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Principal Investigator: Josiane Fofana
Organization: BOSTON UNIVERSITY MEDICAL CAMPUS
Fiscal Year: 2022
Award: $46,752
Funding agency: National Institute of Allergy and Infectious Diseases
PROJECT SUMMARY/ABSTRACT
HIV remains a global threat despite the tremendous progress of combinatorial antiretroviral therapy (cART).
Chronic inflammation and immune activation support an increased risk of non-AIDS co-morbidities in cART-
treated HIV patients. This condition is attributed to various factors including antiretroviral (ARV) toxicity and
viral persistence in secondary lymphoid tissues (SLTs) which has been linked to low ARV penetration in these
reservoir sites. Furthermore, uptake of daily antiretrovirals (ARVs) remains a burden resulting in poor
adherence that can lead to viral rebound from the SLTS. In this project, we propose to develop a long-acting
“stealth” nanoformulation composed of lipid wrapped poly-lactic acid nanoparticles (GM3-PLA-NPs) loaded
with a non-nucleoside reverse transcriptase inhibitor, Rilpivirine (RPV) and integrase inhibitor, Cabotegravir
(CAB). These GM3-PLA-NPs have innovative targeting and design features that will increase drug entry and
retention in SLTs, in addition to modulating inflammatory responses. Indeed, the membrane incorporated
monosialo di-hexosylganglioside (GM3) enables specific binding to the sialic acid lectin receptor CD169 on
myeloid cells (macrophages and dendritic cells), leading to the formation of non-acidic membrane
invaginations which can prevent NP degradation, and lead to long-term establishment of cellular drug depots.
These NP collecting compartments (NPCCs) are identical to the previously defined virus containing
compartments (VCCs) formed upon capture of HIV-1 by CD169. Since VCCs are also involved in myeloid cell-
mediated HIV transmission to CD4+ T cells (trans-infection) through the virological synapse, I hypothesize that
NPCCs could potentially promote sustained ARV release to bystander T cells through macrophage – T cell
synaptic junctions. Our preliminary data have demonstrated that these GM3-PLA-NPs are successfully
preserved in NPCCs of CD169+ macrophages over time which extended anti-viral potency in these cells for a
month in vitro. Subsequently, sustained viral inhibition in bystander Jurkat T cells was observed upon co-
culture with NP-exposed CD169+ macrophages. Additionally, our findings suggest that the GM3 lipid coating
confers “stealth” properties to suppress non-specific immune activation induced by loaded ARVs and
nanoparticle core. Thus, in aim 1, we will investigate the extracellular drug release mechanism from CD169+
macrophages to CD4+ T cells. In aim 2, we will assess the long-term toxicity and stealth mechanism of GM3-
PLA-NPs. Finally, we will confirm these results in vivo by assessing the spatial distribution and stealth
phenotype of GM3-PLA-NPs in SLTs in aim 3. These studies will elucidate a new approach for safe and
effective delivery of long-acting therapeutics to SLTs which could be beneficial for HIV prevention and
treatment as well as other diseases such as metastatic cancer.
Terms: <AIDS Virus><AIDS prevention><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Adherence><Anti-Retroviral Agents><Antiretroviral Agents><Binding><Biodistribution><Biotin><Blood Plasma><Blood monocyte><Body Tissues><CD4 Cells><CD4 Positive T Lymphocytes><CD4 T cells><CD4 helper T cell><CD4 lymphocyte><CD4+ T-Lymphocyte><CD4-Positive Lymphocytes><Cell Body><Cell Survival><Cell Viability><Cell membrane><Cell surface><Cells><Chronic><Co-culture><Cocultivation><Coculture><Coculture Techniques><Coloring Agents><Cytokines and Inflammatory Response><Cytoplasmic Membrane><Data><Dendritic Cells><Development><Disease><Disorder><Disseminated Malignant Neoplasm><Dose><Drugs><Dyes><Exposure to><Failure><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><G(M3) Ganglioside><Ganglioside GM3><Goals><HIV><HIV Prevention><HIV therapy><HIV-1><HIV-I><HIV/AIDS prevention><HIV1><Hematoside><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human immunodeficiency virus 1><II3NeuAcLacCer><Image Cytometry><Immune Cell Activation><Immunomodulation><In Vitro><Individual><Infection><Inflammation><Inflammatory><Inflammatory Response><Inflammatory Response Pathway><Injections><Integrase Inhibitors><LAV-HTLV-III><Label><Lead><Lectin Receptors><Ligase><Ligase Gene><Link><Lipid Bilayers><Lipids><Lymphadenopathy-Associated Virus><Lymphatic Tissue><Lymphoid Tissue><Marrow monocyte><Measures><Mediating><Medication><Membrane><Metastatic Cancer><Metastatic Malignant Neoplasm><Mice><Mice Mammals><Molecular Interaction><Morbidity><Morbidity - disease rate><Murine><Mus><Myelogenous><Myeloid><Myeloid Cells><Mφ><N-Acetylneuraminic Acids><NNRTI><Oral><Patients><Pb element><Penetration><Pharmaceutic Preparations><Pharmaceutical Preparations><Phenotype><Plasma><Plasma Membrane><Plasma Serum><Polymers><Prevention><Property><Protein Interaction Map><Protein-Protein Interaction Map><Regimen><Reticuloendothelial System, Serum, Plasma><Reverse Transcriptase Inhibitors><Risk><Role><Secondary to><Sialic Acids><Sialyl Lactosylceramide><Sialyllactosylceramide><Site><Spatial Distribution><Synapses><Synaptic><Synthetases><T-Cells><T-Lymphocyte><T4 Cells><T4 Lymphocytes><Testing><Therapeutic><Time><Tissues><Toxic effect><Toxicities><Transmission><Veiled Cells><Viral><Virus><Virus-HIV><Vitamin H><anti-retroviral><anti-retroviral therapy><anti-retroviral treatment><antiretroviral><antiretroviral therapy><antiretroviral treatment><co-morbid><co-morbidity><coenzyme R><combinatorial><comorbidity><cytokine><design><designing><developmental><drug/agent><extracellular><flow cytophotometry><heavy metal Pb><heavy metal lead><immune activation><immune modulation><immune regulation><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><in vivo><innovate><innovation><innovative><lipid bilayer membrane><live cell image><live cell imaging><live cellular image><live cellular imaging><macrophage><membrane structure><monocyte><nano formulation><nano particle><nano therapeutic><nano-sized particle><nanoformulation><nanoparticle><nanosized particle><nanotherapeutic><new approaches><non-human primate><non-nucleoside RT inhibitors><non-nucleoside reverse transcriptase inhibitors><nonhuman primate><nonnucleoside reverse transcriptase inhibitors><novel approaches><novel strategies><novel strategy><plasmalemma><poly(lactic acid)><polylactic acid><preservation><prevent><preventing><response><site targeted delivery><social role><synapse><targeted delivery><thymus derived lymphocyte><transmission process><uptake><viral rebound><viral transmission><virological synapse><virus rebound><virus transmission>