Once Monthly Antiretroviral Nanoparticles for HIV-1 Treatment

Project: Research project

Project Details

Description

Abstract: The goal of this RO1 application is to continue the research on antiretroviral nanoparticles (AR NPs)
based on the previous R15 award. Antiretroviral nanoparticles containing ritonavir, lopinavir, and efavirenz
have been able to show success as a sustained drug delivery system. This application is designed to answer
several questions regarding dissemination of AR NPs, efficacy in a mouse model of HIV-1 and finally, efficacy
associated with macaques. Specific Aim 1 will determine the dissemination of fluorescent NPs using a small
animal fluorescent imager and nude mice as the model system. This model will also determine length of time
these NPs remain in specific areas of the body. A 2nd Specific Aim is to determine the most appropriate dose
and route of administration of AR NPs using the Rag2-/-gamma interferon-/- double knockout mouse model of
HIV-1. These mice will be reconstituted with human CD34 cells, infected with HIV, and then administered AR
NPs at pre-defined intervals. The animals will be sacrificed after specific times to determine amount of HIV-1
virus, CD4/CD8 human cells within both plasma and spleen. These values will be compared to mice that
receive HIV-1 and blank NPs. Finally, we would like to collaborate with Drs. Jason Kimata and Marie-Claire
Gauduin at Baylor College of Medicine and Southwest National Primate Research Center, respectively to
determine the most appropriate dose and route of administration of AR NPs in a pigtail macaque model of HIV-
1 infection using RT-SHIVmne. We are proposing that four animals undergo a pilot pharmacokinetic study to
determine the most appropriate dose and route of administration of the AR NPs based on the HIV-1 mouse
model experiments. Then these macaques and four additional pigtail macaques will be infected with RTSHIVmne.
Four macaques will serve as control animals and four will receive AR NPs. Blood and lymph node
biopsies will be harvested at specific times to determine immunological and virological analyses. Animals will
receive AR NPs every 4 weeks for a minimum of 20 weeks. Animals will stop receiving AR NPs and plasma
will be checked weekly to determine virologic and immunologic status. AR NPs animals will receive additional
doses of AR NPs at every 4-weekly dosage if virologic studies meet a define threshold. Animals will be
euthanized and necropsy will be performed to determine if the AR NPs affect viral reservoirs. Determination of
resistant populations of HIV-1 will be performed (Specific Aim 3). It is our intention to determine whether
these AR NPs are able to impact HIV-1 viral loads, CD4/CD8 cell counts, viral reservoirs, and resistance in
animal models of HIV-1. This will be the first step to determine the utility of AR NPs as a treatment option
suitable for human use.
StatusFinished
Effective start/end date6/15/115/31/13

Funding

  • National Institute of Allergy and Infectious Diseases: $410,913.00

Fingerprint

Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.