Adenovirus-Vectored Broadly Neutralizing Antibodies Directed Against gp120 Prevent Human Immunodeficiency Virus Type 1 Acquisition in Humanized Mice

Liu, Shan; Jackson, Andrew; Beloor, Jagadish; Kumar, Priti; Sutton, Richard E.

doi:10.1089/hum.2014.146

Cited by 6 publications

(3 citation statements)

References 54 publications

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“…Western blotting. Western blotting of bNAbs in supernatants of transfected cells was performed as described previously (41). Culture supernatants were mixed 1:1 with Laemmli sample buffer (Bio-Rad, Hercules, CA), supplemented with 2-mercaptoethanol, and heated at 100°C for 10 min.…”

Section: Discussionmentioning

confidence: 99%

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Neutralization Synergy between HIV-1 Attachment Inhibitor Fostemsavir and Anti-CD4 Binding Site Broadly Neutralizing Antibodies against HIV

Zhang

Chapman

Ülçay

et al. 2019

J Virol

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Attachment inhibitor (AI) BMS-626529 (fostemsavir) represents a novel class of antiretrovirals which target human immunodeficiency virus type 1 (HIV-1) gp120 and block CD4-induced conformational changes required for viral entry. It is now in phase III clinical trials and is expected to be approved by the U.S. Food and Drug Administration (FDA) in the near future. Although fostemsavir is very potent against HIV in vitro and in vivo, a number of resistant mutants have already been identified. Broadly neutralizing HIV antibodies (bNAbs) can potently inhibit a wide range of HIV-1 strains by binding to viral Env and are very promising candidates for HIV-1 prevention and therapy. Since both target viral Env to block viral entry, we decided to investigate the relationship between these two inhibitors. Our data show that Env mutants resistant to BMS-626529 retained susceptibility to bNAbs. A single treatment of bNAb NIH45-46G54W completely inhibited the replication of these escape mutants. Remarkable synergy was observed between BMS-626529 and CD4 binding site (CD4bs)-targeting bNAbs in neutralizing HIV-1 strains at low concentrations. This synergistic effect was enhanced against virus harboring mutations conferring resistance to BMS-626529. The mechanistic basis of the observed synergy is likely enhanced inhibition of CD4 binding to the HIV-1 Env trimer by the combination of BMS-626529 and CD4bs-targeting bNAbs. This work highlights the potential for positive interplay between small- and large-molecule therapeutics against HIV entry, which may prove useful as these agents enter clinical use. IMPORTANCE As the worldwide HIV pandemic continues, there is a continued need for novel drugs and therapies. A new class of drug, the attachment inhibitors, will soon be approved for the treatment of HIV. Broadly neutralizing antibodies are also promising candidates for HIV prevention and therapy. We investigated how this drug might work with these exciting antibodies that are very potent in blocking HIV infection of cells. These antibodies worked against virus known to be resistant to the new drug. In addition, a specific type of antibody worked really well with the new drug in blocking virus infection of cells. This work has implications for both the new drug and the antibodies that are poised to be used against HIV.

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Section: Discussionmentioning

confidence: 99%

“…Viruses and reagents. HIV-1 Env pseudotyped viruses were produced as described previously (41). Replication-competent HIV-1 NL43-ΔR1 wild-type and mutant viruses were produced by transfecting HEK293T cells with full-length HIV-1 NL43-ΔR1 plasmid or Env mutants.…”

Section: Methodsmentioning

confidence: 99%

Neutralization Synergy between HIV-1 Attachment Inhibitor Fostemsavir and Anti-CD4 Binding Site Broadly Neutralizing Antibodies against HIV

Zhang

Chapman

Ülçay

et al. 2019

J Virol

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“…Gene transfer strategies may help inducing a stable expression of nAbs. HIV-1 in vivo challenge experiments showed a highly attenuated viral replication and protection against deletion in HuMice models expressing the humanized Ab [81][82][83][84][85]. In the studies of Balazs et al, a single nAb was vectorized in an AAV vector and injected intramuscularly into NSG-BLT HuMice.…”

Section: Targeting Mature Virions By Passive Immunization With Gene Tmentioning

confidence: 99%

Lessons From HIV-1 Gene Therapy in Humanized Mice: Is Targeting Viral Entry the Road to Success?

Petit

Marodon²

2016

CGT

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Immunodeficient mice reconstituted with human CD4(+) T cells, which can be achieved either by transfer of mature cells or immature progenitors, represent the only animal model to study HIV-1 infection of human lymphocytes in vivo. However, the immunocompromised status of most of these models currently rule out their use for vaccine studies. Nevertheless, the model might be ideally suited for HIV-1 gene therapy studies since eliciting an efficient anti-viral immune response is not the primary end-point. Rather, HIV-1 gene therapy should protect CD4(+) T cells from HIV-1- induced deletion and/or reduced viral replication. Here, we describe recent advancements in the field of HIV-1 gene therapy, focusing on tools and targets validated in various models of humanized mice. From the analysis of this literature, it appears that strategies targeting viral entry, by means of neutralizing antibodies or fusion inhibitors, are the most promising so far. Indeed, strategies targeting viral entry have moved to the clinic with encouraging results. Thus, humanized mice should be considered as the prime model to devise the safer and most effective HIV-1 gene therapy strategy.

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Viral Vectors, Engineered Cells and the CRISPR Revolution

DiCarlo

Deeconda

Tsang

2017

Advances in Experimental Medicine and Biology

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Over the past few decades the ability to edit human cells has revolutionized modern biology and medicine. With advances in genome editing methodologies, gene delivery and cell-based therapeutics targeted at treatment of genetic disease have become a reality that will become more and more essential in clinical practice. Modifying specific mutations in eukaryotic cells using CRISPR-Cas systems derived from prokaryotic immune systems has allowed for precision in correcting various disease mutations. Furthermore, delivery of genetic payloads by employing viral tropism has become a crucial and effective mechanism for delivering genes and gene editing systems into cells. Lastly, cells modified ex vivo have tremendous potential and have shown effective in studying and treating a myriad of diseases. This chapter seeks to highlight and review important progress in the realm of the editing of human cells using CRISPR-Cas systems, the use of viruses as vectors for gene therapy, and the application of engineered cells to study and treat disease.

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Adenovirus-Vectored Broadly Neutralizing Antibodies Directed Against gp120 Prevent Human Immunodeficiency Virus Type 1 Acquisition in Humanized Mice

Cited by 6 publications

References 54 publications

Neutralization Synergy between HIV-1 Attachment Inhibitor Fostemsavir and Anti-CD4 Binding Site Broadly Neutralizing Antibodies against HIV

Neutralization Synergy between HIV-1 Attachment Inhibitor Fostemsavir and Anti-CD4 Binding Site Broadly Neutralizing Antibodies against HIV

Lessons From HIV-1 Gene Therapy in Humanized Mice: Is Targeting Viral Entry the Road to Success?

Viral Vectors, Engineered Cells and the CRISPR Revolution

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