Prevalence, genotypic associations and phenotypic characterization of K65R, L74V and other HIV-1 RT resistance mutations in a commercial database.
BACKGROUND
Nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations (NAMs) can affect response to treatment with NRTIs and might also result in HIV-1 with reduced replication capacity.


METHODS
A large commercial HIV-1 database (n=60,487) was analysed for the prevalence of NAMs, antiviral drug susceptibilities and viral replication capacity.


RESULTS
Thymidine analogue mutations (TAMs) and M184V were the most commonly observed NAMs (>25%). L74V/I was detected in 11% of isolates. K65R was detected in 3.3% of isolates and its frequency remained stable from 2003 to 2006, similar to trends observed for other NAMs. TAMs were rarely observed in combination with K65R, but frequently associated with L74V/I. HIV-1 with K65R or L74V/I alone were fully susceptible to zidovudine and stavudine. K65R was associated with reduced susceptibility to tenofovir, didanosine, abacavir and lamivudine; L74V/I was associated with reduced susceptibility to abacavir and didanosine. The addition of M184V to either K65R or L74V/I improved susceptibility to tenofovir, zidovudine and stavudine, but reduced susceptibility to abacavir, didanosine and lamivudine. Other NAMs commonly associated with K65R were A62V, S68G and Y115F; their NRTI susceptibilities were similar to those of viruses containing K65R alone. The replication capacity for HIV-1 with M184V/I or K65R was significantly reduced compared with wild-type (median 68%/ and 72%, respectively; P<0.0001), whereas replication capacity for HIV-1 with L74V or TAMs was not significantly reduced (88% and 97%, respectively).


CONCLUSIONS
These results demonstrate a relative stability in the prevalence of HIV-1 clinical isolates with NAMs from 2003 to 2006. Differences between the genotypic patterns, phenotype and replication capacity associated with common NAMs are described.
McColl
Damian J
DJ
Gilead Sciences, Foster City, CA 94404, USA.
Chappey
Colombe
C
Parkin
Neil T
NT
Miller
Michael D
MD
D019380:Anti-HIV Agents / Q000494:pharmacology; D030541:Databases, Genetic; D024882:Drug Resistance, Viral; D005838:Genotype; D015658:HIV Infections / Q000453:epidemiology* / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D009154:Mutation; D010641:Phenotype; D015995:Prevalence; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology; D014481:United States; D014779:Virus Replication
D019380:Anti-HIV Agents; D018894:Reverse Transcriptase Inhibitors; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase