Biology subjects

Vanzo, T.

Publications and source records attributed to Vanzo, T..

3 recordsLinked to original sources

bioRxiv2026

HTLV-1 intasome recruits the PP2A-B56 holoenzyme and restricts its phosphatase activity

Integrase catalyses the insertion of a DNA copy of the retroviral genome into host cell chromatin. Human T-cell lymphotropic virus type 1 (HTLV-1) and other deltaretroviral integrases associate with protein phosphatase 2A holoenzymes containing B56 regulatory subunits (PP2A-B56). Here, we show that integrase mutants defective in binding to most B56 isoforms retain intrinsic DNA strand transfer activity but are impaired in establishing infection. Using single-particle cryo-EM, we determined the structure of the simian T-cell lymphotropic virus type 1 (STLV-1) intasome in a 0.5-MDa complex with two copies of the heterotrimeric PP2A-B56{gamma} holoenzyme at 2.8 [A] resolution. The structure reveals that, in addition to engaging B56, integrase forms direct contacts with the catalytic subunit of PP2A and sterically occludes the phosphatase active site, preventing substrate access. Consistent with these findings, we show that the HTLV-1 intasome suppresses PP2A catalytic activity in a manner dependent on the integrase LxxIxE short linear motif. We further demonstrate that pharmacological inhibition of PP2A does not impair HTLV-1 infection. Together, our results indicate that recruitment of PP2A-B56 by the intasome serves a structural rather than catalytic function.

microbiology↗

bioRxiv2025

SERINC5 Is the Primary Target of Retroviral Antagonists Among Human SERINC Paralogs and Requires a Tri-Cysteine Motif for Its Counteraction by HIV-1 Nef

The human transmembrane protein SERINC5 incorporates into budding HIV-1 particles and inhibits their fusion with new target cells. Among the five members of the SERINC family, SERINC3 and SERINC1 exhibit modest antiviral activity, whereas SERINC2 lacks this function. HIV-1 counteracts SERINC5 by promoting its endocytosis in a Nef- dependent manner. SERINC5 is also downregulated by glycoGag of Moloney murine leukaemia virus (MoMLV) and by the S2 glycoprotein of equine infectious anaemia virus (EIAV). Here, we demonstrate that all human SERINCs, despite their differing antiviral potencies, are incorporated into HIV-1 virions. SERINC5 is the most sensitive to viral antagonists, whereas its paralogs display moderate (SERINC2, SERINC3) or no (SERINC1) susceptibility, suggesting that SERINC5 has exerted stronger selective pressure on retroviral evolution. To identify the determinants of SERINC5 sensitivity to Nef, we performed structure- guided mutagenesis and identified a critical tri-cysteine motif (Cys355, Cys356, Cys358) within intracellular loop 4 (ICL4) required for Nef-mediated downregulation. Substitution of these residues with glutamines conferred resistance to Nef antagonism. While this motif is essential for SERINC5 internalization by diverse HIV-1 and SIV Nef alleles, it is dispensable for downregulation by MoMLV glycoGag and EIAV S2, indicating that these viral antagonists exploit distinct structural features of SERINC5. Finally, we show that SERINC5 is palmitoylated at the tri-cysteine motif, raising the possibility that this modification modulates its sensitivity to Nef. Together, these results confirm the central role of SERINC5 as a target of retroviral counteraction and highlight the crucial importance of ICL4 in mediating its engagement by Nef. ImportanceThe SERINC family of multipass transmembrane proteins includes host factors capable of restricting retrovirus infectivity. Among the five human paralogs, SERINC5 displays the strongest antiviral activity and is the only member efficiently targeted by all known retroviral antagonists, including HIV-1 Nef, MLV glycoGag, and the EIAV S2. This selectivity indicates that the evolutionary pressure exerted by SERINC proteins on retroviruses has been primarily driven by SERINC5 rather than by its relatives. Through structure-guided mutagenesis, we identified a tri-cysteine motif within intracellular loop 4 as a crucial determinant for SERINC5 downregulation by Nef, providing a molecular explanation for its distinctive susceptibility. These findings establish SERINC5 as the principal target of viral counteraction and suggest that its molecular features have contributed to shaping the adaptation of primate lentiviral Nef proteins to the host.

microbiology↗

bioRxiv2021

Immunogenicity and pre-clinical efficacy of an OMV-based SARS-CoV-2 vaccine

The vaccination campaign against SARS-CoV-2 relies on the world-wide availability of effective vaccines, with a potential need of 20 billion vaccine doses to fully vaccinate the world population. To reach this goal, the manufacturing and logistic processes should be affordable to all countries, irrespectively of economical and climatic conditions. Outer membrane vesicles (OMVs) are bacterial-derived vesicles that can be engineered to incorporate heterologous antigens. Given the inherent adjuvanticity, such modified OMVs can be used as vaccine to induce potent immune responses against the associated protein. Here we show that OMVs engineered to incorporate peptides derived from the receptor binding motif (RBM) of the spike protein from SARS-CoV-2 elicit an effective immune response in immunized mice, resulting in the production of neutralizing antibodies. The immunity induced by the vaccine is sufficient to protect K18-hACE2 transgenic mice from intranasal challenge with SARS-CoV-2, preventing both virus replication in the lungs and the pathology associated with virus infection. Furthermore, we show that OMVs can be effectively decorated with RBM peptides derived from a different genetic variant of SARS-CoV-2, inducing a similarly potent neutralization activity in vaccinated mice. Altogether, given the convenience associated with ease of engineering, production and distribution, our results demonstrate that OMV-based SARS-CoV-2 vaccines can be a crucial addition to the vaccines currently available.

immunology↗