CD4 ⁺ T Cell-Mimicking Nanoparticles Broadly Neutralize HIV-1 and Suppress Viral Replication through Autophagy

Abstract

Therapeutic strategies that provide effective and broad‐spectrum neutralization against HIV-1 infection are highly desirable. Here, we investigate the potential of nanoengineered CD4+ T cell membrane-coated nanoparticles (TNP) to neutralize a broad range of HIV-1 strains. TNP displayed outstanding neutralizing breadth and potency; they neutralized all 125 HIV-1-pseudotyped viruses tested, including global subtypes/recombinant forms, and transmitted/founder viruses, with a geometric mean 80% inhibitory concentration (IC80) of 819 μg ml−1 (range, 72 to 8,570 μg ml−1). TNP also selectively bound to and induced autophagy in HIV-1-infected CD4+ T cells and macrophages, while having no effect on uninfected cells. This TNP-mediated autophagy inhibited viral release and reduced cell-associated HIV-1 in a dose- and phospholipase D1-dependent manner. Genetic or pharmacological inhibition of autophagy ablated this effect. Thus, we can use TNP as therapeutic agents to neutralize cell-free HIV-1 and to target HIV-1 gp120-expressing cells to decrease the HIV-1 reservoir. IMPORTANCE HIV-1 is a major global health challenge. The development of an effective vaccine and/or a therapeutic cure is a top priority. The creation of vaccines that focus an antibody response toward a particular epitope of a protein has shown promise, but the genetic diversity of HIV-1 hinders this progress. Here we developed an approach using nanoengineered CD4+ T cell membrane-coated nanoparticles (TNP). Not only do TNP effectively neutralize all strains of HIV-1, but they also selectively bind to infected cells and decrease the release of HIV-1 particles through an autophagy-dependent mechanism with no drug-induced off-target or cytotoxic effects on bystander cells.

Nanotechnology for virus treatment

“…It has been demonstrated that T cell membrane-coated nanoparticles (TNPs) can bind to HIV and neutralize its infectivity ( Fig. 11 ) [ 328 , 329 ]. The formulation took advantage of the CD4 receptor displayed on the T cell surface that HIV uses for docking.…”

Nanoplatforms for Sepsis Management: Rapid Detection/Warning, Pathogen Elimination and Restoring Immune Homeostasis

“…Membrane coating derived from immune cells usually exhibits advantages of targeting inflammatory microenvironment, cytokines/PAMPs neutralization, blocking infectious events, and so on. Zhang and coworkers adopted CD4 + T cells as membrane donor to coat PLGA NPs, and obtained a nanoengineered CD4 + T cell membrane-coated NP (TNP) with broad-panel activity to 125 HIV-1-pseudotyped viruses [ 113 ]. As a therapeutic agent, TNP can neutralize cell-free HIV-1 and induce autophagy of HIV-1 gp120-expressing cells, thereby doubly hindering the HIV-1 reservoir [ 113 ].…”

“…Zhang and coworkers adopted CD4 + T cells as membrane donor to coat PLGA NPs, and obtained a nanoengineered CD4 + T cell membrane-coated NP (TNP) with broad-panel activity to 125 HIV-1-pseudotyped viruses [ 113 ]. As a therapeutic agent, TNP can neutralize cell-free HIV-1 and induce autophagy of HIV-1 gp120-expressing cells, thereby doubly hindering the HIV-1 reservoir [ 113 ]. Compared with naked NPs, NPs coated with cancer cell-derived membrane show lower distribution in normal tissues and improved accumulation in tumor tissues and hence have been widely used as carriers of imaging agents and/or therapeutic drugs for cancer theranostics [ 105 ].…”

Biomimetic Nanomaterial Strategies for Virus Targeting: Antiviral Therapies and Vaccines

“…[ 85 ] A follow‐up study confirmed that the T cell membrane‐coated nanoparticles could inhibit a wide range of HIV‐1 strains and surprisingly induced autophagy of HIV‐infected cells to suppress viral genome replication but had no effect on uninfected cells. [ 86 ] Recently, cell membrane‐coated nanoparticles have also been developed to inhibit SARS‐CoV‐2 infection of Vero E6 cells in vitro (Figure 5d). [ 84 ] Nanoparticles coated with extracts from human lung epithelial type II or macrophage cells inhibited SARS‐CoV‐2 in a dose‐dependent fashion while nanoparticles coated with extracts from red blood cells were inactive (Figure 5e).…”