Emerging Nanotechnology Approaches for HIV/AIDS Treatment and Prevention

Tewodros Mamo; E Ashley Moseman; Nagesh Kolishetti; Carolina Salvador-Morales; Jinjun Shi; Daniel R Kuritzkes; Robert Langer; Ulrich von Andrian; Omid C Farokhzad

Disclosures

Nanomedicine. 2010;5(2):269-285. 

In This Article

Immunotherapy for HIV/AIDS

The various treatment approaches described above focus on treating HIV/AIDS by directly targeting HIV at the level of the host cell or the virus itself. An alternative approach is immunotherapy aimed at modulating the immune response against HIV. CD8+ cytotoxic T-cell responses to acute HIV infection appear to be relatively normal, while neutralizing antibody production by B cells is delayed or even absent.[83] Over time, viral mutation leads to loss of the CD8+ T cell cytotoxic function. However, the major effect of an infection by HIV is the loss of CD4+ T cells. These 'helper' T cells are responsible for a number of supportive functions for other immune populations and their loss leads to profound immunosuppression, manifested by the presence of dysfunctional B-cells, natural killer cells and the macrophages in chronically HIV-infected patients.[84] In recent years, there has been increasing interest in the therapeutic use of immune responses to restore the regular function of the immune system as an effective way to treat HIV/AIDS.[85–87] There has been increasing evidence that the immune system is capable of controlling HIV in certain individuals.[87] Hence, strategies to rebuild or allow the reconstitution of immune function could be one of the best approaches for effective treatment.

Immunotherapy is a treatment approach involving the use of immunomodulatory agents to modulate the immune response against a disease. Similar to vaccines, it is based on immunization of individuals with various immunologic formulations; however, the purpose is to treat HIV-infected patients as opposed to protect healthy individuals (preventive vaccines will be discussed in an upcoming section). The various immunotherapy approaches for HIV/AIDS could be based on delivering cytokines (such as IL-2, IL-7 and IL-15) or antigens.[84,85] The development of cellular immunity, and to a large degree humoral immunity, requires antigen-presenting cells (APCs) to process and present antigens to CD4+ and CD8+ T cells. Dendritic cells (DCs) are the quintessential professional APCs responsible for initiating and orchestrating the development of cellular and humoral (antibody) immunity.[88,89] Protein/peptide antigens or DNA immunogens (which lead to endogenous protein expression) could then be delivered through viral vectors to endogenous or ex vivo-generated DCs.

Since the first immunotherapeutic clinical trial for HIV/AIDS in 1983, various trials have been carried out and are still ongoing.[90–93] Unfortunately, despite the preclinical studies that showed enhanced immune responses, most of the clinical studies have consistently failed to provide clinical improvements for patients.[90] Most of these clinical trials have been based on the delivery of the immunogenic factors through viruses or ex vivo DCs. As discussed under the gene therapy section above, delivery through viral vectors involves various risks. In addition, ex vivo generation of autologous DCs is a difficult therapeutic strategy to utilize widely as it involves a very labor-intensive procedure with high costs and multiple procedures for product control at different sites.[94] Hence, new approaches using targeted nanotechnology platforms for delivery of immunomodulatory factors and targeting antigens to DC surface receptors in vivo provide immense opportunities.[87] The rationale for nanotechnology-based DC targeting and vaccine delivery will be discussed in more detail in the upcoming section. Here, the most important advances of nanotechnology-based immunotherapy will be described.

Various polymeric systems have been explored for in vivo targeting of DCs and delivery of small molecules, proteins or DNAs showing potential for immunotherapy. Poly(ethylene glycol) (PEG) stabilized poly(propylene sulfide) polymer nanoparticles accumulated in DCs in lymph nodes.[95] Following nanoparticle injection, DCs containing nanoparticles accumulated in lymph nodes, peaking at 4 days with 40–50% of DCs and other APCs having internalized nanoparticles. In a separate study, cross-linked polymer nanoparticles with a pH-responsive core and hydrophilic charged shell were used for delivery of proteins and small molecules to DCs.[96] The cross-linked polymers were composed of 2-diethylamino ethyl methacrylate, PEG dimethacrylate and 2-aminoethyl methacrylate. Fluorescence microscopy showed delivery of the model protein antigen ovalbumin to the cytosol of bone marrow-derived DCs, where antigens can potentially be processed for cross-presentation to CD8+ T cells, in addition to more classical exogenous antigen presentation to CD4+ T cells.

In another study, nanoparticles of the copolymer poly(D,L-lacticide-co-glycolide) (PLGA) showed efficient delivery of antigens to murine bone marrow-derived DCs in vitro, suggesting their potential use in immunotherapy.[97] More recently, a very interesting work showed that HIV p24 protein adsorbed on the surface of surfactant-free anionic poly(D,L-lactide) (PLA) nanoparticles were efficiently taken-up by mouse DCs, inducing DC maturation.[98] The p24-nanoparticles induced enhanced cellular and mucosal immune responses in mice. Although this targeting is seen in ex vivo-generated DCs and not in vivo DCs, the efficient delivery of the antigen to DCs through the nanoparticles is an important demonstration that may eventually be applied to in vivo DC targeting.

The most clinically advanced application of nanotechnology for immunotherapy of HIV/AIDS is the DermaVir patch that has reached Phase II clinical trials.[99] DermaVir is a targeted nanoparticle system based on polyethyleimine mannose (PEIm), glucose and HIV antigen coding DNA plasmid formulated into nanoparticles (~100 nm) and administered under a patch after a skin preparation. The nanoparticles are delivered to epidermal Langerhans cells that trap the nanoparticles and mature to become highly immunogenic on their way to the lymph nodes. Mature DCs containing the nanoparticles present antigens to T cells inducing cellular immunity. Preclinical studies and Phase I clinical trials showed safety and tolerability of the DermaVir patch, which led the progression to Phase II trials. This is the first nanotechnology-based immunotherapy for HIV/AIDS that has reached the clinic and encourages further work in this area. A selection of nanotechnology platforms used for antiretroviral drug delivery, gene therapy and immunotherapy are listed in Table 1.

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