Author: Xu, Lipeng ; Shan, Yaming ; Yan, Jingtian ; Nie, Jiaojiao ; Han, Changge ; Kong, Wei ; Chen, Zhiyuan ; Chang, Yaotian ; Yao, Xin ; Wu, Bingya ; Wang, Qingyu ; Shi, Yuhua

IntroductionBroadly neutralizing antibodies (bNAbs) have the ability to neutralize a considerable breadth of genetically diverse human immunodeficiency virus (HIV) strains. Passive immunization can potentially provide protection against HIV infection in animal models. However, the direct antibody infusion effect is limited due to the short half-life and deficient immunogenicity of the antibody. As an alternative strategy, we propose the use of nano viral vectors, specifically the adeno-associated virus (AAV), to continuously and systematically produce bNAbs against HIV.MethodsPlasmids expressing bNAbs PG9, PG16, 10E8, and NIH45-46 antibodies were constructed, targeting three different epitopes of HIV. Additionally, the bNAbs gene mediated by rAAV8 was administered to generate long-term expression with a single injection. We established both single and combined immunization groups. The neutralizing activity of antibodies expressed in mice sera was subsequently evaluated.ResultsThe expression of bNAbs in BALB/c mice can last for >24 weeks after a single intramuscular injection of rAAV8. Further studies show that neutralization of the HIV pseudovirus by sera from co-immunized mice with rAAV8 expressing 10E8 and PG16 was enhanced compared with mice immunized with 10E8 or PG16 alone.ConclusionThe prolonged expression of neutralizing antibodies can be maintained over long periods in BALB/c mice. This combined immunization is a promising candidate strategy for HIV treatment.

01 Oct 2021·Journal of Controlled ReleaseQ1 · MEDICINE

Broad and potent bispecific neutralizing antibody gene delivery using adeno-associated viral vectors for passive immunization against HIV-1

Q1 · MEDICINE

Article

Author: Shan, Yaming ; Qiao, Yongbo ; Jiang, Shun ; Wang, Bo ; Kong, Wei ; Li, Shuang

Broadly neutralizing antibodies (bNAbs) possess favorable safety, and passive immunization using these can prevent or control human immunodeficiency virus type 1 (HIV-1) infection. However, bNAbs generally used for monotherapy (IC₈₀ > 5 μg/mL) have limited breadth and potency and neutralize only 70-90% of all HIV-1 strains. To address the need for broader coverage of the HIV-1 epidemic and enhance the ability of bNAbs to target HIV-1, we fused the single-chain variable antibody fragment (scFv) of bNAbs (PG9, PGT123, or NIH45-46) with full-length ibalizumab (iMab) in an scFv-monoclonal antibody tandem format to construct bispecific bNAbs (BibNAbs). Additionally, we described the feasibility of BibNAb gene delivery mediated by recombinant adeno-associated virus 8 (rAAV8) for generating long-term expression with a single injection as opposed to short-term passive immunization requiring continuous injections. Our results showed that the expressed BibNAbs targeting two distinct epitopes exhibited neutralizing activity against 20 HIV-1 pseudoviruses in vitro. After injecting a single rAAV8 vector, the expression and neutralizing activity of the BibNAbs in serum were sustained for 24 weeks. To the best of our knowledge, very few studies have been published on BibNAb gene delivery using rAAV8 vectors against HIV-1. BibNAb gene delivery using rAAV8 vectors may be promising for passive immunization against HIV-1 infection.

15 Jul 2019·Journal of VirologyQ2 · MEDICINE

eCD4-Ig Limits HIV-1 Escape More Effectively than CD4-Ig or a Broadly Neutralizing Antibody

Q2 · MEDICINE

Article

Author: Alfant, Barnett ; Weber, Jesse A. ; Gardner, Matthew R. ; Farzan, Michael ; Zhou, Amber S. ; Fellinger, Christoph H.

HIV-1 broadly neutralizing antibodies (bNAbs) and engineered antibody-like inhibitors have been compared for their breadths, potencies, and in vivo half-lives. However, a key limitation in the use of antibodies to treat an established HIV-1 infection is the rapid emergence of fully resistant viruses. Entry inhibitors of similar breadths and potencies can differ in the ease with which viral escape variants arise. Here we show that HIV-1 escape from the potent and exceptionally broad entry inhibitor eCD4-Ig is more difficult than that from CD4-Ig or the bNAb NIH45-46. Indeed, full escape was not observed under conditions under which escape from CD4-Ig or NIH45-46 was readily detected. Moreover, viruses that were partially resistant to eCD4-Ig were markedly less infective and more sensitive to antibodies in the serum of an infected person. These data suggest that eCD4-Ig will be more difficult to escape and that even partial escape will likely extract a high fitness cost.

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Indication	Highest Phase	Country/Location	Organization	Date
HIV Infections	Preclinical	US	The Rockefeller University	02 Dec 2011
HIV Infections	Preclinical	US	California Institute of Technology	02 Dec 2011

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