Rapid propagation of low-fitness drug-resistant mutants of human immunodeficiency virus type 1 by a streptococcal metabolite sparsomycin.
Here we report that sparsomycin, a streptococcal metabolite, enhances the replication of HIV-1 in multiple human T cell lines at a concentration of 400 nM. In addition to wild-type HIV-1, sparsomycin also accelerated the replication of low-fitness, drug-resistant mutants carrying either D30N or L90M within HIV-1 protease, which are frequently found mutations in HIV-1-infected patients on highly active antiretroviral therapy (HAART). Of particular interest was that replication enhancement appeared profound when HIV-1 such as the L90M-carrying mutant displayed relatively slower replication kinetics. The presence of sparsomycin did not immediately select the fast-replicating HIV-1 mutants in culture. In addition, sparsomycin did not alter the 50% inhibitory concentration (IC50) of antiretroviral drugs directed against HIV-1 including nucleoside reverse transcriptase inhibitors (lamivudine and stavudine), non-nucleoside reverse transcriptase inhibitor (nevirapine) and protease inhibitors (nelfinavir, amprenavir and indinavir). The IC50s of both zidovudine and lopinavir against multidrug resistant HIV-1 in the presence of sparsomycin were similar to those in the absence of sparsomycin. The frameshift reporter assay and Western blot analysis revealed that the replication-boosting effect was partly due to the sparsomycin's ability to increase the -1 frameshift efficiency required to produce the Gag-Pol transcript. In conclusion, the use of sparsomycin should be able to facilitate the drug resistance profiling of the clinical isolates and the study on the low-fitness viruses.
Miyauchi
Kosuke
K
AIDS Research Center, National Institute of Infectious Diseases, Toyama, Shinjuku, Tokyo, Japan.
Komano
Jun
J
Myint
Lay
L
Futahashi
Yuko
Y
Urano
Emiko
E
Matsuda
Zene
Z
Chiba
Tomoko
T
Miura
Hideka
H
Sugiura
Wataru
W
Yamamoto
Naoki
N
D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D024882:Drug Resistance, Viral / Q000187:drug effects*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D020128:Inhibitory Concentration 50; D008954:Models, Biological; D009154:Mutation; D013033:Sparsomycin / Q000494:pharmacology*; D013289:Streptococcaceae / Q000378:metabolism; D014162:Transfection; D014779:Virus Replication / Q000187:drug effects*
D013033:Sparsomycin