Jostling latent HIV from slumber
1 April 2011. Related: Basic science and immunology.
Richard Jefferys, TAG
A study in the new issue of the Journal of Immunology suggests that triggering a cell surface molecule called toll-like receptor 8 (TLR8) may be a means to activating latent HIV infection. [1]
Erika Schlaepfer and Roberto Speck report that, in vitro, targeting TLR8 with the drug resiquimod (aka R-848) prompted HIV activity in latently infected cells of myeloid-monocytic origin (which include monocytes, macrophages, dendritic cells, microglial cells, and hematopoietic stem cells) and also had an activating effect on HIV in latently infected CD4 T cells, by causing production of the cytokine TNF-alpha. The researchers took a very preliminary look at whether individuals on HAART might be able to respond to such an approach, and found that–solely based on TNF-alpha production–their monocytes reacted to TLR8 stimulation comparably to those from HIV negative controls.
The conclusion from the findings is that TLR8 agonists, in combination with HAART, are intriguing compounds for purging HIV from its latent reservoirs and sanctuary sites. Schlaepfer and Speck caution, however, that we believe that compounds, and, in particular, TLR8 agonists, acting on the latent reservoir should be given in cycles, because a longer-term administration of any such compound might be too toxic.
Resiquimod has been studied in humans with hepatitis C infection and appeared quite potent in terms of inducing alpha interferon production (and associated side effects). [2]
The manufacturer, 3M, does not appear to be developing it further but has recently offered it to the pharmaceutical industry for license. [3]
Development of a TLR7 agonist as a hepatitis C treatment was stopped in 2007 due to toxicology studies showing intense immune stimulation in animals.
Source: TAG Basic Science Blog (23 Mar 2011).
http://tagbasicscienceproject.typepad.com
References:
- Schlaepfer E, Speck RF. TLR8 activates HIV from latently infected cells of myeloid-monocytic origin directly via the MAPK pathway and from latently infected CD4+ T cells indirectly via TNF-alpha. Journal of Immunology, April 1, 2011, vol. 186 no. 7 4314-4324.
http://www.jimmunol.org/content/186/7/4314.abstract - Pockros PJ et al. Oral resiquimod in chronic HCV infection: safety and efficacy in 2 placebo-controlled, double-blind phase IIa studies. J Hepatol. 2007 Aug;47(2):174-82. Epub 2007 May 4.
http://www.ncbi.nlm.nih.gov/pubmed/17532523 - 3M press release. Immune response modifiers from 3M available for the pharmaceutical industry. (2 Dec 2010).
http://solutions.3m.com/wps/portal/3M/en_WW/DrugDeliverySystems/DDSD/technology-solutions/tlr-agonists/?PC_7_RJH9U523080CC0IA3DRQB50OJ0_assetId=1273663090851 - Development discontinued for ANA975, an early stage compound for treatment of hepatitis C virus infection. (July 2007)
http://www.drugs.com/news/development-discontinued-ana975-early-stage-compound-hepatitis-c-virus-infection-6604.html