Bifunctional CD4–DC-SIGN Fusion Proteins Demonstrate Enhanced Avidity to gp120 and Inhibit HIV-1 Infection and Dissemination

• DOI: 10.1128/aac.00623-12
• Publication Date: 2012-06-12T05:39:27Z
• Authors: Tao Du; Kai Hu; Jun Yang; Jing Jin; Chang Li; Daniel Stieh; George E. Griffin; Robin J. Shattock; Qinxue Hu
• Keywords: DC-SIGN; Linker; Avidity

ABSTRACT Early stages of mucosal infection are potential targets for HIV-1 prevention. CD4 is the primary receptor in whereas DC-SIGN likely plays an important role dissemination, particularly during sexual transmission. To test hypothesis that inhibitor simultaneously targeting both and binding sites on gp120 may provide a potent anti-HIV strategy, we designed constructs by fusing extracellular domains together with varied arrangements lengths CD4, linker. We expressed, purified characterized series soluble CD4-linker–DC-SIGN (CLD) fusion proteins. Several CLDs, composed longer linker extra neck domain DC-SIGN, had enhanced affinity as evidenced molecular-interaction analysis. Furthermore, such CLDs exhibited significantly neutralization activity against laboratory-adapted isolates. Moreover, efficiently inhibited trans via DC-SIGN-expressing cell line human dendritic cells. This was further strengthened results from cervical explant model, showing potently prevented localized disseminated infections. first time DC-SIGN-based bifunctional proteins have demonstrated potency. Our study provides proof concept represents novel antiviral strategy. Given to increases exposure site forms occur vivo , improvement render them potentially useful prophylaxis or therapeutics.