Cap-independent translation initiation of the unspliced RNA of retroviruses.

Retroviruses are a unique family of RNA viruses that utilize a virally encoded reverse transcriptase (RT) to replicate their genomic RNA (gRNA) through a proviral DNA intermediate. The provirus is permanently integrated into the host cell chromosome and is expressed by the host cell transcription, RNA processing, and translation machinery. Retroviral messenger RNAs (mRNAs) entirely resemble a cellular mRNA as they have a 5′cap structure, 5′untranslated region (UTR), an open reading frame (ORF), 3′UTR, and a 3′poly(A) tail. The primary transcription product interacts with the cellular RNA processing machinery and is spliced, exported to the cytoplasm, and translated. However, a proportion of the pre-mRNA subverts typical RNA processing giving rise to the full-length RNA. In the cytoplasm, the full-length retroviral RNA fulfills a dual role acting as mRNA and as the gRNA. Simple retroviruses generate two pools of full-length RNA, one for each purpose. However, complex retroviruses have a single pool of full-length RNA, which is destined for translation or encapsidation. As for eukaryotic mRNAs, translational control of retroviral protein synthesis is mostly exerted at the step of initiation. Interestingly, some retroviral mRNAs, both simple and complex, use a dual mechanism to initiate protein synthesis, a cap-dependent initiation mechanism, or via internal initiation using an internal ribosome entry site (IRES). In this review, we describe and discuss data regarding the molecular mechanism driving the canonical cap-dependent and IRES-mediated translation initiation for retroviral mRNA, focusing the discussion mainly on the most studied retroviral mRNA, the HIV-1 mRNA.