Chemokine receptors and the clinical course of HIV-1 infection

Husman, Ana-Maria de Roda; Schuitemaker, Hanneke

doi:10.1016/s0966-842x(98)01249-9

Cited by 43 publications

(36 citation statements)

References 92 publications

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“…The potential use of CCR5 antagonists for pre-and post-exposure prophylaxis is an active area of research given that R5 viruses are by far the most common types present in sexual transmission [79][80][81] and early infection [78,106,107]. Proof-of-concept for CCR5 antagonist prophylaxis has been demonstrated in a non-human primate model using a novel oral CCR5 antagonist (CMPD167) [108,109].…”

Section: Future Directionsmentioning

confidence: 99%

CCR5 Antagonists: Host-Targeted Antiviral Agents for the Treatment of HIV Infection, 4 Years on

Westby

Ryst

2010

Antivir Chem Chemother

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. We reviewed the various categories of agents and compared the three small-molecule CCR5 antagonists that had progressed to clinical development: maraviroc, vicriviroc and aplaviroc. At that time, several key questions needed to be addressed by large-scale clinical trials, concerning not only the clinical efficacy and long-term safety of these agents, but also the pathways to CCR5 antagonist resistance in vivo and the effect of therapeutic administration of CCR5 antagonists on CXCR4-using virus populations. The purpose of the current review was to provide an update on developments in the field of CCR5 antagonist therapy since 2005, including the outcomes of the various Phase II/III trials conducted over the past 4-5 years, the progress that has been made in our understanding of resistance to CCR5 antagonists and the evolving body of evidence supporting the current and future role of small-molecule CCR5 antagonists in the treatment of HIV infection. Status of CCR5 antagonists in clinical development in 2005Of the three small-molecule CCR5 antagonists in clinical development in 2005, only maraviroc ( Figure 1A) is currently approved for clinical use. Development of aplaviroc was discontinued in 2006, following reports of severe idiosyncratic hepatotoxicity in Phase IIb treatment-naive and Phase III treatmentexperienced studies [2][3][4]. These reports of hepatotoxicity included cases of simultaneous increases in serum alanine aminotransferase and bilirubin breaching the 'Hy's Law' threshold, considered by the US Food and Drug Administration (FDA) to identify drug-induced hepatotoxicity of particular clinical concern [5], and a case of increased alanine aminotransferase that demonstrated a clear dechallenge-rechallenge reaction [2].Development of vicriviroc [6] ( Figure 1B) has been slowed by poor early virological results in dose-ranging studies and by safety concerns over a cluster of unexplained malignancies in a Phase II trial of treatmentexperienced patients. Development of vicriviroc for treatment-naive patients was suspended for several years following interim results from a Phase II dose-ranging study in which treatment-naive patients with CCR5-tropic (R5) virus received either 600 mg of efavirenz once daily or 25, 50 or 75 mg vicriviroc once daily, each

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Section: Future Directionsmentioning

confidence: 99%

CCR5 Antagonists: Host-Targeted Antiviral Agents for the Treatment of HIV Infection, 4 Years on

Westby

Ryst

2010

Antivir Chem Chemother

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“…These strains, also known as syncytium-inducing (SI) viruses, are associated with a more rapid disease course exemplified by an accelerated rate of CD4 ϩ T cell loss (reviewed in ref. 5). This loss may be because the ability to use CXCR4 allows the virus to better target naive CD4 ϩ T cells and͞or more effectively inhibit T cell production (6,7).…”

mentioning

confidence: 99%

HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use

Trkola

Kuhmann

Strizki

et al. 2002

Proc. Natl. Acad. Sci. U.S.A.

294

300

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To study HIV-1 escape from a coreceptor antagonist, the R5 primary isolate CC1͞85 was passaged in peripheral blood mononuclear cells with increasing concentrations of the CCR5-specific small molecule inhibitor, AD101. By 19 passages, an escape mutant emerged with a >20,000-fold resistance to AD101. This virus was cross-resistant to a related inhibitor, SCH-C, and partially resistant to RANTES but still sensitive to CCR5-specific mAbs. The resistant phenotype was stable; the mutant virus retained AD101 resistance during nine additional passages of culture in the absence of inhibitor. Replication of the escape mutant in peripheral blood mononuclear cells completely depended on CCR5 expression and did not occur in cells from CCR5-⌬32 homozygous individuals. The escape mutant was unable to use CXCR4 or any other tested coreceptor to enter transfected cells. Acquisition of CXCR4 use is not the dominant in vitro escape pathway for a small molecule CCR5 entry inhibitor. Instead, HIV-1 acquires the ability to use CCR5 despite the inhibitor, first by requiring lower levels of CCR5 for entry and then probably by using the drug-bound form of the receptor.

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“…Studies on the mechanism of HIV tropism have revealed that chemokine receptors such as CCR5 and CXCR4 serve as essential cofactors specific for the entry of macrophage (M)-and T-lymphocytetropic HIV-1 isolates, respectively (reviewed in Refs. [3][4][5]. Consequently, infection of cells by both types of HIV-1 isolates could be inhibited by chemokines interacting specifically with their respective receptors (5-7).…”

mentioning

confidence: 99%

The Anti-HIV Pseudopeptide HB-19 Forms a Complex with the Cell-surface-expressed Nucleolin Independent of Heparan Sulfate Proteoglycans

Nisole¹,

Krust²,

Callebaut³

et al. 1999

Journal of Biological Chemistry

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Chemokine receptors and the clinical course of HIV-1 infection

Cited by 43 publications

References 92 publications

CCR5 Antagonists: Host-Targeted Antiviral Agents for the Treatment of HIV Infection, 4 Years on

CCR5 Antagonists: Host-Targeted Antiviral Agents for the Treatment of HIV Infection, 4 Years on

HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use

The Anti-HIV Pseudopeptide HB-19 Forms a Complex with the Cell-surface-expressed Nucleolin Independent of Heparan Sulfate Proteoglycans

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