Host cell peptidylprolyl cis-trans isomerases as immune modulators of HIV-1 infection

• Applicant: Professor Dr. Hans-Georg Kräusslich, since 1/2018
• Subject Area: Virology ; Immunology ; Parasitology and Biology of Tropical Infectious Disease Pathogens
• Term: from 2016 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 318243699

Human immunodeficiency virus 1 (HIV-1) is the primary cause of the acquired immunodeficiency syndrome (AIDS). Worldwide, ~37 million people are infected (UNAIDS, 2014), most of them in developing countries. A vaccine is not available and current treatments and diagnostics are expensive and require appropriate medical infrastructure, demanding the search for novel treatment strategies.Acute HIV-1 infection is characterized by a reduction of CD4+ T cells accompanied by the production of large amounts of pro-inflammatory cytokines, including type I interferons (IFNs). Type I IFNs induce a potent post-entry block to HIV-1 infection at the stage of reverse transcription (RT), which contributes to limiting viral spread at the end of the acute phase. The host cell factors mediating this early block as well as the underlying molecular mechanisms are unknown. Detailed analyses of the IFN-induced cell-autonomous HIV-1 restrictions and how HIV-1 can overcome these during the course of infection may reveal targets for novel therapeutic strategies. The importance of this proposal is highlighted by the fact that phase II clinical trials with IFNalpha are currently ongoing, linking this proposal directly to a possible clinical application. Host cell peptidylprolyl cis-trans isomerases (PPIs) include the cyclophilins (Cyps), the FK-506 binding proteins (FKBPs) as well as the parvulin-like PPIs, and members of all families have been proposed to contribute to the earliest post-entry steps of HIV-1. Pharmacological inhibition of Cyps using the immunosuppressive drug cyclosporine (Cs) or non-immunosuppressive analogue SDZ-NIM-811 activates innate sensing of incoming HIV-1 by cytoplasmic nucleic acid sensors, suggesting that Cyp binding to incoming viral cores protects the virus. Using CRISPR/Cas9 knock-out technology as well as defined HIV-1 capsid (CA) mutants we have shown that CypA not only protects HIV-1 from innate sensing but also shields incoming HIV-1 capsids from type I IFN-induced genes (ISGs), thereby providing dual protection. HIV-1 CA mutant P90A, which is resistant to CypA-mediated isomerization displays an increased sensitivity to type I IFN-induced blocks in primary macrophages and CD4+ T cells. CRISPR/Cas9-mediated CypA gene disruption renders wild type HIV-1 more sensitive to type I IFN. Surprisingly, both wild type HIV-1 as well as CA P90A infectivity could be rescued from type I IFN-induced blocks by Cs, as well as SDZ-NIM-811, suggesting that other Cyps may be involved in a more complex way than currently is appreciated. We have identified potential candidates for follow-up.Using state of the art technology and in connection with other SPP proposals, we will investigate the contribution of PPIs, in particular members of the Cyp family, to HIV-1 early infection steps, to the protection of incoming HIV-1 from innate sensing mechanisms as well as from ISGs which could advance the development of novel treatment strategies.

• DFG Programme: Priority Programmes
• Subproject of: SPP 1923: Innate Sensing and Restriction of Retroviruses
• Ehemaliger Antragsteller: Dr. Torsten Schaller, until 1/2018