Pharmacodynamic and antiretroviral activities of combination nanoformulated antiretrovirals in HIV-1-infected human peripheral blood lymphocyte- reconstituted mice

Upal Roy, JoEllyn M McMillan, Yazen Alnouti, Nagsen Gautum, Nathan Smith, Shantanu Balkundi, Prasanta Dash, Santhi Gorantla, Andrea Martinez-Skinner, Jane L Meza, Georgette D Kanmogne, Susan Swindells, Samuel Monroe Cohen, R Lee Mosley, Larisa Y Poluektova, Howard Eliot Gendelman

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Abstract

Lack of adherence, inaccessibility to viral reservoirs, long-term drug toxicities, and treatment failures are limitations of current antiretroviral therapy (ART). These limitations lead to increased viral loads, medicine resistance, immunocompromise, and comorbid conditions. To this end, we developed long-acting nanoformulated ART (nanoART) through modifications of existing atazanavir, ritonavir, and efavirenz suspensions in order to establish cell and tissue drug depots to achieve sustained antiretroviral responses. NanoART's abilities to affect immune and antiviral responses, before or following human immunodeficiency virus type 1 infection were tested in nonobese severe combined immune-deficient mice reconstituted with human peripheral blood lymphocytes. Weekly subcutaneous injections of drug nanoformulations at doses from 80 mg/kg to 250 mg/kg, 1 day before and/or 1 and 7 days after viral exposure, elicited drug levels that paralleled the human median effective concentration, and with limited toxicities. NanoART treatment attenuated viral replication and preserved CD4+ Tcell numbers beyond that seen with orally administered native drugs. These investigations bring us one step closer toward using long-acting antiretrovirals in humans.

Original languageEnglish (US)
Pages (from-to)1577-1588
Number of pages12
JournalJournal of Infectious Diseases
Volume206
Issue number10
DOIs
StatePublished - Nov 15 2012

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HIV-1
Lymphocytes
efavirenz
Pharmaceutical Preparations
Ritonavir
Virus Diseases
Subcutaneous Injections
Drug-Related Side Effects and Adverse Reactions
Viral Load
Treatment Failure
Antiviral Agents
Suspensions
Therapeutics
Medicine

ASJC Scopus subject areas

  • Immunology and Allergy
  • Infectious Diseases

Cite this

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title = "Pharmacodynamic and antiretroviral activities of combination nanoformulated antiretrovirals in HIV-1-infected human peripheral blood lymphocyte- reconstituted mice",
abstract = "Lack of adherence, inaccessibility to viral reservoirs, long-term drug toxicities, and treatment failures are limitations of current antiretroviral therapy (ART). These limitations lead to increased viral loads, medicine resistance, immunocompromise, and comorbid conditions. To this end, we developed long-acting nanoformulated ART (nanoART) through modifications of existing atazanavir, ritonavir, and efavirenz suspensions in order to establish cell and tissue drug depots to achieve sustained antiretroviral responses. NanoART's abilities to affect immune and antiviral responses, before or following human immunodeficiency virus type 1 infection were tested in nonobese severe combined immune-deficient mice reconstituted with human peripheral blood lymphocytes. Weekly subcutaneous injections of drug nanoformulations at doses from 80 mg/kg to 250 mg/kg, 1 day before and/or 1 and 7 days after viral exposure, elicited drug levels that paralleled the human median effective concentration, and with limited toxicities. NanoART treatment attenuated viral replication and preserved CD4+ Tcell numbers beyond that seen with orally administered native drugs. These investigations bring us one step closer toward using long-acting antiretrovirals in humans.",
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AU - McMillan, JoEllyn M

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AU - Gautum, Nagsen

AU - Smith, Nathan

AU - Balkundi, Shantanu

AU - Dash, Prasanta

AU - Gorantla, Santhi

AU - Martinez-Skinner, Andrea

AU - Meza, Jane L

AU - Kanmogne, Georgette D

AU - Swindells, Susan

AU - Cohen, Samuel Monroe

AU - Mosley, R Lee

AU - Poluektova, Larisa Y

AU - Gendelman, Howard Eliot

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