus ◽  
Sara Harward ◽  
Roxanne C Jewell ◽  
Mark Johnson ◽  
Etienne Dumont ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Immunodeficiency Virus Type ◽  
Virus Type ◽  
Second Generation ◽  
Proof Of Concept ◽  
Once Daily ◽  
Immunodeficiency Virus ◽  
Maturation Inhibitor ◽  
Hiv 1

Abstract Background GSK2838232 is a second-generation, potent, small-molecule, oral human immunodeficiency virus type 1 (HIV-1) maturation inhibitor for once-daily administration boosted with a pharmacoenhancer. Methods The phase 2a, proof-of-concept study was an open-label, adaptive dose-ranging design. Safety, pharmacokinetics, and efficacy of GSK2838232 boosted by cobicistat were evaluated in individuals with HIV-1 infection. The study participants (N = 33) received GSK2838232 once daily across a range of doses (20–200 mg) with cobicistat 150 mg for 10 days. Results GSK2838232 was safe and well tolerated with no clinically meaningful changes in safety parameters or adverse events. Exposure (maximum concentration and area under the concentration-time curve from time zero to the concentration at 24 hours postdose) increased 2- to 3-fold with repeated dosing in an approximately dose-proportional manner, reaching steady-state by day 8 with a half-life (t½) from 16.3 to 19.2 hours. Clearance and t½ values were not dependent on dose. Viral load declined from baseline with all GSK2838232 doses. Mean maximum declines from baseline to day 11 in HIV-1 RNA log10 copies/mL with the 20-mg, 50-mg, 100-mg, and 200-mg cohorts were −0.67, −1.56, −1.32, and −1.70, respectively. CD4+ cell counts increased at doses ≥50 mg. Conclusions GSK2838232 with cobicistat was well tolerated and exhibited efficacy as a short-term monotherapy in participants with HIV-1. This positive proof-of-concept study supports the continued development of GSK2838232 for the treatment of HIV as part of combination antiretroviral therapy. Clinical Trials Registration NCT03045861.

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