Highly potent and broadly neutralizing anti-CD4 trimeric nanobodies inhibit HIV-1 infection by inducing CD4 conformational alteration.

Zhu, Linjing; Huang, Bilian; Wang, Xiangyao; Ni, Fengfeng; Ao, Mingjun; Wang, Ruoke; Zheng, Bin; Chen, Chen; Xue, Jing; Zhu, Lin; Yang, Chenbo; Shi, Lingen; Geng, Shengya; Hu, Jiaqian; Yang, Mengshi; Zhang, Doudou; Yang, Ping; Li, Miaomiao; Li, Yuncheng; Hu, Qinxue

Despite advancements in antiretroviral therapy (ART) suppressing HIV-1 replication, existing antiviral drugs pose limitations, including lifelong medication, frequent administration, side effects and viral resistance, necessitating novel HIV-1 treatment approaches. CD4, pivotal for HIV-1 entry, poses challenges for drug development due to neutralization and cytotoxicity concerns. Nevertheless, Ibalizumab, the sole approved CD4-specific antibody for HIV-1 treatment, reignites interest in exploring alternative anti-HIV targets, emphasizing CD4's potential value for effective drug development. Here, we explore anti-CD4 nanobodies, particularly Nb457 from a CD4-immunized alpaca. Nb457 displays high potency and broad-spectrum activity against HIV-1, surpassing Ibalizumab's efficacy. Strikingly, engineered trimeric Nb457 nanobodies achieve complete inhibition against live HIV-1, outperforming Ibalizumab and parental Nb457. Structural analysis unveils Nb457-induced CD4 conformational changes impeding viral entry. Notably, Nb457 demonstrates therapeutic efficacy in humanized female mouse models. Our findings highlight anti-CD4 nanobodies as promising HIV-1 therapeutics, with potential implications for advancing clinical treatment against this global health challenge. In this study, Zhu et al. report Nb457, an alpaca-derived nanobody with broad-spectrum anti-HIV1 activity and show that Nb457 induces conformational changes in CD4, blocking viral entry and completely inhibiting HIV-1 in its trimeric form.

IMMUNOGLOBULINS; CYTOTOXINS; ANTIVIRAL agents; ANTIRETROVIRAL agents; HIV

Nature Communications, 2024, Vol 15, Issue 1, p1

2041-1723

Academic Journal

10.1038/s41467-024-51414-6