Many retroviruses are known to induce antisense transcription of mRNA from transcription start sites in the 3’ LTR. In 1988, the existence of an open reading frame in the antisense strand of HIV-1 was noted by Roger Miller, and many subsequent studies have since been conducted on the protein encoded by this open reading frame. The open reading frame is absent in most SIV-chimanzee genomes, most HIV-1 O group genomes, and some HIV-1 M group genomes, but it is present in a large majority of HIV-1 M group genomes. A study of more than 23,000 HIV genomes showed the prevalence of the ASP open reading to be 89% in CRF01_AE, 74% in subtype A, 84% in subtype C, and 85% in subtype B (Cassan et al. 2016). The open reading frame occurs in a region of the genome where the envelope gene is being selected for divergence. Since many mutations that might occur in envelope would introduce stop codons in alternate reading frames, the high retention of this antisense reading frame strongly suggests a role for the antisense protein product. The Cassan et al. 2016 paper provides citations for many other publications researching the antisense protein.
Gene map of HIV-1 HXB2 showing the location of the ASP open reading frame (thick arrow), which spans HXB2 coordinates 7942-7373. Transcription initiation sites are present at 9322-8861. Figure adapted from Torresilla et al. 2015.Data
The alignments published by Cassan et al. 2016 can be obtained from figshare (https://figshare.com/s/9668ef62E84488d4787a). Their alignments are the complete envelope gene from more than 23,000 HIV and SIV sequences, aligned in the envelope reading frame in order to use their method of detecting selection pressure on the antisense protein.
The sequence alignments we provide below, as DNA and protein translation, are from the 2015 HIV-1/SIVcpz/SIVgor envelope web alignment, clipped to the antisense ORF region, reverse complemented, then codon-aligned in the antisense protein reading frame. Many of these sequences contain in-frame stop codons. In particular, subtype A contains a stop codon at codon 12, followed by a second start codon at codon 26 in most isolates.
DNA alignment codon-aligned for the reading frame of ASP.
Translation of the alignment above.
Human immunodeficiency virus may encode a novel protein on the genomic DNA plus strand.
Science. 1988 Mar 18;239(4846):1420-2.
Reviving an old HIV-1 gene: The HIV-1 antisense protein.
Torresilla C, Mesnard JM, Barbeau B.
Curr HIV Res. 2015;13(2):117-24.
Concomitant emergence of the antisense protein gene of HIV-1 and of the pandemic.
Cassan E, Arigon-Chifolleau AM, Mesnard JM, Gross A, Gascuel O.
Proc Natl Acad Sci U S A. 2016 Oct 11;113(41):11537-11542.
Different HIV-1 env frames: gp120 and ASP (antisense protein) biosynthesis, and theirs co-variation tropic amino acid signatures in X4- and R5-viruses.
J Med Virol. 2017 Jan;89(1):112-122. doi: 10.1002/jmv.24611.
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