The role of type I interferon and nuclear membrane proteins in early HIV-1 infection steps

• Applicant: Professor Dr. Hans-Georg Kräusslich, since 1/2018
• Subject Area: Virology ; Immunology ; Cell Biology
• Term: from 2015 to 2019
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 274526689

The early steps during HIV infection, from the release of the viral capsid into the cytoplasm up to the establishment of a provirus through integration into the host genome, represent a vulnerable phase, critical for viral spread. This is underlined by the observation that type I interferon (IFN) treatment of macrophages as well as CD4+ T cells, both natural targets for HIV-1, causes a potent block at multiple post-entry stages, including reverse transcription and nuclear import, likely through the activation of resistance factors. The viral capsid protein (CA) is critical for multiple aspects in these early steps, including trafficking to the nucleus, uncoating and nuclear import, processes likely to be directly linked to progression of reverse transcription, as well as protection from innate immune sensors and IFN-stimulated antiviral effector proteins. The IFN-induced antiviral state in myeloid cells can be overcome through provision of the HIV-2/SIV accessory protein Vpx during infection but the molecular details underlying this rescue remain elusive. In this proposal we address two important questions. Firstly, we will investigate the Vpx-mediated rescue of HIV-1 infection from the IFN-induced block in macrophages and determine the underlying molecular mechanisms. Secondly, we have identified two nuclear envelope-associated proteins, SUN1 and SUN2, which efficiently block nuclear import of certain lab adapted HIV strains, whereas natural HIV-1 strains, in particular some transmitted founder viruses, display a CA-dependent resistance. Crucially, SUN2 protein levels are low in cells permissive for HIV-1 infection but high in resting CD4+ T cells, a target cell that is refractory to HIV-1 infection at multiple post-entry stages. We will investigate the role of SUN1/2 in the early stages of HIV-1 infection and the post-entry block in resting CD4+ T cells. Together the proposed research will advance our understanding of the initial steps during the HIV-1 infection cycle and the interplay with the host innate/ intrinsic immune system. It will shed light on how HIV-1 is able to overcome the IFN-induced early block, and will identify the role of HIV CA in this process. Given the suggested potential for therapeutic intervention in the post-entry phase, it is critical to understand how HIV interacts with the host during these early steps.

• DFG Programme: Research Grants
• Ehemaliger Antragsteller: Dr. Torsten Schaller, until 1/2018