Project Summary/Abstract Highly active combination antiretroviral therapy (cART) has revolutionized the treatment of HIV/AIDS. However, cART must be maintained for life, as HIV-1 continues to replicate in anatomical and cellular reservoirs for the lifetime of the individuals receiving cART. Cellular and anatomical reservoirs of HIV-1 represent major impediments to eradication. Lymphoid tissues (i.e. lymph nodes (LN), spleen, gut associated lymphoid tissues (GALT), among others) harbor most of the body’s CD4+ T cells. Replication competent HIV-1 persists in reservoirs throughout the body despite seemingly effective suppressive cART, with viral recrudescence inevitably occurring when cART is halted. HIV-1 cure research aims at removal of HIV-1 provirus from latent cells and targeting cARVs to HIV-1 reservoirs. The main challenge in all cure strategies lies in inefficient delivery of the therapeutic agents to viral reservoirs. Many cART drugs and latency reversing agents (LRAs) differ in solubility, bioavailability, and toxicity which make dosing and formulation very challenging to deliver physicochemically diverse cure agents simultaneously. Nanotechnology has emerged as a promising approach for HIV cure due to several key attributes: ability to encapsulate diverse agents, increased circulation or tissue retention time, sustained drug release, enhanced solubility and bioavailability, reduced toxicity or side effects, and enhanced drug potency. Some nanocarriers can also be modified to target specific cells or tissues. We intend to harness the promising properties of nanoparticles to address problems in current novel strategies toward HIV cure (LRAs combination for reactivating latently infected cells and administration of cARVs to HIV reservoirs). HIV persists in lymph nodes during aggressive drug treatment. Targeting nanoparticles to CD4+ T cells in the lymph node may provide site-specific delivery of drugs (cARVs and LRAs). The spleen contains 25% of the body’s lymphocytes. Studies have shown that the spleen has a very high blood flow; it is one of the most perfused organs in the body. We hypothesize the development of biodegradable polymeric nanotechnological platforms using (A) CD4 binding peptide (CKGIRIGPGRAVYAAE) and separately (B) CD4 binding monoclonal antibody (ibalizumab: FDA approved) which targets the extracellular CD4 domain of CD4+ Tcells) as targeting moieties for delivery of targeted nanoparticle formulations (cARVs: cabotegravir and rilpivirine and LRAs: vorinostat and chaetocin) to lymph nodes. Further, we hypothesize the development of biodegradable polymeric nanotechnological platforms using (C) monoclonal antibody rituximab, which targets splenic antigens (i.e., CD20 antigens on B cells and splenocytes) in the spleen and (D) CD4 binding monoclonal antibody (ibalizumab) as targeting moieties for targeting nanoparticle to the spleen (to target cARVs (cabotegravir and rilpivirine) and LRAs (vorinostat and chaetocin) to the spleen...