The efficiency of Vpx-mediated SAMHD1 antagonism does not correlate with the potency of viral control in HIV-2-infected
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RESEARCH
Open Access
The efficiency of Vpx-mediated SAMHD1 antagonism does not correlate with the potency of viral control in HIV-2-infected individuals Hangxing Yu1, Shariq M Usmani1, Alexandra Borch1, Julia Krämer1, Christina M Stürzel1, Mohammad Khalid1, Xuehua Li1, Daniela Krnavek1, Marchina E van der Ende2, Albert D Osterhaus3, Rob A Gruters3 and Frank Kirchhoff1*
Background: The presence of a vpx gene distinguishes HIV-2 from HIV-1, the main causative agent of AIDS. Vpx degrades the restriction factor SAMHD1 to boost HIV-2 infection of macrophages and dendritic cells and it has been suggested that the activation of antiviral innate immune responses after Vpx-dependent infection of myeloid cells may explain why most HIV-2-infected individuals efficiently control viral replication and become long-term survivors. However, the role of Vpx-mediated SAMHD1 antagonism in the virological and clinical outcome of HIV-2 infection remained to be investigated. Results: Here, we analyzed the anti-SAMHD1 activity of vpx alleles derived from seven viremic and four long-term aviremic HIV-2-infected individuals. We found that effective Vpx-mediated SAMHD1 degradation and enhancement of myeloid cell infection was preserved in most HIV-2-infected individuals including all seven that failed to control the virus and developed AIDS. The only exception were vpx alleles from an aviremic individual that predicted a M68K change in a highly conserved nuclear localization signal which disrupted the ability of Vpx to counteract SAMHD1. We also found that HIV-2 is less effective than HIV-1 in inducing innate immune activation in dendritic cells. Conclusions: Effective immune control of viral replication in HIV-2-infected individuals is not associated with increased Vpx-mediated degradation of SAMHD1. Keywords: AIDS, HIV-2, Vpx, SAMHD1, Viral immune sensing
Background SAM domain and HD domain-containing protein 1 (SAMHD1), the product of a gene linked to a rare and severe inherited autoimmune disease named Aicardi-Goutières syndrome [1], has recently been identified as the cellular factor that prevents HIV-1 infection in dendritic cells and macrophages [2-4]. SAMHD1 is a dGTP-stimulated triphosphohydrolase that converts deoxynucleoside triphosphates (dNTPs) to deoxynucleoside and inorganic triphosphate [5,6]. Thus, in contrast to other antiretroviral host restriction factors, such as TRIM-5alpha, ABOPEC3G proteins, and tetherin [7-9], SAMHD1 does not directly target viral components to suppress viral replication but seems to restrict * Correspondence: [email protected] 1 Institute of Molecular Virology, Ulm University Medical Center, Ulm 89081, Germany Full list of author information is available at the end of the article
HIV-1 infection of non-dividing cells by decreasing the dNTP pool concentration below the threshold required for effective reverse transcription [10,11]. A variety of primate lentiviruses has evolved effective antagonists of SAMHD1. The SIVsmm/HIV-2 lineage and SIVs infecting drills and mandrills use their Vp
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