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AIDS Research


Case Western Reserve University Center for Aids Research Scientists Identify a New HIV-1 Restriction Mechanism

Unlike HIV-type 1, HIV-type 2 and monkey Simian Immunodeficiency Virus (SIVsm/mac) can infect cells of the myeloid lineage owing to their accessory protein Vpx. Mutation or deletion of Vpx renders HIV-2 and SIVsm/mac unable to infect monocyte derived macrophages. The observation that Vpx associates with a subunit of E3 ubiquitin ligase strengthened the hypothesis that Vpx eliminated the HIV cellular restriction factor in a proteasome degradation-dependent manner. This unknown factor has been long sought by the scientific community to no avail. Well, not anymore. A team of scientists at the Center for AIDS Research (CFAR) at Case Western Reserve University led by Jacek Skowronski have identified this cellular protein factor as SAM domain HD domain-containing protein-1 (SAMHD1).

As described in a recent article published in Nature, titled "Vpx relieves inhibition of HIV-1 infection of macrophages mediated by the SAMHD1 protein", Skowronski’s group performed a search for cellular protein factors marked for degradation when Vpx was present in the cell. Of the 150 potential candidate proteins found, SAMHD1 was the most abundant and made the most biological sense. The article was authored by Kasia Hrecka, a CFAR fellow and researcher at the Department of Molecular Biology and Microbiology and Jacek Skowronski as first and lead author respectively. Other authors on the article are Caili Hao1, Malgorzata Kesik-Brodacka, and collaborating scientists Magda Gierszewska , Smita Srivastava, Selene K. Swanson, Laurence Florens and Michael P. Washburn. The full article can be accessed at this link.

SAMHD1 is a component of the body's innate defense mechanism that works with other factors to get rid of nucleic acid debris in cells. Mutations in SAMHD1 had previously been implicated in an autoimmune disrase called Aicardi-Goutières syndrome. The findings help to broaden our understanding of how the immune system responds to HIV infection. "The identification of SAMHD and its function may result in new therapeutic approaches designed to inhibit HIV infection or replication in infected individuals" Dr. Skowronski predicts. "Strategies in manipulation of SAMHD1 function might result in more robust immune responses against this virus" he adds. According to Dr. Hrecka, the implication of SAMHD1 in HIV-1 restriction will help to attract more attention to this molecule and subsequently result in solutions that benefit both HIV and Aicardi-Goutières syndrome patients.

However even the authors still agree that there are more unanswered questions that they or others will have to answer in the future. How does SAMHD1 ensure myeloid cell specificity in HIV restriction given that there are other non-myeloid cell types that express SAMHD1 but have no lentiviral restriction effect? It might be that SAMHD1 is required, but not sufficient to achieve lentiviral restriction in myeloid cells and that there are additional cellular factors required for SAMHD1 activity. What are the implications of HIV-1 susceptibility to SAMHD1 restriction for the virus? Did HIV-1 evolve to avoid infection of myeloid cells such as dendritic cells and macrophages in order to evade the immune response? Is HIV-2 therefore at a selective disadvantage by infecting these cells linking the innate and adaptive arms of the immune response? In this case, does SAMHD1 restriction partly explain the difference in virulence and progression to AIDS that exist between HIV-1 and HIV-2?

Looking in the future, Skowronski's going to try and understand the molecular pathway for SAMHD1 restriction of HIV-1 and the contribution of this pathway to development of full blown AIDS in different HIV-1 infected individuals.