Developing clinical role of a CCR5 co-receptor antagonist in HIV-1 infection

ArticleinExpert Opinion on Pharmacotherapy 9(18):3231-42 · January 2009with8 Reads
DOI: 10.1517/14656560802576324 · Source: PubMed
Maraviroc is the only approved CCR5 coreceptor antagonist on the market for treatment of HIV-1 infection. It uses a previously untargeted step in the HIV-1 replication cycle necessary for viral entry into the host cell. This review will describe and evaluate recent clinical literature regarding maraviroc, focusing on safety, efficacy, and mechanisms of treatment failure. A search of the primary literature and conference abstracts was conducted using the keywords CCR5 antagonist, maraviroc, and UK-427857. Resulting articles were then compiled and analyzed in this review. Maraviroc is a potent inhibitor of HIV-1 replication and contributes to effective viral suppression in combination with traditional antiretroviral medications. Due to its numerous drug interactions, potential for severe adverse events, and relative paucity of clinical data in long-term randomized, controlled trials, maraviroc should be one of the final agents utilized in salvage therapy in combination with other active antiretroviral agents.
    • "After initial findings that the CC chemokines RANTES, MIP-1a and MIP-1b can inhibit HIV infection in vitro (Cocchi et al., 1995), the essential involvement of CCR5 in HIV infection has been finally confirmed by the observation that individuals homozygous for a 32-basepair deletion in the CCR5 gene (D32/D32), which disrupts membrane expression of CCR5, are very resistant to HIV infection (Liu et al., 1996; Samson et al., 1996). Drugs that target this chemokine receptor for HIV disease are currently available (Caldwell and Evans, 2008; Dolin, 2008; Long et al., 2009). Interesting evidence has been reported that, besides its role in chronic inflammation, immune responses and HIV-1 infection, the CCR5/RANTES system could be involved in human reproductive events both in physiological and pathological conditions. "
    [Show abstract] [Hide abstract] ABSTRACT: Chemokine receptor CCR5, the main HIV-1 coreceptor, is present in the human spermatozoa. This study aimed to investigate (i) whether the percentage of CCR5-positive spermatozoa varies under conditions associated with changes in the membrane architecture, such as capacitation and fixation/permeabilization procedures; (ii) whether there is any relationship between individual variability in sperm CCR5 expression and semen parameters. In cytometric analysis, the percentage of CCR5-positive unfixed spermatozoa varied from approximately 10 to approximately 60%, and it significantly decreased after 5 h capacitation. The percentage of CCR5-positive spermatozoa was increased to more than 90% following fixation and permeabilization, suggesting the existence of large intracellular pools of the receptor. Immunocytochemistry showed positive staining in the anterior region of the sperm head. In ejaculates from male partner of 102 infertile couples, the CCR5 expression rate significantly correlated with sperm count, total sperm number and forward motility, but not with sperm morphology. In stepwise analysis, only forward motility entered into the model; however, this explained only approximately 8% of the variability in CCR5 expression. Interquartile analysis showed significant differences between the first and fourth quartiles of CCR5 expression for all semen parameters, except morphology. The percentage of CCR5-positive spermatozoa may vary under conditions associated with changes in membrane architecture and spermatozoa showed large intracellular pools of CCR5. A lower expression of CCR5 in asthenozoospermia seems to be suggested; however, it would only partially contribute to the inter-individual variability in the CCR5 expression. A genetic basis can be hypothesized to explain the variability.
    Full-text · Article · Oct 2009
    • "RNAi-mediated downregulation of cellular co-factors required for HIV infection is an attractive alternative or complementary approach. One such target that holds particular promise is the macrophagetropic chemokine (C-C motif) receptor 5 (CCR5) [42] that HIV uses as the most important co-receptor during the infection. CCR5 is non-essential for normal immune function. "
    [Show abstract] [Hide abstract] ABSTRACT: RNAi technology has brought a new category of treatments for various diseases including genetic diseases, viral diseases, and cancer. Despite the great versatility of RNAi that can down regulate almost any protein in the cells, the delicate and precise machinery used for silencing is the same. The major challenge indeed for RNAi-based therapy is the delivery system. In this review, we start with the uniqueness and mechanism of RNAi machinery and the utility of RNAi in therapeutics. Then we discuss the challenges in systemic siRNA delivery by dividing them into two categories-kinetic and physical barriers. At the end, we discuss different strategies to overcome these barriers, especially focusing on the step of endosome escape. Toxicity issues and current successful examples for lipid-based delivery are also included in the review.
    Article · Apr 2009
    • "Therefore, these activated cells could be targets for preventing newly-formed M/ MΦ from becoming infected as they enter the circulation. New R5-inihibitor drugs could be identified as targets for future consideration in treatment or preventative strategies [16]. In conclusion, we believe that M/MΦ activation by LPS leads to a phenotype that supports R5- tropic virus. "
    [Show abstract] [Hide abstract] ABSTRACT: BACKGROUND: Microbial translocation has been recognized as an important factor in monocyte activation and contributing to AIDS pathogenesis with elevated plasma lipopolysaccharide (LPS) levels, as a marker for microbial translocation, seen in advanced HIV disease. Therefore, the current study was undertaken to assess monocyte activation in vitro by LPS and to determine its impact on monocyte phenotype. METHODS: Monocytes from non-HIV-infected donors were analyzed for CD14, CD16, CD69, TNFα, and CCR5 by flow cytometry pre- and post-stimulation with LPS. In-vitro cultures were then set up to expose non-activated and activated monocytes to R5-, X4-, and dual (R5/X4)-tropic viruses; and the amount of HIV present on the cells was assayed. RESULTS: Non-HIV-infected monocytes, after LPS stimulation, were confirmed to have an activated phenotype with increase in CD16 and CD69 surface expressions (p<0.05). The activation phenotype was supported by increase in TNFα production, p<0.05. The activated monocytes had increased surface CCR5 (from 21% to 98%; p=0.05); and were found to have more R5-tropic virus than non-activated monocytes (p<0.05). CONCLUSIONS: Following activation by LPS, non-HIV-infected monocytes were found to have increase in surface CCR5. These activated monocytes, when exposed to R5-tropic virus, were found to have more virus compared to non-activated monocytes. The significance of the findings could lie in explaining how microbial translocation plays a role in HIV progression; and possibly promoting CCR5-directed strategies in treating HIV.
    Full-text · Article · Jan 2009
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