Assessing chemokine co-receptor usage in HIV

  title={Assessing chemokine co-receptor usage in HIV},
  author={Eoin Coakley and Christos J. Petropoulos and Jeannette M. Whitcomb},
  journal={Current Opinion in Infectious Diseases},
Purpose of review HIV entry into cells is mediated through sequential interactions between HIV envelope proteins (Env) and two cellular molecules: CD4 and a co-receptor, typically either CCR5 or CXCR4. Co-receptor preference has been associated with other viral traits; specifically, CXCR4-tropic viruses have been associated with increased host cell pathogenicity and more rapid progression of disease. Recently, much attention has been focused on the development of CCR5 and CXCR4 antagonists as… 

CCR5 Antagonists: Host-Targeted Antivirals for the Treatment of HIV Infection

The completion of ongoing Phase IIb/III studies of marviroc, aplaviroc and vicriviroc will provide further insight into co-receptor tropism, HIV pathogenesis and the suitability of CCR5 antagonists as a potent new class of antivirals for the treatment of HIV infection.

Current tests to evaluate HIV-1 coreceptor tropism

Different methodologies used to determine the ability of the virus to use one or both coreceptors and their potential role in managing HIV-infected individuals treated with these novel drugs are reviewed.

HIV tropism: diagnostic tools and implications for disease progression and treatment with entry inhibitors

It is clear that HIV co-receptor usage may be associated with disease progression, as in vitro, R5 viruses usually correspond to NSI on T-cell lines and are able to replicate in monocyte–macrophages (M-tropic), all features that previously had been linked to less virulent strains.

Resistance to CCR5 antagonists

  • M. Westby
  • Biology, Medicine
    Current opinion in HIV and AIDS
  • 2007
New ways of interpreting phenotypic resistance data may be required for CCR5 antagonists, aided by a consideration of receptor pharmacology rather than enzyme kinetics, as growing in-vitro evidence identifies an alternative pathway to resistance.

HIV-1 escape to CCR5 coreceptor antagonism through selection of CXCR4-using variants in vitro

The results suggest that HIV-1 may escape CCR5 drug pressure through coreceptor switch, and a cell culture model of the evolution of HIV- 1 coreceptor use may be relevant to assess the propensity of clinical isolates to develop resistance through core receptor change.

Genotypic determination of HIV-1 tropism in the clinical setting

Genotypic tropism testing is necessary prior to treatment with CCR5 antagonist medication to rule out the presence of CXCR4-using (X4) virus, with the phenotypic Trofile™ assay being the most commonly used test for HIV coreceptor usage.

Maraviroc, a CCR5 Coreceptor Antagonist That Blocks Entry of Human Immunodeficiency Virus Type 1

Inhibition of the human immunodeficiency virus type 1 (HIV‐1) coreceptor is an encouraging new approach to pharmacotherapy against HIV, and emerging therapies targeting CXCR4, the other HIV coreceptor, have shown promise in decreasing plasma concentrations of HIV‐1 RNA.

Primary CXCR4 co-receptor use in acute HIV infection leads to rapid disease progression in the AE subtype.

The results indicate that in acute HIV infection of rapid progressors (low CD4 count; group 1), the primary co-receptor usage is CXCR4, while in the highCD4 count group (group 2), the co- receptors usage is predominantly CCR5.

HIV‐1 coreceptor preference is distinct from target cell tropism: a dual‐parameter nomenclature to define viral phenotypes

A comprehensive classification schema of HIV‐1 Env phenotypes that addresses both tropism and coreceptor use is proposed, important for understanding changes in Env that evolve over time in vivo, and for discerning differences among viral species that underlie aspects of pathogenesis and transmission.

Bioinformatic analysis of HIV-1 entry and pathogenesis.

This review provides novel preliminary analyses for enabling identification of linkages between amino acids in V3 with other components of the HIV-1 genome and demonstrates that these linkages are different between X4 and R5 viruses.



Preferential suppression of CXCR4-specific strains of HIV-1 by antiviral therapy.

It is demonstrated that the predominant viral population shifted from X4 at baseline to R5 strains after treatment, and Multivariate analyses showed that the shift was independent of changes in plasma HIV-1 RNA level and CD4+ cell count.

Co-receptor antagonists as HIV-1 entry inhibitors

Chemokine receptor antagonists offer great promise as a much-needed new class of antiviral agent and raise questions that are unique to agents targeting these cellular receptors, including whether drug resistance will lead to variants with altered co-receptor selectivity, the tolerability of chronically blocking receptors involved in inflammation (CCR5, CX CR4) or essential in development and hematopoesis (CXCR4).

HIV-1 coreceptor usage, transmission, and disease progression.

This article critically review those studies published over the last few years that purport to examine the relationship between HIV-1 coreceptor usage, transmission, CD4+ T-cell depletion, and disease progression.

Epidemiology and predictive factors for chemokine receptor use in HIV-1 infection.

The prevalence of CCR5-tropic HIV-1 phenotype declines with decreasing CD4 cell count and increasing viral load, and the determination of coreceptor tropism may be required before C CR5 or CXCR4 antagonists are initiated, unless reliable predictive markers ofcoreceptor use are established.

The entry of entry inhibitors: A fusion of science and medicine

  • John P. MooreR. Doms
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 2003
Because all entry inhibitors target in some manner the highly variable Env protein of HIV-1, there are likely to be challenges in their efficient application that are unique to this class of drugs.

The antiviral activity of the CXCR4 antagonist AMD3100 is independent of the cytokine-induced CXCR4/HIV coreceptor expression level.

The data indicate that CXCR4 antagonists such as AMD3100 act independently of the HIV-1 coreceptor expression level, and should therefore be useful in suppressing HIV- 1 infection in all stages of the disease.

Impact of antiretroviral treatment on the tropism of HIV-1 plasma virus populations

Differences in target cell populations, tissue distribution and replication characteristics between R5 and X4 viruses could explain the preferential suppression of X4 virus.

High Frequency of Syncytium-Inducing and CXCR4-Tropic Viruses among Human Immunodeficiency Virus Type 1 Subtype C-Infected Patients Receiving Antiretroviral Treatment

It is suggested that CX CR4-tropic viruses are present within the quasispecies of patients infected with subtype C virus and that antiretroviral treatment may create an environment for the emergence of CXCR4 tropism.

Establishment of a novel CCR5 and CXCR4 expressing CD4+ cell line which is highly sensitive to HIV and suitable for high-throughput evaluation of CCR5 and CXCR4 antagonists

The establishment of a novel CD4+ cell line that reliably supported HIV-1 infection of diverse laboratory-adapted strains and primary isolates with varying coreceptor usage and allows to investigate the antiviral efficacy of combined CCR5 and CXCR4 blockade is described.

CCR5- and CXCR4-Utilizing Strains of Human Immunodeficiency Virus Type 1 Exhibit Differential Tropism and Pathogenesis In Vivo

X4 and R5 strains of HIV-1 were compared for tropism and pathogenesis in SCID-hu Thy/Liv mice, an in vivo model of human thymopoiesis, and X4 strains are highly cytopathic after infection of the human Thymus.