Biology subjects

Renner, N.

Publications and source records attributed to Renner, N..

4 recordsLinked to original sources

bioRxiv2025

Mechanistic Insights into Lenacapavir-Induced Off-Pathway HIV-1 Capsid Assembly

The HIV-1 capsid is a fullerene-like shell composed of hexamer and pentamer arrangements of the capsid (CA) proteins. The cone shape of the capsid is particularly important for packaging the viral genome and coordinating nuclear entry. Lenacapavir (LEN), a potent long-acting inhibitor, has been shown to disrupt capsid morphogenesis by binding at the FG-binding pocket located between neighboring CA subunits. Interestingly, inositol hexakisphosphate (IP6), a cellular polyanion, binds within the central pore of capsid pentamers and some hexamers while playing a key role in regulating the hexamer/pentamer switch. As LEN and IP6 interact with overlapping structural elements, they can compete to influence the capsid assembly pathway and outcomes. Using coarse-grained molecular simulations, we examined capsid assembly across varying IP6 and LEN conditions. Our results reveal a concentration-dependent shift in assembly outcomes: LEN accelerates hexamer assembly and reduces pentamer incorporation, leading to malformed, multilayered, or incomplete capsids. Simulations including a model for the viral ribonucleoprotein (RNP) complex further show that LEN-treated capsids frequently fail to encapsidate the RNA genome, indicating impaired maturation. Our calculations confirm that LEN impairs the formation of high-curvature CA lattice regions necessary for closure, supporting a model of off-pathway assembly as a mechanism of viral inhibition.

biophysics↗

bioRxiv2025

The central pore of HIV-1 capsomers promotes sustained stability of the viral capsid

The HIV-1 capsid, which orchestrates several key post-entry events to facilitate infection in target cells, is composed of hexamers and pentamers (capsomers) of the capsid (CA) protein arranged in a closed, conical structure known as the capsid that protects the viral RNA genome and replicative enzymes reverse transcriptase (RT) and integrase (IN). Each capsomer contains a central pore lined with rings of positively charged amino acid side chains - Arg-18 (R18) and Lys-25 (K25). The R18 and K25 rings drive capsid assembly by binding the host polyanion inositol hexakisphosphate (IP6) and are proposed to mediate the import of dNTPs into the capsid to facilitate reverse transcription. Here we demonstrate that the R18 ring can be functionally replaced by the introduction of a mutation (N21K) that establishes a new electropositive ring within the central pore. In contrast with previous studies in which R18 mutants were unable to adapt in culture, the N21K mutation facilitated the acquisition of second-site compensatory mutations that restored near-WT fitness to viral mutants lacking the R18 ring. Comparative analysis of several central pore mutants lacking the R18 ring revealed that particle infectivity was not correlated with IP6 binding or capsid assembly, but rather with capsid stability and key post-entry events including reverse transcription and nuclear entry. Our results indicate that the central pore plays critical roles in both the assembly of capsids and their sustained stability post-entry.

microbiology↗

bioRxiv2022

Pharmacologic hyperstabilisation of the HIV-1 capsid lattice induces capsid failure

The HIV-1 capsid has emerged as a tractable target for antiretroviral therapy. Lenacapavir, developed by Gilead Sciences, is the first capsid-targeting drug approved for medical use. Here we investigate the effect of Lenacapavir on HIV capsid stability and uncoating. We employ a single particle approach that simultaneously measures capsid content release and lattice persistence. We demonstrate that Lenacapavirs potent antiviral activity is predominantly due to lethal hyperstabilisation of the capsid lattice and resultant loss of compartmentalisation. This study highlights that disrupting capsid metastability is a powerful strategy for the development of novel antivirals.

biophysics↗

bioRxiv2020

Substrate-induced clustering activates Trim-Away of pathogens and proteins

Trim-Away is a powerful new technology that exploits off-the-shelf antibodies and the E3 RING ligase and cytosolic antibody receptor TRIM21 to carry out rapid protein depletion. How TRIM21 is catalytically-activated upon substrate engagement during either its normal immune function or when re-purposed for targeted protein degradation is unknown. Here we show that a mechanism of substrate-induced clustering triggers intermolecular dimerization of the RING domain to switch on the ubiquitination activity of TRIM21 and induce an antiviral response or drive Trim-Away. We harness this mechanism to expand the Trim-Away toolbox with highly-active TRIM21-nanobody chimeras that can also be controlled optogenetically. This work provides a mechanism for cellular activation of TRIM RING ligases and has important implications for targeted protein degradation technologies.

molecular biology↗