Resistance to the CCR5 Inhibitor 5P12-RANTES Requires a Difficult Evolution from CCR5 to CXCR4 Coreceptor Use

ABSTRACT Aplaviroc (AVC), an experimental CCR5 inhibitor, potently blocks in vitro the infection of R5-tropic human immunodeficiency virus type 1 (R5-HIV-1) at subnanomolar 50% inhibitory concentrations. Although maraviroc is presently clinically available, further studies are required to determine the role of CCR5 inhibitors in combinations with other drugs. Here we determined anti-HIV-1 activity using combinations of AVC with various anti-HIV-1 agents, including four U.S. Food and Drug Administration-approved drugs, two CCR5 inhibitors (TAK779 and SCH-C) and two CXCR4 inhibitors (AMD3100 and TE14011). Combination effects were defined as synergistic or antagonistic when the activity of drug A combined with B was statistically greater or less, respectively, than the additive effects of drugs A and A combined and drugs B and B combined by using the Combo method, described in this paper, which provides (i) a flexible choice of interaction models and (ii) the use of nonparametric statistical methods. Synergistic effects against R5-HIV-1Ba-L and a 50:50 mixture of R5-HIV-1Ba-L and X4-HIV-1ERS104pre (HIV-1Ba-L/104pre) were seen when AVC was combined with zidovudine, nevirapine, indinavir, or enfuvirtide. Mild synergism and additivity were observed when AVC was combined with TAK779 and SCH-C, respectively. We also observed more potent synergism against HIV-1Ba-L/104pre when AVC was combined with AMD3100 or TE14011. The data demonstrate a tendency toward greater synergism with AVC plus either of the two CXCR4 inhibitors compared to the synergism obtained with combinations of AVC and other drugs, suggesting that the development of effective CXCR4 inhibitors may be important for increasing the efficacies of CCR5 inhibitors.

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Generation and properties of a human immunodeficiency virus type 1 isolate resistant to the small molecule CCR5 inhibitor, SCH-417690 (SCH-D)

Virology ◽

10.1016/j.virol.2005.04.035 ◽

2005 ◽

Vol 338 (1) ◽

pp. 182-199 ◽

Cited By ~ 132

Author(s):

Andre J. Marozsan ◽

Shawn E. Kuhmann ◽

Thomas Morgan ◽

Carolina Herrera ◽

Enid Rivera-Troche ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Small Molecule ◽

Immunodeficiency Virus ◽

Ccr5 Inhibitor

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Evolutionary game theoretical approach for understanding CCR5 to CXCR4 coreceptor switch

Proceedings of the 2010 American Control Conference ◽

10.1109/acc.2010.5531370 ◽

2010 ◽

Author(s):

Jing Wu ◽

S Bewick ◽

Ruoting Yang ◽

S C Lenaghan ◽

Mingjun Zhang

Keyword(s):

Theoretical Approach ◽

Evolutionary Game ◽

Coreceptor Switch ◽

Game Theoretical Approach ◽

Cxcr4 Coreceptor

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In VitroPhenotypic Susceptibility of HIV-2 Clinical Isolates to CCR5 Inhibitors

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.05313-11 ◽

2011 ◽

Vol 56 (1) ◽

pp. 137-139 ◽

Cited By ~ 16

Author(s):

Benoit Visseaux ◽

Charlotte Charpentier ◽

Margarita Hurtado-Nedelec ◽

Alexandre Storto ◽

Romain Antoine ◽

...

Keyword(s):

Drug Class ◽

Effective Concentration ◽

Clinical Isolates ◽

Peripheral Blood Mononuclear ◽

Nonnucleoside Reverse Transcriptase Inhibitors ◽

First Time ◽

Ccr5 Inhibitor ◽

Hiv 1 ◽

Median Maximum

ABSTRACTHIV-2 is naturally resistant to nonnucleoside reverse transcriptase inhibitors, to a fusion inhibitor, and to some of the protease inhibitors. Maraviroc is the first drug of the new anti-CCR5 drug class and is effective only on CCR5-tropic (R5) HIV-1. No previous studies concerning HIV-2 susceptibility to maraviroc have been reported yet. We developed a phenotypic maraviroc susceptibility test using a peripheral blood mononuclear cell (PBMC) model. We analyzed the maraviroc susceptibility of 13 R5 HIV-2, 2 X4R5 (dual) HIV-2, and 2 CXCR4-tropic (X4) HIV-2 clinical isolates. We also tested, with the same protocol, 1 X4 HIV-1 and 4 R5 HIV-1 clinical isolates. For the R5 HIV-2 clinical isolates, the 50% effective concentration (EC50) for maraviroc was 0.80 nM (interquartile range [IQR], 0.48 to 1.39 nM), similar to that observed for the R5 HIV-1 isolates. The median maximum percentage of inhibition in the R5 HIV-2 isolates was 93% (IQR, 84 to 98%), similar to that observed in the R5 HIV-1 isolates. As expected, both X4 HIV-1 and HIV-2 were highly resistant to maraviroc. Our study showed for the first time that maraviroc is activein vitroagainst R5 HIV-2. The new tools we developed will allow identification of HIV-2-infected patients eligible for CCR5 inhibitor use and management of virological failure when receiving a maraviroc-based regimen.

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Industry Watch

Asia-Pacific Biotech News ◽

10.1142/s0219030307000626 ◽

2007 ◽

Vol 11 (09) ◽

pp. 570-591

Keyword(s):

Large Scale ◽

Malaria Vaccine ◽

Life Sciences ◽

Cell Transplant ◽

License Agreement ◽

Phase Ii Clinical Trials ◽

Demonstration Plant ◽

Ccr5 Inhibitor ◽

Therapeutic Administration ◽

Large Scale Clinical Trial

Apollo Life Sciences Develops Needle Free Topical Vaccine. Avexa Collaborates with TargetDrug for CCR5 Inhibitor HIV Program. BioMaxx Systems to Build Biodiesel Demonstration Plant in Asia. GSK Plans to Launch Cervarix Vaccine Approved by Australia's Therapeutic Administration. LabTech Systems Signs License Agreement with BioMérieux for Innovative Robotic Microbiological Instrumentation. Living Cell Technologies to Conduct Trials of Pig Islet Cell Transplant in Diabetes Patients. Peptech Plans to Merge with Evogenix. Phylogica Collaborates with Opsona Therapeutics for Drug Discovery. China Sky One Medical Receives Grant from Heilongjiang Government. SinoBiomed's Malaria Vaccine Granted US Patent. Biocon to Enter Phase II Clinical Trials for Oral Insulin. Indian Drug Makers, Ranbaxy and Dr Reddy, Build Therapeutic Bridges in Japan. Medtronic Commences Large-Scale Clinical Trial of CRT-D in Japan. Japan's Bioventures Today — Sun Care Fuels Corporation. MerLion Pharmaceuticals to Conduct Trials for Two Anti-infection Drugs.

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CD4-Independent Infection of Two CD4−/CCR5−/CXCR4+ Pre-T-Cell Lines by Human and Simian Immunodeficiency Viruses

Journal of Virology ◽

10.1128/jvi.74.14.6689-6694.2000 ◽

2000 ◽

Vol 74 (14) ◽

pp. 6689-6694 ◽

Cited By ~ 14

Author(s):

Alessandra Borsetti ◽

Cristina Parolin ◽

Barbara Ridolfi ◽

Leonardo Sernicola ◽

Andrea Geraci ◽

...

Keyword(s):

T Cell ◽

Cell Lines ◽

Chemokine Receptors ◽

Immunodeficiency Virus ◽

Cxcr4 Coreceptor ◽

T Cell Lines ◽

Hiv 1

ABSTRACT The infection of CD4-negative cells by variants of tissue culture-adapted human immunodeficiency virus type 1 (HIV-1) or HIV-2 strains has been shown to be mediated by the CXCR4 coreceptor. Here we show that two in vitro-established CD4−/CCR5−/CXCR4+ human pre-T-cell lines (A3 and A5) can be productively infected by wild-type laboratory-adapted T-cell-tropic HIV-1 and HIV-2 strains in a CD4-independent, CXCR4-dependent fashion. Despite the absence of CCR5 expression, A3 and A5 cells were susceptible to infection by the simian immunodeficiency viruses SIVmac239 and SIVmac316. Thus, at least in A3 and A5 cells, one or more of the chemokine receptors can efficiently support the entry of HIV and SIV isolates in the absence of CD4. These findings suggest that to infect cells of different compartments, HIV and SIV could have evolved in vivo to bypass CD4 and to interact directly with an alternative receptor.

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Biological and Structural Characterization of Rotamers of C–C Chemokine Receptor Type 5 (CCR5) Inhibitor GSK214096

ACS Medicinal Chemistry Letters ◽

10.1021/ml5004124 ◽

2014 ◽

Vol 5 (12) ◽

pp. 1296-1299 ◽

Cited By ~ 7

Author(s):

Wieslaw M. Kazmierski ◽

Susan Danehower ◽

Maosheng Duan ◽

Robert G. Ferris ◽

Vassil Elitzin ◽

...

Keyword(s):

Chemokine Receptor ◽

Structural Characterization ◽

Receptor Type ◽

Ccr5 Inhibitor

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Effect of HIV-1 Env on SERINC5 Antagonism

Journal of Virology ◽

10.1128/jvi.02214-16 ◽

2016 ◽

Vol 91 (4) ◽

Cited By ~ 45

Author(s):

Saina Beitari ◽

Shilei Ding ◽

Qinghua Pan ◽

Andrés Finzi ◽

Chen Liang

Keyword(s):

Antiviral Activity ◽

High Frequency ◽

Neutralizing Antibodies ◽

Broadly Neutralizing Antibodies ◽

Viral Loads ◽

Virion Incorporation ◽

Viral Particles ◽

Ccr5 Inhibitor ◽

Hiv 1

ABSTRACT SERINC5 is able to restrict HIV-1 infection by drastically impairing the infectivity of viral particles. Studies have shown that the HIV-1 Nef protein counters SERINC5 through downregulating SERINC5 from the cell surface and preventing the virion incorporation of SERINC5. In addition, the Env proteins of some HIV-1 strains can also overcome SERINC5 inhibition. However, it is unclear how HIV-1 Env does so and why HIV-1 has two mechanisms to resist SERINC5 inhibition. The results of this study show that neither Env nor Nef prevents high levels of ectopic SERINC5 from being incorporated into HIV-1 particles, except that Env, but not Nef, is able to resist inhibition by virion-associated SERINC5. Testing of a panel of HIV-1 Env proteins from different subtypes revealed a high frequency of SERINC5-resistant Envs. Interestingly, although the SERINC5-bearing viruses were not inhibited by SERINC5 itself, they became more sensitive to the CCR5 inhibitor maraviroc and some neutralizing antibodies than the SERINC5-free viruses, which suggests a possible influence of SERINC5 on Env function. We conclude that HIV-1 Env is able to overcome SERINC5 without preventing SERINC5 virion incorporation. IMPORTANCE HIV-1 Nef is known to enhance the infectivity of HIV-1 particles and to contribute to the maintenance of high viral loads in patients. However, the underlying molecular mechanism remained elusive until the recent discovery of the antiviral activity of SERINC5. SERINC5 profoundly inhibits HIV-1 but is antagonized by Nef, which prevents the incorporation of SERINC5 into viral particles. Here, we show that HIV-1 Env, but not Nef, is able to resist high levels of SERINC5 without excluding SERINC5 from incorporation into viral particles. However, the virion-associated SERINC5 renders HIV-1 more sensitive to some broadly neutralizing antibodies. It is possible that, under the pressure of some neutralizing antibodies in vivo, HIV-1 needs Nef to remove SERINC5 from viral particles, even though viral Env is able to resist virion-associated SERINC5.

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