Identification of early-induced broadly neutralizing activities against transmitted founder HIV strains

Lucas, Julie Ann; Lin, Liyun; Paul, Nicodéme; Laumond, Géraldine; Klingler, Jéromine; Schmidt, Sylvie; Frappier, Julia; Essat, Asma; Meyer, Laurence; Gordon, Alicia Castro; Goujard, Cécile; Bahram, Seiamak; Moog, Christiane

doi:10.1097/qad.0000000000003371

Cited by 2 publications

(2 citation statements)

References 14 publications

(19 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…6A). These mice were challenged with 10 pg of P24 HIV-1 CH058 , originating from a transmitted/founder virus, known to be a tier 2 virus, and exhibiting resistance to most antibody neutralization 22 . Notably, neutralization assays revealed potent inhibition of HIV-1 CH058 by Nb 457 -Fc, Nb 457 -Nb HSA -Nb 457 and Ibalizumab.…”

Section: Therapeutic E Cacy Of Nb457 Treating Hiv-1-infected Humanize...mentioning

confidence: 99%

“…NDG-HuPBL Mice with a proportion of human CD45 + cells exceeding 5% were selected for the study. NDG-HuPBL mice were challenged with 10 ng p24 of live of HIV CH058 , originating from a transmitted/founder virus (generously provided by the NIH), known to be a tier 2 virus, and exhibiting resistance to most antibody neutralization 22 . The infected NDG-HuPBL mice (n = 8) were treated with 400 µg of nanobodies per mouse via intraperitoneal (i.p.)…”

Section: In Vivo Evaluation Of Nbs Inhibition Of Hiv Infection In Ndg...mentioning

confidence: 99%

See 1 more Smart Citation

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

Wu,

Zhu,

Wang

et al. 2023

Preprint

View full text Add to dashboard Cite

Despite substantial progress in antiretroviral therapy (ART) effectively suppressing HIV-1 replication in the bloodstream, a cure for HIV remains elusive. Existing antiviral drugs pose limitations, including lifelong medication, frequent administration, side effects, and viral resistance, necessitating novel HIV-1 treatment approaches. CD4, the primary receptor for HIV-1 entry into host cells, was once a prime target for drug or vaccine development. However, challenges, such as the potency and breadth of neutralization and cytotoxicity associated with anti-CD4 antibodies, hindered progress. Nevertheless, Ibalizumab, the sole approved CD4-specific antibody for HIV-1 treatment, reignited interest in exploring alternative anti-HIV targets, emphasizing CD4's potential value for effective drug development. Here, we investigated anti-CD4 nanobodies, with a focus on Nb457 isolated from a human CD4-immunized alpaca. Nb457 displayed remarkable ultra-high potency and broad-spectrum activity against HIV-1, surpassing Ibalizumab's efficacy. Importantly, Nb457 showed no impact on CD4+ T cell function, akin to Ibalizumab. Strikingly, engineered trimeric Nb457 nanobodies, Nb457-NbHSA-Nb457, achieved 100% inhibition against live HIV-1, outperforming Ibalizumab and parental Nb457. Structural analysis revealed that Nb457 binding induced a CD4 conformational change, impeding viral entry. Molecular Dynamics simulations elucidated the structural basis for the complete inhibition of HIV-1 by Nb457-NbHSA-Nb457. Furthermore, Nb457 exhibited significant therapeutic efficacy against HIV-1 infection in humanized mouse models. In conclusion, our study highlights ultra-potent anti-CD4 nanobodies as a compelling source of new HIV-1 therapeutics. The development of Nb457-based drugs holds the potential to revolutionize clinical HIV-1 treatment, providing a powerful tool in the battle against this persistent global health challenge.

show abstract

Section: Therapeutic E Cacy Of Nb457 Treating Hiv-1-infected Humanize...mentioning

confidence: 99%

Section: In Vivo Evaluation Of Nbs Inhibition Of Hiv Infection In Ndg...mentioning

confidence: 99%

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

Wu,

Zhu,

Wang

et al. 2023

Preprint

View full text Add to dashboard Cite

show abstract

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

Zhu,

Huang,

Wang

et al. 2024

Nat Commun

View full text Add to dashboard Cite

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.

show abstract

Identification of early-induced broadly neutralizing activities against transmitted founder HIV strains

Cited by 2 publications

References 14 publications

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

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

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

Contact Info

Product

Resources

About