Assessing chemokine co-receptor usage in HIV

@article{Coakley2005AssessingCC,
  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},
  year={2005},
  volume={18},
  pages={9–15}
}
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… 

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References

SHOWING 1-10 OF 52 REFERENCES

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

TLDR
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

TLDR
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.

TLDR
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.

TLDR
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
TLDR
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.

TLDR
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

TLDR
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

TLDR
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

TLDR
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

TLDR
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.
...