Clinical resistance to vicriviroc through adaptive V3 loop mutations in HIV-1 subtype D gp120 that alter interactions with the N-terminus and ECL2 of CCR5.
The HIV-1 CCR5 co-receptor is a member of the chemokine receptor family of G-protein coupled receptors; for which a number of small molecule antagonists, such as vicriviroc (VCV), have been developed to inhibit HIV-1 R5-tropic replication. In this study, we analyzed an HIV-1 subtype D envelope gene from a clinical trial subject who developed complete resistance to VCV. The HIV-1 resistant envelope has six predominant amino acid changes in the V3 loop, together with one change in the C4 domain of gp120, which are fully responsible for the resistance phenotype. V3 loop mutations Q315E and R321G are essential for resistance to VCV, whereas E328K and G429R in C4 contribute significantly to the infectivity of the resistant variant. Collectively, these amino acid changes influenced the interaction of gp120 with both the N-terminus and ECL2 region of CCR5.
Ogert
Robert A
RA
Merck Research Laboratories, Department of Infectious Diseases, 2015 Galloping Hill Road, K-15-4945, Kenilworth, NJ 07033, USA.
Hou
Yan
Y
Ba
Lei
L
Wojcik
Lisa
L
Qiu
Ping
P
Murgolo
Nicholas
N
Duca
Jose
J
Dunkle
Lisa M
LM
Ralston
Robert
R
Howe
John A
JA
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000911:Antibodies, Monoclonal; D065100:CCR5 Receptor Antagonists; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics / Q000502:physiology; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics* / Q000472:pathogenicity / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010446:Peptide Fragments / Q000737:chemistry / Q000235:genetics* / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D019713:Receptors, CCR5 / Q000737:chemistry; D053586:Virus Internalization
D000911:Antibodies, Monoclonal; D065100:CCR5 Receptor Antagonists; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; C059762:HIV envelope protein gp120 (305-321); D010446:Peptide Fragments; D010879:Piperazines; D011743:Pyrimidines; D019713:Receptors, CCR5; C486781:vicriviroc