POL GENE QUASI-SPECIES OF HUMAN-IMMUNODEFICIENCY-VIRUS - MUTATIONS ASSOCIATED WITH DRUG-RESISTANCE IN VIRUS FROM PATIENTS UNDERGOING NO DRUG-THERAPY

The nucleotide sequences of two pol gene regions (codons 31 to 108 and 181 to 219 of reverse transcriptase) of 60 human immunodeficiency vir us type 1 genomes obtained directly from primary lymphocytes from infe cted individuals are reported. In addition, the mutant spectra of seve ral quasispecies have been sampled by repetitive sequencing of molecul ar clones representing the same pol genomic regions. Average mutation frequencies ranged from 1.6 x 10(-2) to 3.4 x 10(-2) substitutions per nucleotide for independent samples (relative to their consensus nucle otide sequence) and from 3.6 x 10(-3) to 1.1 x 10(-2) substitutions pe r nucleotide for individual quasispecies distributions. Several mutati ons leading to amino acid substitutions related to loss of sensitivity to reverse transcriptase inhibitors have been identified in samples f rom patients not subjected to antiretroviral therapy. Mutation frequen cies in the codons previously identified as involved in resistance to reverse transcriptase inhibitors were very similar to the average muta tion frequencies in the pol region analyzed. Thus, the finding of muta tions related to drug resistance (even in the absence of positive sele ction by the corresponding drugs) is the expected consequence of the s tatistical distribution of mutations along the pol gene. The presence of such critical amino acid replacements in human immunodeficiency vir us type 1 populations underscores the importance of viral quasispecies as reservoirs of phenotypic virus variants and has a number of implic ations for AIDS control.