Infection with the human immunodeficiency virus 1 (HIV-1) is now a manageable condition, rather than a death sentence, as it once was. This is largely due to the development and commercialization of antiretroviral therapy (ART). In 2010 the annual cost of ART was US$ 23,000, an increase in absolute terms compared to 2006. This leads to the estimated cost of US$ 380,000 over the course of an individual’s lifetime. According to the US Centers for Disease Control and Prevention (CDC) the HIV diagnosis rate in the USA has been fairly constant over recent years with approximately 35,000 cases diagnosed per year in men and 10,000 per year in women. Now more than ever, more effective, ideally one-off treatments, with a reduced price tag relative to ART are needed. Therapeutic vaccines are one possibility.
María Angeles Muñoz-Fernández of the Spanish HIV HGM BioBank, Hospital General Universitario Gregorio Marañón, Madrid, and colleagues used nanoparticles to deliver HIV gag-derived peptides to antigen presenting cells (APCs), namely human dendritic cells (DCs), in an attempt to elicit a therapeutic response. DCs were derived from peripheral blood mononuclear cells (PBMCs) obtained from healthy donors, and modified by exposure to peptides, which following testing and validation could be administered to patients, creating a potential form of allogeneic cell therapy for HIV. The preclinical testing results were published in the journal called Pharmaceutics.
Two different nanoparticles were tested, one a dendrimer, the other a basket-shaped polyanionic amphiphilic β-cyclodextrin core called AMC6. For delivery of peptide into DCs, AMC6 performed better than peptide alone or peptide plus dendrimer following two hours of incubation. However, by 24 hours incubation the dendrimer performed similarly to AMC6, both of which were better than peptide alone.
As judged by CD80, CD83, and CD86 expression dendrimer, AMC6 and gag peptide did not significantly induce DC maturation, which is required for antigen presentation to T-cells. The anti-PD-1 immune checkpoint antibody Nivolumab was required to induce proliferation of the cells in response to loading with gag peptide, which may indicate maturation.
Transfected DCs did not, however, activate T and B cells. Transfection and coculture did stimulate the release of TNF-α and IL-2. Transfection with dendrimer alone also induced the release of these cytokines, but not the peptide on its own. It is therefore not clear whether this observation is a side effect of the dendrimer nanoparticle, which is a limitation of the study.
“A better knowledge of the interactions of the polycationic carriers with the molecular mechanisms involved in antigen presentation from uptake into DC to HLA-socket presentation would help to design much more efficient nanocompounds that would facilitate efficient antigen presentation and, accordingly, an efficient immune response,” concluded the authors.
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