Retroviral Replication

Abstract

Retroviruses, are enveloped animal ribonucleic acid (RNA) viruses that replicate via a deoxyribonucleic acid (DNA) intermediate, which is integrated into the host genome as a provirus. Expression of viral RNA and proteins from proviral DNA utilises the transcription and translation machinery of the host. Retrovirus particles are assembled through protein–protein, protein–RNA and protein–lipid interactions, released from the cell by budding and subsequently matured by a viral protease. Interaction of the viral envelope protein with a target cell receptor triggers entry of the viral nucleoprotein core by fusion of viral and cellular membranes. After entry, the viral enzymes reverse transcriptase and integrase mediate reverse transcription of viral RNA and integration of the resulting double‐stranded DNA copy of the viral genome, respectively. A provirus can be transmitted through the germ line from parents to offspring as an endogenous retrovirus. Multiple steps of retroviral replication can be targeted by host cell restriction factors in a complex interplay of virus–host interactions. Key Concepts Reverse transcription and integration into the host genome are hallmarks of retroviral replication. The viral RNA genome contains a packaging signal for selective encapsidation into viral particles and a binding site for a tRNA primer for initiation of reverse transcription. The integrated virus contains long‐terminal repeats harbouring signals for transcriptional initiation and polyadenylation, which define the retroviral transcription unit. Open reading frames for Gag, Pol and Env are found in all retroviruses, but some retroviruses encode additional proteins such as Tat and Rev of HIV‐1. A stop codon between gag and pol can be bypassed by readthrough or frameshifting during translation of retroviral mRNA to make the Gag–Pol polyprotein. Retroviruses have specialised strategies for export of unspliced genomic‐length viral RNA from the nucleus. The metastable retroviral envelope protein drives the fusion of viral and cellular membranes by a type I fusion mechanism to allow retroviral entry in a receptor‐dependent manner. The retroviral protease is required for maturation of viral particles after their release from producer cells by budding. A retrovirus can integrate into the genome of germ cells and become part of the genetic material transmitted from parents to offspring. A provirus can be maintained through species diversification as an endogenous retrovirus that may serve as a marker of phylogenetic relationship and evolutionary distance. A battery of diverse host cell restriction factors operates at multiple steps of retroviral replication.