HIV-1 Escape from the CCR5 Antagonist Maraviroc Associated with an Altered and Less-Efficient Mechanism of gp120-CCR5 Engagement That Attenuates Macrophage Tropism

ABSTRACT Inhibiting human immunodeficiency virus type 1 (HIV-1) infection by blocking the host cell coreceptors CCR5 and CXCR4 is an emerging strategy for antiretroviral therapy. Currently, several novel coreceptor inhibitors are being developed in the clinic, and early results have proven promising. In this report, we describe a novel CCR5 antagonist, vicriviroc (formerly SCH-D or SCH 417690), with improved antiviral activity and pharmacokinetic properties compared to those of SCH-C, a previously described CCR5 antagonist. Like SCH-C, vicriviroc binds specifically to the CCR5 receptor and prevents infection of target cells by CCR5-tropic HIV-1 isolates. In antiviral assays, vicriviroc showed potent, broad-spectrum activity against genetically diverse and drug-resistant HIV-1 isolates and was consistently more active than SCH-C in inhibiting viral replication. This compound demonstrated synergistic anti-HIV activity in combination with drugs from all other classes of approved antiretrovirals. Competition binding assays revealed that vicriviroc binds with higher affinity to CCR5 than SCH-C. Functional assays, including inhibition of calcium flux, guanosine 5′-[35S]triphosphate exchange, and chemotaxis, confirmed that vicriviroc acts as a receptor antagonist by inhibiting signaling of CCR5 by chemokines. Finally, vicriviroc demonstrated diminished affinity for the human ether a-go-go related gene transcript ion channel compared to SCH-C, suggesting a reduced potential for cardiac effects. Vicriviroc represents a promising new candidate for the treatment of HIV-1 infection.

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Lack of Autologous Neutralizing Antibody to Human Immunodeficiency Virus Type 1 (HIV‐1) and Macrophage Tropism Are Associated with Mother‐to‐Infant Transmission

The Journal of Infectious Diseases ◽

10.1086/314886 ◽

1999 ◽

Vol 180 (2) ◽

pp. 344-350 ◽

Cited By ~ 45

Author(s):

Janet L. Lathey ◽

Jeff Tsou ◽

Karen Brinker ◽

Karen Hsia ◽

William A. Meyer III ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Human Immunodeficiency Virus Type ◽

Virus Type ◽

Neutralizing Antibody ◽

Macrophage Tropism ◽

Immunodeficiency Virus ◽

Hiv 1

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Modulation of HIV-1 macrophage-tropism among R5 envelopes occurs before detection of neutralizing antibodies

Retrovirology ◽

10.1186/1742-4690-7-48 ◽

2010 ◽

Vol 7 (1) ◽

pp. 48 ◽

Cited By ~ 8

Author(s):

Kathryn H Richards ◽

Marlén MI Aasa-Chapman ◽

Áine McKnight ◽

Paul R Clapham

Keyword(s):

Neutralizing Antibodies ◽

Macrophage Tropism ◽

Hiv 1

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HIV-1 Resistance to CCR5 Antagonists Associated with Highly Efficient Use of CCR5 and Altered Tropism on Primary CD4+ T Cells

Journal of Virology ◽

10.1128/jvi.00374-10 ◽

2010 ◽

Vol 84 (13) ◽

pp. 6505-6514 ◽

Cited By ~ 47

Author(s):

Jennifer M. Pfaff ◽

Craig B. Wilen ◽

Jessamina E. Harrison ◽

James F. Demarest ◽

Benhur Lee ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Virologic Failure ◽

Cell Subset ◽

Ccr5 Antagonist ◽

Effector Memory ◽

Drug Resistant ◽

Degree Of Protection ◽

Ccr5 Antagonists ◽

Hiv 1

ABSTRACT We previously reported on a panel of HIV-1 clade B envelope (Env) proteins isolated from a patient treated with the CCR5 antagonist aplaviroc (APL) that were drug resistant. These Envs used the APL-bound conformation of CCR5, were cross resistant to other small-molecule CCR5 antagonists, and were isolated from the patient's pretreatment viral quasispecies as well as after therapy. We analyzed viral and host determinants of resistance and their effects on viral tropism on primary CD4+ T cells. The V3 loop contained residues essential for viral resistance to APL, while additional mutations in gp120 and gp41 modulated the magnitude of drug resistance. However, these mutations were context dependent, being unable to confer resistance when introduced into a heterologous virus. The resistant virus displayed altered binding between gp120 and CCR5 such that the virus became critically dependent on the N′ terminus of CCR5 in the presence of APL. In addition, the drug-resistant Envs studied here utilized CCR5 very efficiently: robust virus infection occurred even when very low levels of CCR5 were expressed. However, recognition of drug-bound CCR5 was less efficient, resulting in a tropism shift toward effector memory cells upon infection of primary CD4+ T cells in the presence of APL, with relative sparing of the central memory CD4+ T cell subset. If such a tropism shift proves to be a common feature of CCR5-antagonist-resistant viruses, then continued use of CCR5 antagonists even in the face of virologic failure could provide a relative degree of protection to the TCM subset of CD4+ T cells and result in improved T cell homeostasis and immune function.

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The magnitude of HIV-1 resistance to the CCR5 antagonist maraviroc may impart a differential alteration in HIV-1 tropism for macrophages and T-cell subsets

Virology ◽

10.1016/j.virol.2013.03.026 ◽

2013 ◽

Vol 442 (1) ◽

pp. 51-58 ◽

Cited By ~ 18

Author(s):

Jacqueline K. Flynn ◽

Geza Paukovics ◽

Miranda S. Moore ◽

Anne Ellett ◽

Lachlan R. Gray ◽

...

Keyword(s):

T Cell ◽

T Cell Subsets ◽

Ccr5 Antagonist ◽

Hiv 1

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Engineering of Lactobacillus jensenii To Secrete RANTES and a CCR5 Antagonist Analogue as Live HIV-1 Blockers

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.01492-09 ◽

2010 ◽

Vol 54 (7) ◽

pp. 2994-3001 ◽

Cited By ~ 40

Author(s):

Luca Vangelista ◽

Massimiliano Secchi ◽

Xiaowen Liu ◽

Angela Bachi ◽

Letong Jia ◽

...

Keyword(s):

T Cells ◽

Sexual Transmission ◽

Ccr5 Antagonist ◽

Strong Activity ◽

Promising Strategy ◽

Lactobacillus Jensenii ◽

Proinflammatory Activity ◽

Anti Hiv ◽

Hiv 1 ◽

Prevention Of Hiv

ABSTRACT The development of effective microbicides for the prevention of HIV-1 sexual transmission represents a primary goal for the control of AIDS epidemics worldwide. A promising strategy is the use of bacteria belonging to the vaginal microbiota as live microbicides for the topical production of HIV-1 inhibitors. We have engineered a human vaginal isolate of Lactobacillus jensenii to secrete the anti-HIV-1 chemokine RANTES, as well as C1C5 RANTES, a mutated analogue that acts as a CCR5 antagonist and therefore is devoid of proinflammatory activity. Full-length wild-type RANTES and C1C5 RANTES secreted by L. jensenii were purified to homogeneity and shown to adopt a correctly folded conformation. Both RANTES variants were shown to inhibit HIV-1 infection in CD4+ T cells and macrophages, displaying strong activity against HIV-1 isolates of different genetic subtypes. This work provides proof of principle for the use of L. jensenii-produced C1C5 RANTES to block HIV-1 infection of CD4+ T cells and macrophages, setting the basis for the development of a live anti-HIV-1 microbicide targeting CCR5 in an antagonistic manner.

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A Topical Microbicide Gel Formulation of CCR5 Antagonist Maraviroc Prevents HIV-1 Vaginal Transmission in Humanized RAG-hu Mice

PLoS ONE ◽

10.1371/journal.pone.0020209 ◽

2011 ◽

Vol 6 (6) ◽

pp. e20209 ◽

Cited By ~ 47

Author(s):

C. Preston Neff ◽

Theresa Kurisu ◽

Thomas Ndolo ◽

Kami Fox ◽

Ramesh Akkina

Keyword(s):

Ccr5 Antagonist ◽

Vaginal Transmission ◽

Hiv 1 ◽

Topical Microbicide

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X4 Tropic Virus Prediction Is Associated with a Nadir CD4 T-Cell Count below 100 Cells/mm3

Intervirology ◽

10.1159/000398798 ◽

2015 ◽

Vol 58 (3) ◽

pp. 155-159 ◽

Cited By ~ 5

Author(s):

Matthieu Sechet ◽

Catherine Roussel ◽

Jean-Luc Schmit ◽

Carlo Saroufim ◽

Kamel Ghomari ◽

...

Keyword(s):

T Cell ◽

Cell Count ◽

False Positive Rate ◽

Cd4 T Cell ◽

Ccr5 Antagonist ◽

Net Charge ◽

Antagonist Therapy ◽

Hiv 1 ◽

Cd4 T Cell Count ◽

Tropism Prediction

Objective: The aim of this study was to evaluate tropism prediction performances of three algorithms [geno2pheno false-positive rate 10% (G2P10), position-specific scoring matrix (PSSM) and a combination of the 11/25 and net charge rules] and to investigate the viral and host factors potentially involved in the X4 or R5 prediction in human immunodeficiency virus-1 (HIV-1) patients. Methods: Viral tropism was determined in 179 HIV-1-infected patients eligible for CCR5 antagonist therapy. HIV-1 RNA or DNA was extracted and amplified for env gp120 sequencing. In parallel, demographic, viral, immunological and clinical determinants were analyzed. Results: According to the G2P10 algorithm, 48 patients harbored X4 or X4R5 virus. The tropism prediction was concordant for 87.7 and 88.2% of samples when comparing G2P10 with PSSM or with a combination of the 11/25 and net charge rules, respectively. X4 prediction was significantly associated with more than 35 amino acids in the V3 domain (p < 0.0001) and loss of an N-linked glycosylation site (p < 0.0001). Of the factors studied, only the nadir CD4 T-cell count was significantly associated with X4 tropism (p = 0.01). Conclusion: We determined that the X4 virus detection is closely linked to the nadir CD4 T-cell count below 100 cells/mm3 that must be taken into account when considering a CCR5 antagonist therapy switch.

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