scholarly journals In VitroAntiviral Activity of Cabotegravir against HIV-2

2018 ◽  
Vol 62 (10) ◽  
Author(s):  
Robert A. Smith ◽  
Vincent H. Wu ◽  
Christopher G. Zavala ◽  
Dana N. Raugi ◽  
Selly Ba ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Antiretroviral Therapy ◽  
Antiviral Activity ◽  
Integrase Inhibitor ◽  
Single Cycle ◽  
Preexposure Prophylaxis ◽  
Hiv 1 ◽  
Potential Option

ABSTRACTWe examined the antiviral activity of the integrase inhibitor (INI) cabotegravir against HIV-2 isolates from INI-naive individuals. HIV-2 was sensitive to cabotegravir in single-cycle and spreading-infection assays, with 50% effective concentrations (EC50s) in the low to subnanomolar range; comparable results were obtained for HIV-1 in both assay formats. Our findings suggest that cabotegravir should be evaluated in clinical trials as a potential option for antiretroviral therapy and preexposure prophylaxis in HIV-2-prevalent settings.

scholarly journals Comparison of the Antiviral Activity of Bictegravir against HIV-1 and HIV-2 Isolates and Integrase Inhibitor-Resistant HIV-2 Mutants

2019 ◽  
Vol 63 (5) ◽  
Author(s):  
Robert A. Smith ◽  
Dana N. Raugi ◽  
Vincent H. Wu ◽  
Christopher G. Zavala ◽  
Jennifer Song ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Antiviral Activity ◽  
Integrase Inhibitor ◽  
Single Cycle ◽  
Hiv 1

ABSTRACTWe compared the activity of the integrase inhibitor bictegravir against HIV-1 and HIV-2 using a culture-based, single-cycle assay. Values of 50% effective concentrations ranged from 1.2 to 2.5 nM for 9 HIV-1 isolates and 1.4 to 5.6 nM for 15 HIV-2 isolates. HIV-2 integrase mutants G140S/Q148R and G140S/Q148H were 34- and 110-fold resistant to bictegravir, respectively; other resistance-associated mutations conferred ≤5-fold changes in bictegravir susceptibility. Our findings indicate that bictegravir-based antiretroviral therapy should be evaluated in HIV-2-infected individuals.

scholarly journals Flavonol 7-O-Glucoside Herbacitrin Inhibits HIV-1 Replication through Simultaneous Integrase and Reverse Transcriptase Inhibition

2019 ◽  
Vol 2019 ◽  
pp. 1-6 ◽  
Author(s):  
Éva Áy ◽  
Attila Hunyadi ◽  
Mária Mezei ◽  
János Minárovits ◽  
Judit Hohmann
Keyword(s):  
Antiviral Activity ◽  
Reverse Transcriptase ◽  
Cell Cultures ◽  
Core Protein ◽  
Integrase Inhibitor ◽  
Host Cells ◽  
Cytotoxic Activities ◽  
Protein Levels ◽  
Hiv 1 ◽  
Antiretroviral Activity

Here we report the evaluation of the antiretroviral effect of two flavonoid 7-O-glucosides, herbacitrin (1) and gossypitrin (2), together with quercetin (3), a well-studied flavonol. Antiviral activity of the flavonoids was assessed by analyzing HIV-1 p24 core protein levels in the supernatants of HIV-1 infected MT-4 and MT-2 cell cultures. The compounds showed mild to weak cytotoxic activities on the host cells; herbacitrin was the strongest in this regard (CC50=27.8 and 63.64 μM on MT-4 and MT-2 cells, respectively). In nontoxic concentrations, herbacitrin and quercetin reduced HIV-1 replication, whereas gossypitrin was ineffective. Herbacitrin was found to inhibit reverse transcriptase at 21.5 μM, while it was a more potent integrase inhibitor already active at 2.15 μM. Therefore, our observations suggest that herbacitrin exerts antiretroviral activity through simultaneously acting on these two targets of HIV-1 and that integrase inhibition might play a major role in this activity.

scholarly journals Effects of integrase inhibitor-based antiretroviral therapy on brain outcomes according to time since acquisition of HIV-1 infection

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Anna Prats ◽  
Ignacio Martínez-Zalacaín ◽  
Beatriz Mothe ◽  
Eugènia Negredo ◽  
Núria Pérez-Álvarez ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Integrase Inhibitor ◽  
Strand Transfer ◽  
Cognitive Differences ◽  
Integrase Strand Transfer Inhibitors ◽  
Initiation Of Therapy ◽  
Main Component ◽  
Living With Hiv ◽  
The Impact ◽  
Hiv 1

AbstractIntegrase strand transfer inhibitors (INSTI) are a main component of the current antiretroviral regimens recommended for treatment of HIV infection. However, little is known about the impact of INSTI on neurocognition and neuroimaging. We developed a prospective observational trial to evaluate the effects of INSTI-based antiretroviral therapy on comprehensive brain outcomes (cognitive, functional, and imaging) according to the time since HIV-1 acquisition. We recruited men living with HIV who initiated antiretroviral therapy with INSTI < 3 months since the estimated date of HIV-1 acquisition (n = 12) and > 6 months since estimated date of HIV-1 acquisition (n = 15). We also recruited a group of matched seronegative individuals (n = 15). Assessments were performed at baseline (before initiation of therapy in HIV arms) and at weeks 4 and 48. Baseline cognitive functioning was comparable between the arms. At week 48, we did not find cognitive differences between starting therapy with INSTI earlier than 3 months or later than 6 months after acquisition of HIV-1 infection. Functional status was poorer in individuals diagnosed earlier. This effect recovered 48 weeks after initiation of therapy. Regarding brain imaging, we found that men living with HIV initiating antiretroviral therapy later experienced a greater decrease in medial orbitofrontal cortex over time, with expected negative repercussions for decision-making tasks.

scholarly journals Study on Suitable Analysis Method for HIV-1 Non-catalytic Integrase Inhibitor

2020 ◽  
Author(s):  
Ki Hoon Park ◽  
Minjee Kim ◽  
Seoung Eun Bae ◽  
Hee Jung Lee ◽  
Kyung-Chang Kim ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Integrase Inhibitor ◽  
Treatment Method ◽  
Strand Transfer ◽  
Inhibition Assay ◽  
Analysis Method ◽  
Catalytic Core ◽  
Host Chromosome ◽  
Inconsistent Result ◽  
Hiv 1

Abstract Background: Integrase (IN) is an essential protein for HIV replication that catalyzes insertion of the reverse-transcribed viral genome into the host chromosome during the early steps of viral infection. Highly active anti-retroviral therapy (HAART) is a HIV/AIDS treatment method that combines three or more antiviral drugs often formulated from compounds that inhibit the activities of viral reverse transcriptase and protease enzymes. Early IN inhibitors (INIs) mainly serve as integrase strand transfer inhibitors (INSTI) that disrupt strand transfer by binding the catalytic core domain (CCD) of IN. However, mutations of IN can confer resistance to INSTI. Therefore, non-catalytic integrase inhibitors (NCINI) have been developed as next-generation INIs. Methods: In this study, we evaluated and compared the activity of INSTI and NCINI according to the analysis method. Antiviral activity was compared using p24 ELISA with MT2 cell and TZM-bl luciferase system with TZM-bl cell. Each drug was serially diluted and treated to MT2 and TZM-b1 cells, infected with HIV-1 AD8 strain and incubated for 5 and 2 days, respectively. Additionally, to analyze properties of INSTI and NCINI, transfer inhibition assay and 3'-processing inhibition assay were performed. Results: During screening of INIs using the p24 ELISA and TZM-bl luciferase systems, we found an inconsistent result with INSTI and NCINI drugs. Following infection of MT2 and TZM-bl cells with T-tropic HIV-1 strain, both INSTI and NCINI treatments induced significant p24 reduction in MT2 cells. However, NCINI showed no antiviral activity in the TZM-bl luciferase system, indicating that this widely used and convenient antiretroviral assay is not suitable for screening of NCINI compounds that target the second round of HIV-1 replication. Conclusion: Accordingly, we recommend application of other assay procedures, such as p24 ELISA or reverse transcription activity, in lieu of the TZM-bl luciferase system for preliminary NCINI drug screening. Utilization of appropriate analytical methods based on underlying mechanisms is necessary for accurate assessment of drug efficacy.

scholarly journals Preclinical Profile of BI 224436, a Novel HIV-1 Non-Catalytic-Site Integrase Inhibitor

2014 ◽  
Vol 58 (6) ◽  
pp. 3233-3244 ◽  
Author(s):  
Craig Fenwick ◽  
Ma'an Amad ◽  
Murray D. Bailey ◽  
Richard Bethell ◽  
Michael Bös ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Phase 1 ◽  
Integrase Inhibitor ◽  
Parallel Synthesis ◽  
Cell Permeability ◽  
Strand Transfer ◽  
Primary Resistance ◽  
Catalytic Core ◽  
Hiv 1

ABSTRACTBI 224436 is an HIV-1 integrase inhibitor with effective antiviral activity that acts through a mechanism that is distinct from that of integrase strand transfer inhibitors (INSTIs). This 3-quinolineacetic acid derivative series was identified using an enzymatic integrase long terminal repeat (LTR) DNA 3′-processing assay. A combination of medicinal chemistry, parallel synthesis, and structure-guided drug design led to the identification of BI 224436 as a candidate for preclinical profiling. It has antiviral 50% effective concentrations (EC50s) of <15 nM against different HIV-1 laboratory strains and cellular cytotoxicity of >90 μM. BI 224436 also has a low, ∼2.1-fold decrease in antiviral potency in the presence of 50% human serum and, by virtue of a steep dose-response curve slope, exhibits serum-shifted EC95values ranging between 22 and 75 nM. Passage of virus in the presence of inhibitor selected for either A128T, A128N, or L102F primary resistance substitutions, all mapping to a conserved allosteric pocket on the catalytic core of integrase. BI 224436 also retains full antiviral activity against recombinant viruses encoding INSTI resistance substitutions N155S, Q148H, and E92Q. In drug combination studies performed in cellular antiviral assays, BI 224436 displays an additive effect in combination with most approved antiretrovirals, including INSTIs. BI 224436 has drug-likein vitroabsorption, distribution, metabolism, and excretion (ADME) properties, including Caco-2 cell permeability, solubility, and low cytochrome P450 inhibition. It exhibited excellent pharmacokinetic profiles in rat (clearance as a percentage of hepatic flow [CL], 0.7%; bioavailability [F], 54%), monkey (CL, 23%;F, 82%), and dog (CL, 8%;F, 81%). Based on the excellent biological and pharmacokinetic profile, BI 224436 was advanced into phase 1 clinical trials.

scholarly journals Absence of Integrase Inhibitor-Associated Resistance Among Antiretroviral Therapy-Naïve HIV-1-Infected Adults in Guangdong Province, China, in 2018

2020 ◽  
Vol Volume 13 ◽  
pp. 4389-4394
Author(s):  
Yun Lan ◽  
Linghua Li ◽  
Weilie Chen ◽  
Xizi Deng ◽  
Junbin Li ◽  
...  
Keyword(s):  
Antiretroviral Therapy ◽  
Guangdong Province ◽  
Integrase Inhibitor ◽  
Hiv 1

scholarly journals Pharmacokinetics and antiviral activity of cabotegravir and rilpivirine in cerebrospinal fluid following long-acting injectable administration in HIV-infected adults

2019 ◽  
Vol 75 (3) ◽  
pp. 648-655 ◽  
Author(s):  
Scott L Letendre ◽  
Anthony Mills ◽  
Debbie Hagins ◽  
Susan Swindells ◽  
Franco Felizarta ◽  
...  
Keyword(s):  
Cerebrospinal Fluid ◽  
Steady State ◽  
Antiviral Activity ◽  
Plasma Concentrations ◽  
Integrase Inhibitor ◽  
Virological Suppression ◽  
Hiv Integrase ◽  
Long Acting ◽  
Hiv 1

Abstract Background Long-acting (LA) formulations of cabotegravir, an HIV integrase inhibitor, and rilpivirine, an NNRTI, are in development as monthly or 2 monthly intramuscular (IM) injections for maintenance of virological suppression. Objectives To evaluate cabotegravir and rilpivirine CSF distribution and HIV-1 RNA suppression in plasma and CSF in HIV-infected adults participating in a substudy of the Phase 2b LATTE-2 study (NCT02120352). Methods Eighteen participants receiving cabotegravir LA 400 mg + rilpivirine LA 600 mg IM [every 4 weeks (Q4W), n = 3] or cabotegravir LA 600 mg + rilpivirine LA 900 mg IM [every 8 weeks (Q8W), n = 15] with plasma HIV-1 RNA &lt;50 copies/mL enrolled. Paired steady-state CSF and plasma concentrations were evaluable in 16 participants obtained 7 (±3) days after an injection visit. HIV-1 RNA in CSF and plasma were assessed contemporaneously using commercial assays. Results Median total CSF concentrations in Q4W and Q8W groups, respectively, were 0.011 μg/mL and 0.013 μg/mL for cabotegravir (0.30% and 0.34% of the paired plasma concentrations) and 1.84 ng/mL and 1.67 ng/mL for rilpivirine (1.07% and 1.32% of paired plasma concentrations). Cabotegravir and rilpivirine total CSF concentrations exceeded their respective in vitro EC50 for WT HIV-1 (0.10 ng/mL and 0.27 ng/mL, respectively). All 16 participants had HIV-1 RNA &lt;50 copies/mL in plasma and CSF, and 15 of 16 participants had HIV-1 RNA &lt;2 copies/mL in CSF. Conclusions A dual regimen of cabotegravir LA and rilpivirine LA achieved therapeutic concentrations in the CSF resulting in effective virological control in CSF.

scholarly journals Antiviral Activity of Bictegravir and Cabotegravir against Integrase Inhibitor-Resistant SIVmac239 and HIV-1

2017 ◽  
Vol 61 (12) ◽  
Author(s):  
Said A. Hassounah ◽  
Ahmad Alikhani ◽  
Maureen Oliveira ◽  
Simrat Bharaj ◽  
Ruxandra-Ilinca Ibanescu ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Fold Increase ◽  
Integrase Inhibitor ◽  
Antiretroviral Drugs ◽  
Strand Transfer ◽  
Single Cycle ◽  
Genetic Barrier ◽  
Hiv 1

ABSTRACT Animal models are essential to study novel antiretroviral drugs, resistance-associated mutations (RAMs), and treatment strategies. Bictegravir (BIC) is a novel potent integrase strand transfer inhibitor (INSTI) that has shown promising results against HIV-1 infection in vitro and in vivo and against clinical isolates with resistance against INSTIs. BIC has a higher genetic barrier to the development of resistance than two clinically approved INSTIs, termed raltegravir and elvitegravir. Another clinically approved INSTI, dolutegravir (DTG) also possesses a high genetic barrier to resistance, while a fourth compound, termed cabotegravir (CAB), is currently in late phases of clinical development. Here we report the susceptibilities of simian immunodeficiency virus (SIV) and HIV-1 integrase (IN) mutants containing various RAMs to BIC, CAB, and DTG. BIC potently inhibited SIV and HIV-1 in single cycle infection with 50% effective concentrations (EC50s) in the low nM range. In single cycle SIV infections, none of the E92Q, T97A, Y143R, or N155H substitutions had a significant effect on susceptibility to BIC (≤4-fold increase in EC50), whereas G118R and R263K conferred ∼14-fold and ∼6-fold increases in EC50, respectively. In both single and multiple rounds of HIV-1 infections, BIC remained active against the Y143R, N155H, R263K, R263K/M50I, and R263K/E138K mutants (≤4-fold increase in EC50). In multiple rounds of infection, the G140S/Q148H combination of substitutions decreased HIV-1 susceptibility to BIC 4.8-fold compared to 16.8- and 7.4-fold for CAB and DTG, respectively. BIC possesses an excellent resistance profile in regard to HIV and SIV and could be useful in nonhuman primate models of HIV infection.

Sign in / Sign up

Export Citation Format

Share Document