Nat Rev Mol Cell Biol 9:1004C1010

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Nat Rev Mol Cell Biol 9:1004C1010. N-linked glycan armor, which covers almost the entire envelope protein (Env) (6, 7). An alternative is to use bNAbs in passive immunization, with several studies demonstrating the ability of bNAbs to confer protection from contamination, reducing both plasma viremia and the pool of latently infected cells through the recognition of HIV Env around the host cell membrane, potentially facilitating fragment crystallizable (Fc)-mediated clearance (4, 8,C10). However, resistant virus Acetanilide isolates appeared either before or after passive bNAb therapy, limiting any putative therapeutic effect (11, 12). Moreover, VRC-PG05, the only donor-derived antibody isolated to date that binds to the highly glycosylated silent face of gp120, failed to neutralize 73% of HIV strains tested and had a relatively high mean IC50 of 800?g ml?1, leaving uncertain the potential usefulness of this epitope for vaccine design, therapy, or prevention (13). More recently, tandem Acetanilide trispecific and bispecific broadly neutralizing antibodies, such as BiIA-SG, have shown more promise (5). The absence of curative treatments or a potential vaccine underscores the need for innovative therapeutic approaches. The development of nanoengineering has given rise to a new avenue of HIV treatment and prevention research. Nanoparticles are being assessed as vehicles for antiviral drugs to improve drug tolerability, circulation half\life, and efficacy and as carriers for delivery to the central nervous system (14,C19). They are also being evaluated for the delivery of small interfering RNAs (siRNAs) to silence gene expression in CD4+ T cells, macrophages, and dendritic cells, as well as HIV itself (reviewed in reference 20). Nanoparticle\based vaccine strategies may also enhance both vaccine safety and anti\HIV immunogenicity through improved immune targeting and combined presentation of an immunogen and adjuvant (17, 21, 22). Lastly, nanoparticles can also directly interfere with and inhibit viral replication through multivalent presentation of small molecules that block viral assembly processes (17, 23) while also selectively killing latently HIV infected resting memory CD4+ T cells (24). As therapeutic nanoparticles are gaining traction for potential HIV treatment and prevention, cell membrane-coated nanoparticles, made by wrapping plasma membranes of natural cells onto synthetic nanoparticle cores, are emerging as a biomimetic platform to treat various diseases (25,C32). This unique biomimicry led us to assess this technology as a potential HIV treatment. Synthetic nanoparticles conjugated with receptor proteins of host cells to target bacteria or viruses for neutralization conventionally require protein identification and labor-intensive synthesis. Acetanilide The fabrication Rabbit Polyclonal to Fibrillin-1 of Acetanilide these T cell membrane-coated nanoparticles (TNP) bypasses these issues by using natural cell membranes as building materials. Specifically, we fused the plasma membranes of uninfected CD4+ T cells onto poly(lactic\co\glycolic acid) (PLGA) cores, and the resulting TNP mimicked the parent CD4+ T cells. We demonstrated previously that these TNP neutralize both R5 and X4 laboratory strains of HIV while also inhibiting gp120-induced apoptosis of bystander uninfected cells (33). In this study, we examined the neutralization breadth and potency of these TNP by using a global panel of HIV isolates. We also investigated the potential application of TNP to inhibit HIV replication and to induce cell death in macrophages and CD4+ T cells infected with HIV. RESULTS TNP broadly neutralize a global panel of Env-pseudotyped HIV. To assess the breadth and potency of TNP to neutralize HIV, we used three standardized panels of viruses: a global multisubtype 109-virus panel that includes transmitted/founder viruses and early/acute infections (34), the global 12-virus panel (35), and the reduced cross-subtype 5-virus panel (36). There was an overlap of viruses among the panels, such that there were 125 unique HIV pseudoviruses tested (Fig.?1). We validated the neutralization protocol using the bNAbs VRC01 and VRC03 against the global 12-virus panel. Acetanilide Against this panel, we observe that the neutralization potencies (geomean 50% inhibitory concentration [IC50]/IC80) are approximately 0.167/0.871 and 0.325/0.42?g ml?1, respectively, with neutralization breadths of 91 and 50%, respectively, using the IC50 in line with previously published observations (37, 38) (Fig.?1A). Conversely, we observed a TNP neutralizing breadth of 100% against the combined 125-virus panel (Fig.?1B). Neutralization potency was robust against all 125 viruses (geometric mean IC50/IC80, 130.2/819.2test after Welch’s one-way analysis of variance. For each pair of means, a plus sign indicates a significant difference (test after Welch’s one-way analysis of variance. For each pair of means, a plus sign indicates a significant difference (RNA interference (RNAi) and RNAi were effective in silencing their respective genes in both macrophages (Fig.?4A and.