Structural maturation of the matrix lattice is not required for HIV-1 particle infectivity.

HIV-1 assembly is initiated by the binding of Gag polyproteins to the inner leaflet of the plasma membrane, mediated by the myristylated matrix (MA) domain of Gag. Subsequent to membrane binding, Gag oligomerizes and buds as an immature, non-infectious virus particle, which, upon cleavage of the Gag precursor by the viral protease, transforms into a mature, infectious virion. During maturation, the MA lattice underlying the viral membrane undergoes a structural rearrangement and the newly released capsid (CA) protein forms a mature capsid that encloses the viral genome.

The structural and mechanistic bases for the viral resistance to allosteric HIV-1 integrase inhibitor pirmitegravir.

Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are investigational antiretroviral agents that potently impair virion maturation by inducing hyper-multimerization of IN and inhibiting its interaction with viral genomic RNA. The pyrrolopyridine-based ALLINI pirmitegravir (PIR) has recently advanced into phase 2a clinical trials. Previous cell culture-based viral breakthrough assays identified the HIV-1 variant that confers substantial resistance to this inhibitor.

The structural and mechanistic bases for the viral resistance to allosteric HIV-1 integrase inhibitor pirmitegravir.

Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are investigational antiretroviral agents which potently impair virion maturation by inducing hyper-multimerization of IN and inhibiting its interaction with viral genomic RNA. The pyrrolopyridine-based ALLINI pirmitegravir (PIR) has recently advanced into Phase 2a clinical trials. Previous cell culture based viral breakthrough assays identified the HIV-1 variant that confers substantial resistance to this inhibitor.

Molecular architecture and conservation of an immature human endogenous retrovirus.

The human endogenous retrovirus K (HERV-K) is the most recently acquired endogenous retrovirus in the human genome and is activated and expressed in many cancers and amyotrophic lateral sclerosis. We present the immature HERV-K capsid structure at 3.2 Å resolution determined from native virus-like particles using cryo-electron tomography and subtomogram averaging.

Molecular architecture and conservation of an immature human endogenous retrovirus.

A significant part of the human genome consists of endogenous retroviruses sequences. Human endogenous retrovirus K (HERV-K) is the most recently acquired endogenous retrovirus, is activated and expressed in many cancers and amyotrophic lateral sclerosis and possibly contributes to the aging process. To understand the molecular architecture of endogenous retroviruses, we determined the structure of immature HERV-K from native virus-like particles (VLPs) using cryo-electron tomography and subtomogram averaging (cryoET STA).

Performance efficient macromolecular mechanics via sub-nanometer shape based coarse graining.

Dimensionality reduction via coarse grain modeling is a valuable tool in biomolecular research. For large assemblies, ultra coarse models are often knowledge-based, relying on a priori information to parameterize models thus hindering general predictive capability. Here, we present substantial advances to the shape based coarse graining (SBCG) method, which we refer to as SBCG2.

The Drug-Induced Interface That Drives HIV-1 Integrase Hypermultimerization and Loss of Function.

Allosteric HIV-1 integrase (IN) inhibitors (ALLINIs) are an emerging class of small molecules that disrupt viral maturation by inducing the aberrant multimerization of IN. Here, we present cocrystal structures of HIV-1 IN with two potent ALLINIs, namely, BI-D and the drug candidate Pirmitegravir. The structures reveal atomistic details of the ALLINI-induced interface between the HIV-1 IN catalytic core and carboxyl-terminal domains (CCD and CTD).

Deep-learning in situ classification of HIV-1 virion morphology.

Transmission electron microscopy (TEM) has a multitude of uses in biomedical imaging due to its ability to discern ultrastructure morphology at the nanometer scale. Through its ability to directly visualize virus particles, TEM has for several decades been an invaluable tool in the virologist's toolbox. As applied to HIV-1 research, TEM is critical to evaluate activities of inhibitors that block the maturation and morphogenesis steps of the virus lifecycle.