Ability of nucleoside-modified mRNA to encode HIV-1 envelope trimer nanoparticles.
Zekun MuKevin WieheKevin O SaundersRory HendersonDerek W CainRobert ParksDiana MartikKatayoun MansouriRobert J EdwardsAmanda NewmanXiaozhi LuShi-Mao XiaMattia BonsignoriDavid MontefioriQifeng HanSravani VenkatayogiTyler EvangelousYunfei WangWes RountreeYing TamChristopher BarbosaS Munir AlamWilton B WilliamsNorbert PardiDrew WeissmanBarton F HaynesPublished in: bioRxiv : the preprint server for biology (2021)
The success of nucleoside-modified mRNAs in lipid nanoparticles (mRNA-LNP) as COVID-19 vaccines heralded a new era of vaccine development. For HIV-1, multivalent envelope (Env) trimer protein nanoparticles are superior immunogens compared to trimers alone for priming of broadly neutralizing antibody (bnAb) B cell lineages. The successful expression of complex multivalent nanoparticle immunogens with mRNAs has not been demonstrated. Here we show that mRNAs can encode antigenic Env trimers on ferritin nanoparticles that initiate bnAb precursor B cell expansion and induce serum autologous tier 2 neutralizing activity in bnAb precursor VH + VL knock-in mice. Next generation sequencing demonstrated acquisition of critical mutations, and monoclonal antibodies that neutralized heterologous HIV-1 isolates were isolated. Thus, mRNA- LNP can encode complex immunogens and are of use in design of germline-targeting and sequential boosting immunogens for HIV-1 vaccine development.
Keyphrases
- antiretroviral therapy
- hiv positive
- hiv infected
- hiv testing
- human immunodeficiency virus
- hepatitis c virus
- hiv aids
- men who have sex with men
- binding protein
- south africa
- coronavirus disease
- sars cov
- poor prognosis
- type diabetes
- bone marrow
- metabolic syndrome
- gene expression
- dengue virus
- mesenchymal stem cells
- copy number
- amino acid
- fatty acid
- genome wide
- cell therapy
- dna repair
- oxidative stress
- zika virus
- circulating tumor