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Cell Studies Point to Antiinflammatory Activity of Maraviroc
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17th Conference on Retroviruses and Opportunistic Infections, February 16-19, 2010, San Francisco
Mark Mascolini
Data from clinical trials presented at the Conference on Retroviruses suggested that the CCR5 antagonists maraviroc [1] and vicriviroc [2] hold no special advantage over other antiretrovirals in pumping up CD4 counts--results deflating expectation based on earlier research, although previous studies have reported higher CD4 increases associated with maraviroc. Poor results in two phase 3 vicriviroc trials [2] led Merck to suspend development of that drug for antiretroviral-experienced people, (from Jules: as they were unable to find in the overall study a benefit with vicriviroc in patients receiving 3 or more active ARTs in the background regimen but for patients with 2 active drugs or less vicriviroc does provide benefit and this is an issue in trying to design studies for new drugs in highly treatment-experienced patients).
But researchers continue to probe for potential immunologic advantages with the already-licensed maraviroc. Scientists at Sapienza University in Rome reported evidence hinting that maraviroc may have inflammation-quelling qualities apart from its antiviral effects in key immune cells--neutrophils (white blood cells), macrophages, and dendritic cells [3].
The investigators cultured cells in the presence of maraviroc and tested the drug's impact on apoptosis (cell killing) and chemotaxis (cell movement in response to pathogens). The online poster, linked below [3], details experimental conditions.
Maraviroc did not affect apoptosis in peripheral blood mononuclear cells (PBMCs) or polymorphonuclear leukocytes (PMNLs). But the CCR5 antagonist significantly reduced chemotactic activity in PBMCs, PMNLs, mature macrophages, and dendritic cells. At a concentration of 0.1 mM, maraviroc limited chemotaxis of mature macrophages and dendritic cells, but not immature dendritic cells. Only higher maraviroc concentrations (1 or 10 microM) stifled chemotaxis of immature macrophages and dendritic cells.
The Sapienza researchers believe their data suggest that "maraviroc has a direct effect on innate immune cells by [a] mechanism which could be independent of anti-HIV activity." Stalling trafficking of mature dendritic cells and macrophages could curb inflammation in peripheral tissues. As a result, the investigators postulate, maraviroc "might have a potential role in the downregulation of HIV-associated chronic inflammation."
The precise impact of ongoing inflammation in antiretroviral-treated people remains the subject of intense research scrutiny, as a flood of data at this Conference on Retroviruses demonstrates. Whether further damping that inflammation with maraviroc or other agents begets clinical benefits remains to be seen.
References
1. Wilkin T, Lalama C, Tenorio A, et al. Maraviroc intensification for suboptimal CD4+ cell response despite sustained virologic suppression: ACTG 5256. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 285. http://www.retroconference.org/2010/PDFs/285.pdf.
2. Gathe J, Diaz R, Fatkenheuer G, et al. Phase 3 Trials of vicriviroc in treatment-experienced subjects demonstrate safety but not significantly superior efficacy over potent background regimens alone. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 54LB. http://www.natap.org/2010/CROI/croi_12.htm.
3. Sauzullo I, Lichtner M, Mengoni F, et al. Effect in vitro of CCR5 antagonists on innate immune system: maraviroc inhibits the migration of neutrophils, macrophages, and DC. 17th Conference on Retroviruses and Opportunistic Infections. February 16-19, 2010. San Francisco. Abstract 512. http://www.retroconference.org/2010/PDFs/512.pdf.
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