Structural and Mechanistic Bases for Resistance of the M66I Capsid Variant to Lenacapavir.

Unlabelled: Lenacapavir (LEN) is the first in class viral capsid protein (CA) targeting antiretroviral for treating multi-drug-resistant HIV-1 infection. Clinical trials and cell culture experiments have identified resistance associated mutations (RAMs) in the vicinity of the hydrophobic CA pocket targeted by LEN. The M66I substitution conferred by far the highest level of resistance to the inhibitor compared to other RAMs.

Structural Investigations of Interactions between the Influenza a Virus NS1 and Host Cellular Proteins.

The Influenza A virus is a continuous threat to public health that causes yearly epidemics with the ever-present threat of the virus becoming the next pandemic. Due to increasing levels of resistance, several of our previously used antivirals have been rendered useless. There is a strong need for new antivirals that are less likely to be susceptible to mutations.

The Effect of Inositol Hexakisphosphate on HIV-1 Particle Production and Infectivity can be Modulated by Mutations that Affect the Stability of the Immature Gag Lattice.

The assembly of an HIV-1 particle begins with the construction of a spherical lattice composed of hexamer subunits of the Gag polyprotein. The cellular metabolite inositol hexakisphosphate (IP6) binds and stabilizes the immature Gag lattice via an interaction with the six-helix bundle (6HB), a crucial structural feature of Gag hexamers that modulates both virus assembly and infectivity. The 6HB must be stable enough to promote immature Gag lattice formation, but also flexible enough to be accessible to the viral protease, which cleaves the 6HB during particle maturation.

CryoET structures of immature HIV Gag reveal six-helix bundle.

Gag is the HIV structural precursor protein which is cleaved by viral protease to produce mature infectious viruses. Gag is a polyprotein composed of MA (matrix), CA (capsid), SP1, NC (nucleocapsid), SP2 and p6 domains. SP1, together with the last eight residues of CA, have been hypothesized to form a six-helix bundle responsible for the higher-order multimerization of Gag necessary for HIV particle assembly.

A stable immature lattice packages IP for HIV capsid maturation.

HIV virion assembly begins with the construction of an immature lattice consisting of Gag hexamers. Upon virion release, protease-mediated Gag cleavage leads to a maturation event in which the immature lattice disassembles and the mature capsid assembles. The cellular metabolite inositiol hexakisphosphate (IP) and maturation inhibitors (MIs) both bind and stabilize immature Gag hexamers, but whereas IP promotes virus maturation, MIs inhibit it.

HIV-1 Maturation: Lessons Learned from Inhibitors.

Since the emergence of HIV and AIDS in the early 1980s, the development of safe and effective therapies has accompanied a massive increase in our understanding of the fundamental processes that drive HIV biology. As basic HIV research has informed the development of novel therapies, HIV inhibitors have been used as probes for investigating basic mechanisms of HIV-1 replication, transmission, and pathogenesis. This positive feedback cycle has led to the development of highly effective combination antiretroviral therapy (cART), which has helped stall the progression to AIDS, prolong lives, and reduce transmission of the virus.

The influenza NS1 protein modulates RIG-I activation via a strain-specific direct interaction with the second CARD of RIG-I.

A critical role of influenza A virus nonstructural protein 1 (NS1) is to antagonize the host cellular antiviral response. NS1 accomplishes this role through numerous interactions with host proteins, including the cytoplasmic pathogen recognition receptor, retinoic acid-inducible gene I (RIG-I). Although the consequences of this interaction have been studied, the complete mechanism by which NS1 antagonizes RIG-I signaling remains unclear.

Structural analyses reveal the mechanism of inhibition of influenza virus NS1 by two antiviral compounds.

The influenza virus is a significant public health concern causing 250,000-500,000 deaths worldwide each year. Its ability to change quickly results in the potential for rapid generation of pandemic strains for which most individuals would have no antibody protection. This pandemic potential highlights the need for the continuous development of new drugs against influenza virus.

Structural Basis for a Novel Interaction between the NS1 Protein Derived from the 1918 Influenza Virus and RIG-I.

The influenza non-structural protein 1 (NS1) plays a critical role in antagonizing the innate immune response to infection. One interaction that facilitates this function is between NS1 and RIG-I, one of the main sensors of influenza virus infection. While NS1 and RIG-I are known to interact, it is currently unclear whether this interaction is direct or if it is mediated by other biomolecules.