HIV Capsid and Integration Targeting

Abstract

Integration of retroviral reverse transcripts into the chromosomes of the cells that they infect is required for efficient viral gene expression and the inheritance of viral genomes to daughter cells. Before integration can occur, retroviral reverse transcription complexes (RTCs) must access the nuclear environment where the chromosomes reside. Retroviral integration is non-random, with different types of virus-host interactions impacting where in the host chromatin integration takes place. Lentiviruses such as HIV efficiently infect interphase cells because their RTCs have evolved to usurp cellular nuclear import transport mechanisms, and research over the past decade has revealed specific interactions between the HIV capsid protein and nucleoporin (Nup) proteins such as Nup358 and Nup153. The interaction of HIV capsid with cleavage and polyadenylation specificity factor 6 (CPSF6), which is a component of the cellular cleavage and polyadenylation complex, helps to dictate nuclear import as well as post-nuclear RTC invasion. In the absence of the capsid-CPSF6 interaction, RTCs are precluded from reaching nuclear speckles and gene-rich regions of chromatin known as speckle-associated domains, and instead mis-target lamina-associated domains out at the nuclear periphery. Highlighting this area of research, small molecules that inhibit capsid-host interactions important for integration site targeting are highly potent antiviral compounds.

Designing Lentiviral Vectors for Gene Therapy of Genetic Diseases

“…The main viral determinants of the integration process are the PIC, with its major functional component, the IN protein, and the IN binding sites in the LTRs. The IN protein is specific to each retrovirus type and is responsible for most of its integration preferences [ 4 , 22 ]. Since IN is an indispensable component of a retroviral vector packaging process, it will accurately reproduce in the vector the integration characteristics of the parental virus.…”

“…Clinical studies on three more primary immunodeficiencies, i.e., X-linked SCID, chronic granulomatous disease (CGD) and Wiskott-Aldrich syndrome (WAS), resulted in the occurrence of leukemias caused by vector-driven insertional oncogene activation [ 3 ]. These events triggered a renewed interest in retrovirus biology that led to a deeper understanding of the molecular mechanisms by which different retroviruses integrate into, and interact with, the host cell genome [ 4 , 5 ]. These studies were the basis for the development of a safer and more efficacious vectors, derived from the human immunodeficiency lentivirus (HIV) and carrying carefully designed transgene expression cassettes based on cellular promoters and regulatory elements [ 6 ].…”

Molecular Dynamics Free Energy Simulations Reveal the Mechanism for the Antiviral Resistance of the M66I HIV-1 Capsid Mutation

“…In recent years, HIV-1 CA has emerged as a major drug target for antiviral therapeutic development [ 1 , 2 , 3 ]. CA not only acts as the building block of the HIV-1 capsid core formation but also interacts with several host factors [ 4 , 5 , 6 , 7 , 8 ]. Small molecule agents with different chemotypes have been developed in recent years to disrupt the CA biological functions in the virus replication cycle [ 9 , 10 , 11 , 12 ].…”

Direct capsid labeling of infectious HIV-1 by genetic code expansion allows detection of largely complete nuclear capsids and suggests nuclear entry of HIV-1 complexes via common routes

“…The cone-shaped capsid that encases the viral RNA genome and replication proteins is a characteristic feature of infectious human immunodeficiency virus type 1 (HIV-1) particles. Data obtained by many research groups over the past decade have revised our understanding of the role of the mature capsid in HIV-1 replication, placing this structure at the center stage of post-entry replication steps (reviewed in Campbell and Hope, 2015; Novikova et al ., 2019; Engelman, 2021; Guedán et al ., 2021; Toccafondi, Lener and Negroni, 2021). Upon fusion of the virion envelope with the cell membrane, the capsid, which consists of ∼1,200-1,500 monomers of the capsid protein CA (Briggs et al 2003), is released into the cytosol.…”