The differential binding and activity of PRO 2000 against diverse HIV-1 envelopes.
OBJECTIVE
PRO 2000 is a polyanionic microbicide that binds directly to the glycoprotein 120 (gp120) envelope protein to inhibit HIV-1 entry. We studied the breadth of PRO 2000 activity against HIV-1 derived from recently transmitted R5 viruses. We also investigated the interaction of this compound with X4 and R5 HIV-1 envelope glycoproteins using an epitope-mapping strategy.


METHODS
The anti-HIV activity of PRO 2000 against subtype B and C Env-pseudotyped viruses was assessed in saline and cervicovaginal lavage fluid. Competitive binding assays were performed with X4 and R5 monomeric and virus-associated gp120.


RESULTS
PRO 2000 was found to be active against recently transmitted subtype B and C viruses tested in vitro, however, at 1 microg/mL in saline, activity against subtype C was decreased compared with subtype B. Epitope mapping using anti-V3 region antibodies showed that PRO 2000 binds to the V3 region of monomeric and virus-associated X4 gp120 with a higher affinity than to V3 of R5 gp120. In contrast, the interaction of PRO 2000 with the CD4-binding site was similar for both X4 and R5 monomeric and virus-associated gp120.


CONCLUSIONS
PRO 2000 has significant activity against recently transmitted viruses, although some activity is lost at low concentrations. Epitope binding studies suggest that this broad activity is due to direct and indirect interactions with multiple gp120 sites rather than V3 binding alone.
Division of Infectious Diseases, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA.
Darpun D
DD
Sachdev
Bouchra
B
Zerhouni-Layachi
Mila
M
Ortigoza
Albert T
AT
Profy
Michael
M
Tuen
Catarina E
CE
Hioe
Mary E
ME
Klotman
D019380:Anti-HIV Agents / Q000378:metabolism* / Q000494:pharmacology*; D001826:Body Fluids; D045744:Cell Line, Tumor; D004305:Dose-Response Relationship, Drug; D015699:HIV Envelope Protein gp120 / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D009282:Naphthalenesulfonates / Q000378:metabolism* / Q000494:pharmacology*; D011108:Polymers / Q000378:metabolism* / Q000494:pharmacology*; D011485:Protein Binding
D019380:Anti-HIV Agents; D015699:HIV Envelope Protein gp120; D009282:Naphthalenesulfonates; C120231:PRO 2000; D011108:Polymers