Despite widespread implementation of antiretroviral therapy (ART) that effectively suppresses virus replication in the periphery, HIV persists in tissue reservoirs and accounts for the rapid plasma viral rebound in HIV- infected individuals who have discontinued ART. It is well appreciated that secondary lymphoid tissues represent a drug-privileged site that account for residual viral persistence in HIV-infected individuals on ART. Hence, effective cure and eradication strategies require development of novel approaches that specifically target lymph node-resident HIV reservoirs. An effective strategy to enhance anti-retroviral (ARV) drug concentrations in secondary lymph nodes is to formulate ARVs in carriers such as nanoparticles that promote transport of compounds via the lymphatics to the draining lymph nodes. Additionally, strategies that prevent rapid clearance and maintain inhibitory concentrations of ARVs in lymph nodes for an extended time are needed to effectively suppress persistent virus expression. Hence in this application, we are proposing to develop GM3-containing membrane encapsulated nanoparticle-based approaches to establish long-term tissue depots of ARVs in lymph nodes to suppress residual viral replication. The design of these nanoparticles is based on our recent findings that demonstrate specific capture of GM3 (?2,3-linked sialic acid containing monosialo-dihexosylganglioside) containing membrane encapsulated gold nanoparticles by CD169 expressing primary human myeloid cells such as macrophages and dendritic cells in vitro and co-localization of GM3-gold NPs with CD169+ cells in lymph nodes of mice. Interestingly, capture of GM3-gold NPs resulted in sequestration and preservation within surface accessible non-lysosomal plasma membrane invaginations in CD169+ myeloid cells. Hence, we will exploit these specific interactions between GM3-containing membrane encapsulated nanoparticles and CD169 to achieve both selective targeting of lymph node resident-myeloid cells and sequestration to specialized non-lysosomal compartments for formation of ?drug depots? that achieve sustained inhibitory concentrations of ARVs. Finally, we will determine the ability of these novel ARV- containing nanocarriers to suppress virus replication in lymph nodes in a humanized mouse model of HIV-1 infection. We believe these studies are critical to development of virus-eradication strategies for eliminating persistent HIV reservoir.

Public Health Relevance

PROJECT SUMMARY The goal of this project is to develop GM3-containing membrane wrapped nanoparticles to specifically target CD169+ myeloid cells and facilitate sustained release of anti-retrovirals within secondary lymphatic tissues to suppress residual HIV replication in drug-privileged tissue sanctuary sites.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI132111-02
Application #
9597575
Study Section
AIDS Discovery and Development of Therapeutics Study Section (ADDT)
Program Officer
Crawford, Keith W
Project Start
2017-11-08
Project End
2022-10-31
Budget Start
2018-11-01
Budget End
2019-10-31
Support Year
2
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Boston University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
604483045
City
Boston
State
MA
Country
United States
Zip Code
02118