The M184V mutation in reverse transriptase confers reduced adaptability to HIV-1 under conditions of stress.
Int Conf AIDS 2000 Jul 9-14; 13:(abstract no. TuOrA350)
Wainberg MA M.A. Wainberg, McGill University AIDS Centre, 3755 Cote Ste-Catherine Rd., Montreal, Canada, Tel.: +1 514 340 8307, Fax: +1 514 340 7537, E-mail: mdwa@musica.mcgill.ca
The M184V mutation in the reverse transcriptase (RT) gene of human immunodeficiency virus type 1 (HIV-1) is associated with high-level (i.e. é ºim1000 fold) resistance against 3TC as well as low-level resistance (i.e. 3-10 fold) against each of ddI, ddC, and Abacavir. In addition, this mutation confers to HIV each of the following: (1) a marginally diminished ability to grow in certain cell types, i.e. "reduced fitness"; (2) a modest increase in the "fidelity" of both the DNA-dependent DNA polymerase and RNA-dependent DNA polymerase steps in reverse transcription, such that the viral RT may make fewer errors or be less error-prone than the RTs of wild-type or drug-sensitive viruses in biochemical assays; (3) a modest decrease in the "processivity" or efficiency with which the viral RT copies viral RNA to produce the DNA that becomes integrated into host cells. (4) A diminished ability of viral RT to enact the reverse reaction of polymerization, i.e. pyrophophorylysis. However, it remains a question of debate as to whether the M184V mutation in RT may be worth maintaining. Toward this end, we have generated a number of deletion constructs that HIV can normally adapt to, by way of compensatory mutations, and have asked whether this will also occur in viruses that contain the 184V substitution in RT is present. The virus constructs used involve deletions of sequences located both upstream of the PBS, i.e. a region termed the A-rich loop, previously shown to be important for initiation of reverse transcription and viral replication, and 3 distinct sequences of bases, located between the viral LTR and the gag gene. Certain of the latter deletions involve a portion of the dimerization initiation site (DIS), known to be important in the dimerization of the two viral RNA strands and in virus assembly. Our results show that viruses containing these deletions were severely impaired in regard to viral replication competence if the 184V mutation in RT was also present. This was especially true if pressure with 3TC was exerted to keep the 184V substitution in place.
Keywords: AEGIS, HIV-1, HIV-1 Reverse Transcriptase, Virus Replication, Lamivudine, Mutation, RNA, Viral, HIV Infections, RNA-Directed DNA Polymerase, Genes, gag, Didanosine, DNA Primers, Human, virology, genetics 000709
TuOrA350
