Biology subjects

Majdoul, S.

Publications and source records attributed to Majdoul, S..

3 recordsLinked to original sources

bioRxiv2025

Restriction of HIV-1 infectivity by interferon and IFITM3 is counteracted by Nef

The viral accessory protein Nef is a major determinant of HIV-1 pathogenicity in vivo. Nef is a multifunctional, immunomodulatory protein that downmodulates cell surface proteins, including CD4 and MHC class I (MHC-I) important for T-cell-mediated immunity. In addition, Nef also regulates cell-intrinsic immunity--Nef boosts the infectivity of virions produced and released from HIV-infected cells, at least in part, by counteracting the antiviral activity of transmembrane proteins SERINC3 and SERINC5. However, it has been reported that the enhancement of HIV-1 infectivity by Nef persists in certain cell lines deficient for SERINC3/5, revealing the existence of other Nef-sensitive host factors that impact HIV-1 infectivity. Here, we show that Nef proteins, especially those derived from many primary isolates of HIV-1, restore infectivity in interferon-treated cells and confer resistance to interferon-induced transmembrane protein 3 (IFITM3). IFITM3 is a restriction factor that reduces retroviral infectivity by incorporating into virions, inhibiting Envelope glycoprotein function, and reducing entry into cells. Using a primary isolate of Nef derived from HIV-1 clade C, we found that Nef interacts with IFITM3 in membranes and uses the endocytic adaptor protein AP-2 to counteract it. Furthermore, Nef reduced IFITM3 cell surface levels, increased IFITM3 levels in early endosomes, and reduced IFITM3 incorporation into HIV-1 virions. Nef also impaired IFITM3 oligomerization and restored membrane fluidity in IFITM3-expressing cells. The antiviral activity of IFITM3 and its inhibition by Nef were unaffected by SERINC5 knockdown, suggesting that the counteraction of IFITM3 represents a unique function of Nef. Our findings reveal a previously unrecognized immunomodulatory role for Nef in the setting of the interferon-induced antiviral state during HIV-1 infection.

microbiology↗

bioRxiv2021

Rapalogs downmodulate intrinsic immunity and promote cell entry of SARS-CoV-2

SARS-CoV-2 infection in immunocompromised individuals is associated with prolonged virus shedding and evolution of viral variants. Rapamycin and its analogs (rapalogs, including everolimus, temsirolimus, and ridaforolimus) are FDA-approved as mTOR inhibitors for the treatment of human diseases, including cancer and autoimmunity. Rapalog use is commonly associated with increased susceptibility to infection, which has been traditionally explained by impaired adaptive immunity. Here, we show that exposure to rapalogs increases susceptibility to SARS-CoV-2 infection in tissue culture and in immunologically naive rodents by antagonizing the cell-intrinsic immune response. By identifying one rapalog (ridaforolimus) that is less potent in this regard, we demonstrate that rapalogs promote Spike-mediated entry into cells by triggering the degradation of antiviral proteins IFITM2 and IFITM3 via an endolysosomal remodeling program called microautophagy. Rapalogs that increase virus entry inhibit the mTOR-mediated phosphorylation of the transcription factor TFEB, which facilitates its nuclear translocation and triggers microautophagy. In rodent models of infection, injection of rapamycin prior to and after virus exposure resulted in elevated SARS-CoV-2 replication and exacerbated viral disease, while ridaforolimus had milder effects. Overall, our findings indicate that preexisting use of certain rapalogs may elevate host susceptibility to SARS-CoV-2 infection and disease by activating lysosome-mediated suppression of intrinsic immunity. SignificanceRapamycin is an immunosuppressant used in humans to treat cancer, autoimmunity, and other disease states. Here, we show that rapamycin and related compounds promote the first step of the SARS-CoV-2 infection cycle--entry into cells--by disarming cell-intrinsic immune defenses. We outline the molecular basis for this effect by identifying a rapamycin derivative that is inactive, laying the foundation for improved mTOR inhibitors that do not suppress intrinsic immunity. We find that rapamycin analogs that promote SARS-CoV-2 entry are those that activate TFEB, a transcription factor that triggers the degradation of antiviral membrane proteins inside of cells. Finally, rapamycin administration to rodents prior to SARS-CoV-2 challenge results in enhanced viral disease, revealing that its use in humans may increase susceptibility to infection.

microbiology↗

bioRxiv2020

Homology-guided identification of a conserved motif linking the antiviral functions of IFITM3 to its oligomeric state

The interferon-inducible transmembrane (IFITM) proteins belong to the Dispanin/CD225 family and inhibit diverse virus infections. IFITM3 reduces membrane fusion between cells and virions through a poorly characterized mechanism. We identified a GxxxG motif in many CD225 proteins, including IFITM3 and proline rich transmembrane protein 2 (PRRT2). Mutation of PRRT2, a regulator of neurotransmitter release, at glycine-305 was previously linked to paroxysmal neurological disorders in humans. Here, we show that glycine-305 and the homologous site in IFITM3, glycine-95, drive protein oligomerization from within a GxxxG motif. Mutation of glycine-95 in IFITM3 disrupted its oligomerization and reduced its antiviral activity against Influenza A and HIV-1. The oligomerization-defective variant was used to reveal that IFITM3 promotes membrane rigidity in a glycine-95-dependent manner. Furthermore, a compound which counteracts virus inhibition by IFITM3, amphotericin B, prevented the IFITM3-mediated rigidification of membranes. Overall, these data suggest that IFITM3 oligomers inhibit virus-cell fusion by promoting membrane rigidity.

evolutionary biology↗