CD4-BFFI: a novel, bifunctional HIV-1 entry inhibitor with high and broad antiviral potency.
Resistance to antiretroviral drugs is a common problem in the treatment of HIV-1-infected patients. To overcome resistance, we generated a novel, bifunctional HIV-1 entry inhibitor by combining the anti-CD4 monoclonal antibody (mAb) 6314 with a fusion inhibitor similar to T-651 (anti-CD4 mAb based BiFunctional Fusion Inhibitor, CD4-BFFI). CD4-BFFI has potent antiviral activity against a multitude of HIV-1 isolates independent of their co-receptor usage and genetic background. It has higher antiviral potency compared to the fusion inhibitor T-651 or the anti-CD4 mAb 6314 used independently. More importantly, every HIV-1 strain tested was fully inhibited by CD4-BFFI while many strains were only partially inhibited by 6314. CD4-BFFI also retained antiviral potency against virus strains resistant to two fusion inhibitors, a CCR5 antagonist and an anti-CCR5 mAb. Pre-incubation of cells with a saturating concentration of anti-CD4 mAbs reduced the antiviral potency of CD4-BFFI, suggesting that binding of CD4-BFFI to the cell surface via its CD4 mAb portion is required for the antiviral potency of its fusion inhibitor moiety. Collectively, we present a novel HIV-1 inhibitor with a dual mode of action and excellent antiviral potency against wildtype and entry-inhibitor resistant virus strains suggesting that CD4-BFFI may have a high barrier to resistance.
Jekle
Andreas
A
Virology Disease Area, Roche Palo Alto LLC, Palo Alto, CA, United States. andreas.jekle@roche.com
Chow
Eugene
E
Kopetzki
Erhard
E
Ji
Changhua
C
Yan
Mei Jun
MJ
Nguyen
Rosa
R
Sankuratri
Surya
S
Cammack
Nick
N
Heilek
Gabrielle
G
D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D015704:CD4 Antigens / Q000276:immunology*; D002460:Cell Line; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D011993:Recombinant Fusion Proteins / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D023581:HIV Fusion Inhibitors; D011993:Recombinant Fusion Proteins