HIV-1 escape from a small molecule, CCR5-specific entry inhibitor does not involve CXCR4 use.
To study HIV-1 escape from a coreceptor antagonist, the R5 primary isolate CC1/85 was passaged in peripheral blood mononuclear cells with increasing concentrations of the CCR5-specific small molecule inhibitor, AD101. By 19 passages, an escape mutant emerged with a >20,000-fold resistance to AD101. This virus was cross-resistant to a related inhibitor, SCH-C, and partially resistant to RANTES but still sensitive to CCR5-specific mAbs. The resistant phenotype was stable; the mutant virus retained AD101 resistance during nine additional passages of culture in the absence of inhibitor. Replication of the escape mutant in peripheral blood mononuclear cells completely depended on CCR5 expression and did not occur in cells from CCR5-Delta32 homozygous individuals. The escape mutant was unable to use CXCR4 or any other tested coreceptor to enter transfected cells. Acquisition of CXCR4 use is not the dominant in vitro escape pathway for a small molecule CCR5 entry inhibitor. Instead, HIV-1 acquires the ability to use CCR5 despite the inhibitor, first by requiring lower levels of CCR5 for entry and then probably by using the drug-bound form of the receptor.
Trkola
Alexandra
A
Division of Infectious Diseases, Department of Medicine, University Hospital Zurich, 8091 Zurich, Switzerland.
Kuhmann
Shawn E
SE
Strizki
Julie M
JM
Maxwell
Elizabeth
E
Ketas
Tom
T
Morgan
Tom
T
Pugach
Pavel
P
Xu
Serena
S
Wojcik
Lisa
L
Tagat
Jayaram
J
Palani
Anandan
A
Shapiro
Sherry
S
Clader
John W
JW
McCombie
Stuart
S
Reyes
Gregory R
GR
Baroudy
Bahige M
BM
Moore
John P
JP
D000595:Amino Acid Sequence; D000911:Antibodies, Monoclonal / Q000378:metabolism; D065100:CCR5 Receptor Antagonists; D002478:Cells, Cultured; D018946:Chemokine CCL5 / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015658:HIV Infections / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008969:Molecular Sequence Data; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000378:metabolism; D010641:Phenotype; D010879:Piperazines / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D014162:Transfection
C523280:AD 101; D000911:Antibodies, Monoclonal; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D010879:Piperazines; D019718:Receptors, CXCR4; D009536:Niacinamide