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. 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. 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 and protein–lipid interactions, released from the cell by budding, and subsequently matured by a viral protease. A provirus can be transmitted through the germline from parents to offspring as an endogenous retrovirus. Host cell restriction factors target multiple steps of retroviral replication 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 transciptional 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 read‐through or frame‐shifting 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.

Keywords: reverse transcription; integrase; protease; Gag–Pol polyprotein; RNA genome; integration; provirus; enveloped viruses; type I fusion; host restriction; endogenous retrovirus

Figure 1.

Retroviral particle and genome structure. (a) Retrovirus particle showing the approximate location of its components using the standardised two‐letter nomenclature for retroviral proteins. (b) Genome organisation and gene expression pattern of a simple retrovirus, showing the structure of an integrated provirus linked to flanking host cellular DNA at the termini of its LTR sequences (U3‐R‐U5) and the full‐length RNA that serves as genomic RNA and as mRNA for translation of the gag and polORFs into polyproteins. envmRNA is generated by splicing and encodes an Env precursor glycoprotein. LTR, long terminal repeat (U3‐R‐U5 for proviral DNA, derived from R‐U5 downstream of 5′ cap and U3‐R upstream of 3′ poly(A) in genome RNA); PBS, primer binding site; Ψ, packaging signal; PPT, polypurine tract; SD, splice donor site and SA, splice acceptor site.

Figure 2.

Replication cycle of a simple retrovirus. The flow of the early part of the replication cycle goes from receptor binding and internalisation at the left through reverse transcription to integration of the proviral DNA. The late part of the replication cycle proceeds from the provirus through transcription and processing and translation of viral RNA to assembly and release of viral particles. Maturation of the released particles involves cleavage of viral polyproteins by PR (protease).

Figure 3.

Reverse transcription and integration processes. (a) Reverse transcription. Outline of the reverse transcriptase (RT)‐catalysed steps leading from single‐stranded genomic RNA (top; black line) to double‐stranded proviral DNA (bottom; red line). (b) Integration. The viral DNA (top) is the product of the completed reverse transcription process of (a). Shown are the integrase (IN)‐mediated cleavage and religation steps leading to joining of proviral and host DNA. Subsequent repair and ligation are carried out by host factors. Note the loss of two terminal nucleotides of the viral DNA and the generation of a short repeat of host sequences of the integration site.

Figure 4.

Examples of host‐mediated restriction of retroviral replication. The symbols and text in red denote the point of restriction during the cycle of replication and in most cases the name of the responsible host gene/gene product. The two assembly pathways refer to C‐type retroviruses and B‐/D‐type retroviruses as indicated.

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Vareta M and Palmarini M (2010) Multitasking: making the most out of the retroviral envelope. Viruses 2: 1571–1576.

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Pedersen, Finn Skou, Pyrz, Magdalena, and Duch, Mogens(Apr 2011) Retroviral Replication. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0000430.pub3]