Multimodal Functionalities of HIV-1 Integrase

Abstract

Integrase is the retroviral protein responsible for integrating reverse transcripts into cellular genomes. Co-packaged with viral RNA and reverse transcriptase into capsid-encased viral cores, human immunodeficiency virus 1 (HIV-1) integrase has long been implicated in reverse transcription and virion maturation. However, the underlying mechanisms of integrase in these non-catalytic-related viral replication steps have remained elusive. Recent results have shown that integrase binds genomic RNA in virions, and that mutational or pharmacological disruption of integrase-RNA binding yields eccentric virion particles with ribonucleoprotein complexes situated outside of the capsid shell. Such viruses are defective for reverse transcription due to preferential loss of integrase and viral RNA from infected target cells. Parallel research has revealed defective integrase-RNA binding and eccentric particle formation as common features of class II integrase mutant viruses, a phenotypic grouping of viruses that display defects at steps beyond integration. In light of these new findings, we propose three new subclasses of class II mutant viruses (a, b, and c), all of which are defective for integrase-RNA binding and particle morphogenesis, but differ based on distinct underlying mechanisms exhibited by the associated integrase mutant proteins. We also assess how these findings inform the role of integrase in HIV-1 particle maturation.

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

“…When HIV-1 virions are produced in the presence of ALLINIs, the genomic RNA is mislocalized outside the viral core ( 10 – 12 , 15 , 26 – 28 ), and, upon their entry into target cells, these virions are unable to complete reverse transcription ( 11 , 12 , 15 , 26 , 28 , 29 ). Strikingly similar phenotypes are displayed by the class II HIV-1 IN mutant viruses ( 30 , 31 ). Unlike class I HIV-1 IN mutants, which are typified by amino acid substitutions within the IN active site and are specifically blocked for integration, class II mutants are characterized by pleiotropic defects and are not confined to a specific IN region or domain.…”

Localization and functions of native and eGFP-tagged capsid proteins in HIV-1 particles

“…We surmise that the interactions between CA and vRNP, which are likely initiated during virion morphogenesis, may play a role in proper assembly, maturation and vRNP-encapsidation inside a conical capsid shell. Intriguingly, vRNP encapsidation is universally disrupted by the large subset of IN mutations that are collectively referred to as class II IN mutation [ 64 , 65 ]. Future research will aim to map CA domains/residues that mediate vRNP binding, and the vRNPs components responsible for CA recruitment and retention in the nucleus.…”

Cis-Allosteric Regulation of HIV-1 Reverse Transcriptase by Integrase

“…In some retroviruses (α-retrovirus), RT enzyme is composed of a heterodimer of RT (α) and incompletely processed RTIN (β) subunits in the avian leukosis viruses [ 57 ]. Interestingly, the β subunit of the α-retrovirus RT has many allosteric properties, including specific binding to tRNA trp primer and controlling IN-mediated DNA endonuclease activity [ 58 ]. Our present data might reflect allosteric regulation of HIV-1 RT by IN, which has been noticed for the β subunit of the α-retrovirus RT.…”