ABSTRACT
Orsolya Lorincz, PhD, and Julianna Lisziewicz, PhD eMMUNITY Inc., Bethesda, Maryland, USA Keywords: DNA-nanomedicine vaccine, immunotherapy, Langerhans cell-targeted DNA delivery, HIV eradication, polyethylenimine (PEI), DermaVir, therapeutic vaccine, plasmid DNA, intracellular trafficking, gene delivery, polyplex
load to undetectable levels for years, has not provided a cure to the disease. Patients on optimal HAART have 12 years shorter life expectancy than HIV-negative people [3-4]. In addition, increased AIDS-related and non-AIDS-related morbidity and mortality has been described in a significant proportion of individuals on optimal HAART due to the lack of normalization of their CD4+ T cell counts [5]. Optimal HAART also failed to decrease the viral reservoirs, especially in the gut mucosa, where the residual low-level viral replication may be the cause of persistent immune activation that facilitates the progression to AIDS and death [6]. One barrier of cure is the stable latent reservoirs of HIV-infected resting memory T cells that are able to produce HIV after cellular activation. HIV producing cells in the reservoirs that are not eliminated by ARVs would be susceptible to immune clearance, but long-term optimal HAART diminishes HIV-specific T cell responses [7]. Therefore, the immune system of successfully treated HIV-infected people is unprepared to kill infected cells, decrease viral reservoirs, and control the virus replication.Immunotherapy improves the reactivity of the immune system to guard the body from internal and external intruders as infections (e.g., HIV), allergens, and malignancies. The innate arm, composed of the phagocytic cells, circulating macrophages and the complement system, is responsible for the immediate defense. Later, the adaptive arm responds in a highly specific manner against molecular determinants of the intruders. Nanoparticles (NPs) made from different types of materials, having various sizes, shapes and surface charges activate the innate and adaptive immune system [8-10]. Therefore, nanotechnology is suitable for improving efficacy and increasing specificity of products indicated as vaccine and immunotherapy. The immunotherapeutic efficacy of NPs is achieved by specific activation (e.g., cancer, infectious diseases) or suppression (e.g., allergy, autoimmune diseases) of the immune system. Efficacy of immune responses is improved by targeted delivery of antigens to professional immune cells specialized for either stimulation or suppression of immune reactivity. This is achieved by using NPs as antigen (virus-like particles; VLPs), NP formulation of soluble antigens (DNA, peptides, proteins) and new administration routes (transdermal, nasal, intratracheal). Increasing the specificity of immunotherapy is achieved by personalization of the antigens in the NP taking into account the
diversity of the disease (e.g., tumor cells) and genomic background of the individual (e.g., HLA type).More than 30 ARVs and drug combinations are currently available to achieve long-term suppression of HIV RNA to <50 copies/mL and control HIV disease. The failure to develop a vaccine for HIV has recently changed the treatment strategy from the long-term suppression of viral load to the cure of the disease. Approaches for HAART intensification with additional potent drugs also failed to provide a cure or any additional treatment benefits [4, 11-15]. Consequently, it became evident that alternatives to vaccines and to ARVs are required to eradicate HIV disease. The first HIV cure approach is eradication of the virus. Eradication was demonstrated in one HIV+ patient after bone marrow transplantation with donor cells resistant to HIV infection [16]. Alternative approach for HIV cure is the induction of a long-term remission, similarly to the cure of Hepatitis C infection. We have previously described the remission of an HIV+ patient (Berlin patient, 1999) whose immune system was activated to kill infected cells by short interruptions of HAART [17]. This work has led to the identification of “elite controllers” representing a model for remission. Elite controllers have large numbers of cells containing replication competent HIV and their viral load is suppressed by the cellular arm of the immune system [18-19]. Recently, Siliciano and his team have demonstrated that boosting of HIV-specific T cell responses (CTL) prior to reactivating latent HIV will be essential for eradication of the virus [20]. These results suggest that HIVspecific immunotherapy is essential for both remission and eradication of HIV, consequently for the cure of HIV.
