Highly active antiretroviral therapy (HAART) can powerfully suppress HIV replication but does not clear virus from infected individuals. Various reservoirs of replication-competent HIV have been identified that may contribute to this persistence, the most prominent and well-characterized of these being latently infected CD4+ T-cells. Several attempts have been made to clear the latent HIV reservoir but these have not been successful in eliminating all latently infected cells or in preventing virus rebound upon cessation of therapy 
. Hence, complete eradication of HIV from infected individuals will probably require further improvements in latency activators and the development of a more optimized virus purging strategy.
One focus of latency research is the identification of factors that can activate HIV from latency and have the potential to be used in a clinical setting. Such factors have included histone deacetylase inhibitors, agonistic anti-CD3 antibodies, and cytokines such as interleukin (IL)-2 and IL-7 
. A promising lead in this context is the protein kinase C (PKC) activator bryostatin, which is part of the marine macrolide class of molecules. Bryostatin has been demonstrated to activate latent HIV at nanomolar concentrations in vitro 
. This molecule is believed to induce expression of HIV by activating NFκB 
, which is required for optimal transcription of viral mRNA from the HIV long terminal repeat promoter (LTR). Although bryostatin-1 has been tested in clinical trials for its anti-cancer properties 
there are no published studies using this class of compounds in clinical HIV purging strategies. Bryostatin-2 was used in our studies and has slightly different properties than the parent compound bryostatin-1, although both can activate PKC at nanomolar concentrations 
A second opportunity for improving latency activation is the development of enhanced delivery vehicles for existing molecules. Nanoparticle delivery systems possess several advantages over more traditional drug delivery methods. For example, nanoparticles can be used to modify drug solubility and bioavailability or to allow multiple drugs to be incorporated into the same delivery vehicle. Nanoparticles can also be targeted to particular cell or tissue types, providing specificity that may not normally be a characteristic of the incorporated drug. Numerous nanotechnological systems have been approved for clinical use, including over 20 products for the delivery of various classes of drugs 
. Liposomes represent one type of nanoparticle that has been a focus of basic research for over 40 years 
. In the past a major drawback in the clinical use of liposomes was their rapid clearance due to uptake by mononuclear phagocytic cells. Recent improvements in liposomal formulations have reduced this uptake by coating the surface of particles with polymers such as polyethylene glycol, thereby increasing the blood circulation time 
. These optimized liposomes have led to more clinically applicable delivery systems as evidenced by the over 10 FDA approved liposomal drug formulations, with several others in clinical trials 
. One example of this is doxorubicin incorporated into liposomes, known as Doxil. In 1995 this became the first liposome based therapeutic to be approved by the FDA. Doxil was initially used for treating HIV-related Kaposi's sarcoma and was later approved for ovarian and other types of cancers. Advantages of Doxil over free drug properties included enhanced biodistribution and prolonged half life in blood circulation 
. Our particular study aimed to test the efficacy of a liposomal formulation of the HIV latency activator bryostatin-2 and to test whether this nanoparticle delivery platform can enhance the ability to activate latent HIV.
Our current work is a proof-of-concept study demonstrating that HIV latency activators can be packaged into nanoparticles, either alone or in conjunction with an antiretroviral drug. Bryostatin-2 loaded lipid nanoparticles (LNP-Bry) produced in this way have enhanced activity compared with drug alone, and can be further modified by adding targeting antibodies to make them more selective for CD4+ T cells. This is the first demonstration of the use of nanotechnology in HIV latency activation and may provide a direction for more effective therapy in future purging strategies.