HIV-1 RNA editing, hypermutation, and error-prone reverse transcription.

Bourara et al. (1) reported that transcripts of the human immunodeficiency virus–type 1 (HIV-1) were subject to RNA editing in chronically infected cells. They observed multiple guanine-to-adenine (G-to-A) and cytosine-to-uracil (C-to-U) changes in several regions of the HIV-1 RNA; commonly, a G-to-A change in the untranslated leader was present exclusively in spliced HIV-1 messenger RNA (mRNA), but not in the unspliced RNA and the proviral DNA ge-nome. Changes in the viral protein R (vpr) gene were present in spliced and unspliced HIV-1 RNA extracted from the cell, but not in the unspliced RNA genome that is packaged in virion particles. Therefore, Bourara et al. proposed that post-transcriptional mRNA-editing events occur for a subset of viral RNAs. Known editing mechanisms, however, cannot easily explain these changes in the HIV-1 genome. We here propose an alternative mechanistic model based on HIV-1 reverse transcription to explain some of the nucleotide changes. Bourara et al. argued that the chronically infected cells represent a clonal population with one proviral genome, based on the idea that reinfection of HIV-producing cells is restricted by a mechanism known as superinfection interference. There is convincing evidence, however, that viral interference is not complete in chronically infected cell cultures (2, 3). Thus, reverse transcribed viral genomes are likely to end up in the DNA of a subset of cells, thereby producing a heterogeneous cell population. Also, it is crucial to understand why a chronically infected cell could be established with this cytopathic virus. Viral la-tency is frequently associated with muta-tional inactivation of the viral transcription machinery, in particular the essential tat-TAR axis (4, 5). These mechanisms can result in a very complex population of chronically infected cells. All cells may harbor the original proviral ge-nome that is transcriptionally impaired, but there may be several subsets of cells with additional proviruses that underwent at least one round of reverse transcription. These minority proviruses will not be picked up by Southern blot analysis, but they may largely determine the HIV-1 RNA content of the cell pool. The proviruses can have the typical mutations due to reverse transcription errors, which— because of mutational inactivation of motifs that regulate either splicing (the rev-RRE axis) or RNA packaging (Gag protein and the psi motif)— may not be distributed equally over the spliced versus unspliced RNA and the cellular versus virion HIV-1 RNA. Thus, the chronically infected cell system is far too complex to provide evidence …