CROI Presentation

Greg presented at the 2014 Conference on Retroviruses and Opportunistic Infections at Croi. His talk entitled  'HIV-1 Evades Innate Immune Recognition Through Specific Co-Factor Recruitment' is available as a podcast.

Nature Publication
Modification of Cyclosporine A at 3' SAR position. From Rasaiyaah et al, Nature, 2013

Rasaiyaah, J., C. P. Tan, A. J. Fletcher, A. J. Price, C. Blondeau, L. Hilditch, D. A. Jacques, D. L. Selwood, L. C. James, M. Noursadeghi and G. J. Towers. 2013. HIV-1 evades innate immune recognition through specific co-factor recruitment. Nature (2013) doi:10.1038/nature12769

Our study, published in Nature, is entitled “HIV-1 evades innate immune recognition through specific co-factor recruitment”. Click for Nature's News and Views "Slipping under the radar" by Steve Goff and click here for a lay summary.

HIV-1 can replicate in primary human macrophages, key sentinel cells of the immune system, that are equipped to detect pathogens and mediate innate immune responses. The virus replicates efficiently, despite turning viral RNA into DNA, an activity that should trigger alarm systems called innate pattern recognition receptors (PRRs). We have identified two host molecules that act to cloak HIV preventing PRR triggering. We show how preventing interaction between HIV capsid and the cofactors CPSF6, or cyclophilin, reveals HIV, leading to triggering of DNA sensing PRR. Infected cells produce interferon and viral replication is completely suppressed. We conclude that HIV has evolved to utilize these proteins to control DNA synthesis and cloak its replication. We also show that we can pharmacologically induce HIV to trigger DNA sensing using a non-immunosuppressive cyclosporine analogue to inhibit cyclophilin recruitment. Thus we demonstrate a new paradigm for the treatment of viral infection in which the virus is uncloaked, revealing it to the innate immune system. Because the drug inhibits the cyclophilin, and not the virus, escape by virus mutation is difficult. Further, the antiviral activity comes from the highly evolved and natural innate immune system making it a particularly potent antiviral treatment.

HIV-1 encoding plasmids from this study are available online from e-lucid.

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