A Novel Class of Anti-HIV Agents with Multiple Copies of Enfuvirtide Enhances Inhibition of Viral Replication and Cellular Transmission In Vitro

Chang, Chien-HsingMorris Plains, New Jersey, United States of America (författare)

We constructed novel HIV-1 fusion inhibitors that may overcome the current limitations of enfuvirtide, the first such therapeutic in this class. The three prototypes generated by the Dock-and-Lock (DNL) technology to comprise four copies of enfuvirtide tethered site-specifically to the Fc end of different humanized monoclonal antibodies potently neutralize primary isolates (both R5-tropic and X4-tropic), as well as T-cell-adapted strains of HIV-1 in vitro. All three prototypes show EC50 values in the subnanomolar range, which are 10- to 100-fold lower than enfuvirtide and attainable whether or not the constitutive antibody targets HIV-1. The potential of such conjugates to purge latently infected cells was also demonstrated in a cell-to-cell viral inhibition assay by measuring their efficacy to inhibit the spread of HIV-1LAI from infected human peripheral blood mononuclear cells to Jurkat T cells over a period of 30 days following viral activation with 100 nM SAHA (suberoylanilide hydroxamic acid). The IgG-like half-life was not significantly different from that of the parental antibody, as shown by the mean serum concentration of one prototype in mice at 72 h. These encouraging results provide a rationale to develop further novel anti-HIV agents by coupling additional antibodies of interest with alternative HIV-inhibitors via recombinantly-produced, self-assembling, modules.

Hinkula, JormaLinköpings universitet,Molekylär virologi,Hälsouniversitetet(Swepub:liu)jorhi40 (författare)
Loo, MeiyuMorris Plains, New Jersey, United States of America (författare)
Falkeborn, TinaLinköpings universitet,Molekylär virologi,Hälsouniversitetet(Swepub:liu)tinlu81 (författare)
Li, RongxiuMorris Plains, New Jersey, United States of America (författare)
Cardillo, Thomas M.Morris Plains, New Jersey, United States of America (författare)
Rossi, Edmund A.Morris Plains, New Jersey, United States of America (författare)
Goldenberg, David M.Morris Plains, New Jersey, United States of America (författare)
Wahren, BrittaKarolinska Institutet,Karolinska Institutet, Stockholm, Sweden (författare)
Morris Plains, New Jersey, United States of AmericaMolekylär virologi (creator_code:org_t)

Ingår i:PLOS ONE: Public Library of Science (PLoS)7:7, s. e41235-e412351932-6203

Av författaren/redakt...: Chang, Chien-Hsi ...; Hinkula, Jorma; Loo, Meiyu; Falkeborn, Tina; Li, Rongxiu; Cardillo, Thomas ...; visa fler...; Rossi, Edmund A.; Goldenberg, Davi ...; Wahren, Britta; visa färre...

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