Polymorphisms in Gag spacer peptide 1 confer varying levels of resistance to the HIV- 1 maturation inhibitor bevirimat.
BACKGROUND
The maturation inhibitor bevirimat (BVM) potently inhibits human immunodeficiency virus type 1 (HIV-1) replication by blocking capsid-spacer peptide 1 (CA-SP1) cleavage. Recent clinical trials demonstrated that a significant proportion of HIV-1-infected patients do not respond to BVM. A patient's failure to respond correlated with baseline polymorphisms at SP1 residues 6-8.


RESULTS
In this study, we demonstrate that varying levels of BVM resistance are associated with point mutations at these residues. BVM susceptibility was maintained by SP1-Q6A, -Q6H and -T8A mutations. However, an SP1-V7A mutation conferred high-level BVM resistance, and SP1-V7M and T8Delta mutations conferred intermediate levels of BVM resistance.


CONCLUSIONS
Future exploitation of the CA-SP1 cleavage site as an antiretroviral drug target will need to overcome the baseline variability in the SP1 region of Gag.
Adamson
Catherine S
CS
Virus-Cell Interaction Section, HIV Drug Resistance Program, National Cancer Institute, Frederick, MD 21702-1201, USA. catherine.adamson@st-andrews.ac.uk
Sakalian
Michael
M
Salzwedel
Karl
K
Freed
Eric O
EO
D019380:Anti-HIV Agents / Q000494:pharmacology*; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000302:isolation & purification; D006801:Humans; D008826:Microbial Sensitivity Tests; D017354:Point Mutation; D011110:Polymorphism, Genetic; D017384:Sequence Deletion; D013386:Succinates / Q000494:pharmacology*; D014315:Triterpenes / Q000494:pharmacology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000235:genetics*; D053978:Pentacyclic Triterpenes
D019380:Anti-HIV Agents; D013386:Succinates; D014315:Triterpenes; D054301:gag Gene Products, Human Immunodeficiency Virus; C479935:bevirimat; D053978:Pentacyclic Triterpenes
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