Abstract
To evaluate the impact of hypermutation on the HIV-1 dissemination at the population level we studied 7072 sequences HIV-1 gene vif retrieved from the public databank. From this dataset 854 sequences were selected because they had associated values of CD4+ T lymphocytes counts and viral loads and they were used to assess the correlation between clinical parameters and hypermutation. We found that the frequency of stop codons at sites 5, 11 and 79 ranged from 2.8x10-4 to 4.2x10-4. On the other hand, at codons 21, 38, 70, 89 and 174 the frequency of stop codons ranged from 1.4x10-3 to 2.5x10-3. We also found a correlation between clinical parameters and hypermutation where patients harboring proviruses with one or more stop codons at the tryptophan sites of the gene vif had higher CD4+ T lymphocytes counts and lower viral loads compared to the population. Our findings indicate that A3 activity potentially restrains HIV-1 replication because individuals with hypermutated proviruses tend to have lower numbers of RNA copies. However, owing to the low frequency of hypermutated sequences observed in the databank (44 out of 7072), it is unlikely that A3 has a significant impact to curb HIV-1 dissemination at the population level.
Highlights
The apolipoprotein mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3; A3) proteins are a family of seven cytidine deaminases (A3A, A3B, A3C, A3D, A3F, A3G, and A3H) that restrict certain lentiviruses, retrotransposons, hepatitis B virus and human papillomavirus [1,2,3,4]
We found that patients harboring proviruses with one or more stop codons at the tryptophan sites of the gene vif had higher CD4+ T lymphocytes counts and lower viral loads compared to the population
These codons will be target by the A3 activity and the TGG codon will be changed into a stop codon (e.g., TAG, TGA, TAA)
Summary
The apolipoprotein mRNA editing enzyme catalytic polypeptide-like 3 (APOBEC3; A3) proteins are a family of seven cytidine deaminases (A3A, A3B, A3C, A3D, A3F, A3G, and A3H) that restrict certain lentiviruses, retrotransposons, hepatitis B virus and human papillomavirus [1,2,3,4]. A3F and A3G are incorporated into viral particles and during reverse transcription, within newly infected cells; by deamination, these proteins alter C in the viral minus-strand DNA to U. This activity of A3 is termed hypermutation because it induces high rates of G-to-A mutation in the newly synthesized plusstrand of viral DNA [2]. A3F and A3G inhibit the HIV-1 life cycle curbing the reverse transcription and the integration [2, 5, 22]. A3F, A3D, and A3H mutate TGG into the TGA stop codon when the TGG codon is followed by an A (TGGA) [1, 2, 8]
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