The human immunodeficiency virus type 1 gag gene encodes an internal ribosome entry site

Several retroviruses have recently been shown to promote translation of the ir gag gene products by internal ribosome entry. In this report, we show th at mRNAs containing the human immunodeficiency virus type 1 (HIV-1) gag ope n reading frame (ORF) exhibit internal ribosome entry site (IRES) activity that can promote translational initiation of pr556(gag). Remarkably, this I RES activity is driven by sequences within the gag ORF itself and is not de pendent on the native gag 5'-untranslated region (UTR). This cap-independen t mechanism for Pr55(gag) translation may help explain the high levels of t ranslation of this protein in the face of major RNA structural barriers to scanning ribosomes found in the gag 5' UTR. The gag IRES activity described here also drives translation of a novel 40-kDa Gag isoform through transla tional initiation at an internal AUG codon found near the amino terminus of the Pr55(gag) capsid domain. Our findings suggest that this low-abundance Gag isoform may be important for wild-type replication of HIV-1 in cultured cells. The activities of the HIV-1 gag IRES may be an important feature of the HIV-l life cycle and could serve as a novel target for antiretroviral therapeutic strategies.