Multiple independent origins of a protease inhibitor resistance mutation in salvage therapy patients.
BACKGROUND
Combination anti-viral therapies have reduced treatment failure rates by requiring multiple specific mutations to be selected on the same viral genome to impart high-level drug resistance. To determine if the common protease inhibitor resistance mutation L90M is only selected once or repeatedly on different HIV genetic backbones during the course of failed anti-viral therapies we analyzed a linked region of the viral genome during the evolution of multi-drug resistance.


RESULTS
Using L90M allele specific PCR we amplified and sequenced gag-pro regions linked to very early L90M containing HIV variants prior to their emergence and detection as dominant viruses in 15 failed salvage therapy patients. The early minority L90M linked sequences were then compared to those of the later L90M viruses that came to dominate the plasma quasispecies. Using Bayesian evolutionary analysis sampling trees the emergence of L90M containing viruses was seen to take place on multiple occasion in 5 patients, only once for 2 patients and an undetermined number of time for the remaining 8 patients.


CONCLUSIONS
These results indicate that early L90M mutants can frequently be displaced by viruses carrying independently selected L90M mutations rather than by descendents of the earlier mutants.
Kapoor
Amit
A
Blood Systems Research Institute, San Francisco, CA 94118, USA. Akapoor@bloodsystems.org
Shapiro
Beth
B
Shafer
Robert W
RW
Shulman
Nancy
N
Rhee
Soo-Yon
SY
Delwart
Eric L
EL
D019380:Anti-HIV Agents / Q000494:pharmacology* / Q000627:therapeutic use; D005075:Biological Evolution; D024921:Drug Resistance, Multiple, Viral / Q000235:genetics*; D016679:Genome, Viral; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology*; D016333:HIV Protease / Q000235:genetics; D017320:HIV Protease Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D006801:Humans; D009154:Mutation; D016879:Salvage Therapy; D017211:Treatment Failure; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics
D019380:Anti-HIV Agents; D017320:HIV Protease Inhibitors; D054301:gag Gene Products, Human Immunodeficiency Virus; D016333:HIV Protease; C514803:p16 protease, Human immunodeficiency virus 1