Biology subjects

Malim, M. M.

Publications and source records attributed to Malim, M. M..

5 recordsLinked to original sources

bioRxiv2026

MX2 Mediates Collapse of the HIV-1 Capsid

The HIV-1 capsid core encapsulates the viral genome and mediates its delivery into the host cells nucleus. It is composed of multiple copies of the Capsid (CA, p24Gag) protein, assembled into hexamers and pentamers to create a lattice that forms a fullerene-like cone. Myxovirus resistance 2 (MX2) is an HIV-1 restriction factor that binds to the capsid core and blocks nuclear import of the viral genome. Here, we define a minimal region of MX2 required for HIV-1 restriction and produce a corresponding functional recombinant protein. We have used cryo-electron microscopy to determine the structure of this MX2 fragment bound to the tri-hexamer interface of the capsid lattice, revealing a large, buried interface combining electrostatic and hydrophobic interactions. This structure, together with assays that measure capsid core destabilisation, shows that MX2 binding induces conformational rearrangements in the capsid lattice that culminate in a loss of integrity. These results support a model whereby MX2 exerts its antiviral activity by disrupting the capsid lattice, inducing premature fragmentation and preventing HIV-1 nuclear import. By revealing the structural basis for MX2-mediated restriction, this work also provides the framework for the development of anti-HIV molecules that mimic MX2 restriction.

microbiology↗

bioRxiv2025

Oncolytic Reovirus mediates innate-driven SARS-CoV-2 elimination in the absence of cell toxicity

Interplay between type I interferon (IFN) driven innate responses and viral antagonism strongly influences SARS-CoV-2 transmission and the COVID-19 disease course. Hence, variant adaptation includes diminished induction of IFN stimulated genes (ISG) and/or evasion of their effector functions. Exogenous IFN treatment "rewires" innate responses to drive virus elimination, yet therapeutic trials to date have been unremarkable. Resolving this paradox could translate to variant-agnostic innate immunotherapy. By contrast, oncolytic viruses (OV) exhibit profoundly attenuated innate antagonism, resulting in potent IFN responses despite the inherently immunosuppressive nature of tumour microenvironments. Moreover, OV only undergo lytic replication within innate-deficient malignant cells, and not in cells where sufficient innate responses exist. This, combined with previous studies showing that OV suppressed replication of underlying oncogenic viruses in tumours, we explored whether clinical grade oncolytic Orthoreovirus (Reo) superinfection could eliminate SARS-CoV-2 from immune-competent lung epithelial cell lines in the absence of toxicity. Reo exerted profound activation of innate responses, including when SARS-CoV-2 infection was already established, rewiring cells towards an antiviral state emulating that of Reo infection alone. Both intracellular and paracrine mechanisms induced ISG repertoires including multiple known anti-SARS-CoV-2 effectors, as well as others that remain unvalidated. Amongst these, we demonstrate the first direct evidence that MX2 and XAF1 restrict SARS-CoV-2 replication. Thus, with an excellent safety record, self-amplification, and respiratory tract tropism, we propose that Reo superinfection may provide a tractable alternative to recombinant cytokines for innate antiviral immunotherapy.

immunology↗

bioRxiv2025

Alpha-BET: Functional labeling of envelope glycoproteins with single domain antibodies for in-virus single molecule imaging

We present Alpha-BET, a structure-guided strategy leveraging AlphaFold to identify optimal ALFA-tag insertion sites for minimally disruptive labeling of viral glycoproteins with high-affinity nanobodies. Applied to HIV-1 Env, SARS-CoV-2 S, and NiV G, Alpha-BET preserves structural integrity and function. For HIV-1 Env, we demonstrate super-resolution DNA-PAINT MINFLUX 3D imaging enabled by tag insertion, showcasing its power for visualizing native trimers in single virions and potential for broader applications in virus research.

biophysics↗

bioRxiv2023

The complement pattern recognition molecule CL-11 promotes invasion and injury of respiratory epithelial cells by SARS-CoV-2.

Collectin-11 is a soluble C-type lectin produced at epithelial surfaces to initiate pathogen elimination by complement. Given the respiratory epithelium is a source of CL-11 and downstream complement-pathway components, we investigated the potential of CL-11 to impact the pathogenicity of SARS-CoV-2. While the SARS-CoV-2 spike trimer could bind CL-11 and trigger complement activation followed by MAC formation, the virus was resistant to lysis. Surprisingly, virus production by infected respiratory epithelial cells was enhanced by CL-11 opsonisation of virus but this effect was fully inhibited by sugar-blockade of CL-11. Moreover, SARS-CoV-2 spike protein expressed at the bronchial epithelial cell surface was associated with increased CL-11 binding and MAC formation. We propose that SARS-CoV-2 pathogenicity is exacerbated both by resistance to complement and CL-11 driven respiratory cell invasion and injury at the portal of entry. Contrary to expectation, CL-11 blockade could offer a novel approach to limit the pathogenicity of SARS-CoV-2.

immunology↗

bioRxiv2021

The lysine-rich intracellular loop and cell type-specific co-factors are required for IFITM3 antiviral immunity in hematopoietic stem cells

The interferon-induced transmembrane protein 3 (IFITM3) inhibits lentiviral gene therapy vector entry into hematopoietic stem cells and can be overcome by Cyclosporine H (CsH), but underlying mechanisms remain unclear. Here, we show that mutating the evolutionarily conserved lysines of the IFITM3 intracellular loop abolishes its antiviral activity without affecting either its localization or its degradation by CsH through non-canonical lysosomal pathways. When confined to the plasma membrane, the lysine-competent IFITM3 lost restriction against VSV-G pseudotyped viral vectors but gained antiviral activity against vectors that fuse directly at the plasma membrane. Interestingly, altering the lysines did not alter IFITM3 homodimerization but impacted higher-order protein complex formation, suggesting loss of interaction with cellular co-factors. In agreement, IFITM3 expression was not sufficient to restrict viral vectors in myeloid K562 cells as opposed to promonocytic THP1 or primary HSC. We exclude the involvement of previously identified factors affecting IFITM3 biology and propose a novel model for IFITM3 restriction that depends on the presence of cellular co-factor(s) that may interact with IFITM3 through the intracellular loop lysine residues. Overall, our work provides significant insight into the mechanisms of action of IFITM3 and CsH that can be exploited for improved gene therapies and broadly acting antiviral strategies.

microbiology↗