Selective Pressure Against AUG Triplets in the 5′ Untranslated Region of Human Immunodeficiency Virus Type 1 Supports Cap-Dependent Translation Initiation Mechanism

The human immunodeficiency virus type 1 (HIV-1) is dependent on the host transcription and translation machinery to complete its life cycle. Different hypotheses have been postulated regarding the mechanism of translation initiation in HIV-1. The cap-dependent ribosomal scanning hypothesis predicts selection against AUG usage in optimal context in the HIV-1 5 UTR to avoid initiation at a wrong AUG by the scanning ribosome which would hamper the detection of the true downstream translation initiation codon. Recent reports have shown evidence of cap-independent translation initiation mechanisms in HIV-1, such as the direct binding of ribosome at internal ribosome entry sites (IRES), distant from the 5 cap. It has been proposed that the IRES-dependent mechanism of translation initiation, allows the ribosome to bypass the stable secondary structures in the HIV-1 5 UTR. This hypothesis predicts no selective pressure against AUG usage in optimal context in the HIV-1 5 UTR since any such AUGs would be embedded in the stable secondary structures. We evaluated these two hypotheses based on their prediction regarding selective pressure against AUG usage in optimal context in the HIV-1 5 UTR. Our results show that there is indeed a selective pressure against AUG usage in optimal context in the HIV-1 5 UTR which supports the cap-dependent translation initiation hypothesis. That is, the HIV-1 mRNAs are translated either by the cap-dependent mechanism alone or in addition to IRES-dependent mechanism in the presence of 5 UTR stable secondary structures. They are clearly not translated by the latter mechanism alone.