Journal
MBIO
Volume 11, Issue 5, Pages -Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/mBio.00903-20
Keywords
HIV; nanoparticle; autophagy; neutralization; CD4(+) T cell; macrophage; phospholipase D; human immunodeficiency virus; neutralizing antibodies; phospholipase
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Funding
- National Institute of Neurological Disorders and Stroke of the NIH [R01 NS084912, R01 NS104015]
- Defense Threat Reduction Agency Joint Science and Technology Office for Chemical and Biological Defense [HDTRA1-14-1-0064]
- International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) Network
- National Institute of Allergy and Infectious Diseases (NIAID) of the NIH [UM1AI068632, UM1AI068616, UM1AI106716]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
- National Institute of Mental Health (NIMH)
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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 mu g ml(-1) (range, 72 to 8,570 mu g 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.
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