Long-acting nanoformulated antiretroviral therapy elicits potent antiretroviral and neuroprotective responses in HIV-1-infected humanized mice

Prasanta K. Dash, Howard Eliot Gendelman, Upal Roy, Shantanu Balkundi, Yazen Alnouti, R Lee Mosley, Harris A. Gelbard, JoEllyn M McMillan, Santhi Gorantla, Larisa Y Poluektova

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Abstract

OBJECTIVES: Long-acting nanoformulated antiretroviral therapy (nanoART) with improved pharmacokinetics, biodistribution and limited systemic toxicities will likely improve drug adherence and access to viral reservoirs. DESIGN: Atazanavir and ritonavir crystalline nanoART were formulated in a poloxamer-188 excipient by high-pressure homogenization. These formulations were evaluated for antiretroviral and neuroprotective activities in humanized NOD/scid-IL-2Rgc (NSG) mice. METHODS: NanoART-treated NSG mice were evaluated for drug biodistribution, pharmacodynamics and toxicity. CD34 human hematopoietic stem cells were transplanted at birth in replicate NSG mice. The mice were infected with HIV-1ADA at 5 months of age. Eight weeks later, the infected animals were treated with weekly subcutaneous injections of nanoformulated ATV and RTV. Peripheral viral load, CD4 T-cell counts and lymphoid and brain histopathology and immunohistochemistry tests were performed. RESULTS: NanoART treatments by once-a-week injections reduced viral loads more than 1000-fold and protected CD4 T-cell populations. This paralleled high ART levels in liver, spleen and blood that were in or around the human minimal effective dose concentration without notable toxicities. Importantly, examination of infected brain subregions showed that nanoART elicited neuroprotective responses with detectable increases in microtubule-associated protein-2, synaptophysin and neurofilament expression when compared to untreated virus-infected animals. Therapeutic interruptions produced profound viral rebounds. CONCLUSION: Long-acting nanoART has translational potential with sustained and targeted efficacy and with limited systemic toxicities. Such success in drug delivery and distribution could improve drug adherence and reduce viral resistance in infected people.

Original languageEnglish (US)
Pages (from-to)2135-2144
Number of pages10
JournalAIDS
Volume26
Issue number17
DOIs
StatePublished - Nov 13 2012

Fingerprint

HIV-1
Viral Load
Pharmaceutical Preparations
Therapeutics
T-Lymphocytes
Poloxamer
Ritonavir
Synaptophysin
Microtubule-Associated Proteins
Intermediate Filaments
Excipients
Brain
Subcutaneous Injections
CD4 Lymphocyte Count
Hematopoietic Stem Cells
Spleen
Pharmacokinetics
Immunohistochemistry
HIV
Parturition

Keywords

  • HIV-1
  • HIV-associated neurocognitive disorders
  • central nervous system
  • drug biodistribution
  • humanized mice
  • nanoformulated antiretroviral therapy

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

Cite this

@article{da48fbadcc954b729d1d7d6232afff2c,
title = "Long-acting nanoformulated antiretroviral therapy elicits potent antiretroviral and neuroprotective responses in HIV-1-infected humanized mice",
abstract = "OBJECTIVES: Long-acting nanoformulated antiretroviral therapy (nanoART) with improved pharmacokinetics, biodistribution and limited systemic toxicities will likely improve drug adherence and access to viral reservoirs. DESIGN: Atazanavir and ritonavir crystalline nanoART were formulated in a poloxamer-188 excipient by high-pressure homogenization. These formulations were evaluated for antiretroviral and neuroprotective activities in humanized NOD/scid-IL-2Rgc (NSG) mice. METHODS: NanoART-treated NSG mice were evaluated for drug biodistribution, pharmacodynamics and toxicity. CD34 human hematopoietic stem cells were transplanted at birth in replicate NSG mice. The mice were infected with HIV-1ADA at 5 months of age. Eight weeks later, the infected animals were treated with weekly subcutaneous injections of nanoformulated ATV and RTV. Peripheral viral load, CD4 T-cell counts and lymphoid and brain histopathology and immunohistochemistry tests were performed. RESULTS: NanoART treatments by once-a-week injections reduced viral loads more than 1000-fold and protected CD4 T-cell populations. This paralleled high ART levels in liver, spleen and blood that were in or around the human minimal effective dose concentration without notable toxicities. Importantly, examination of infected brain subregions showed that nanoART elicited neuroprotective responses with detectable increases in microtubule-associated protein-2, synaptophysin and neurofilament expression when compared to untreated virus-infected animals. Therapeutic interruptions produced profound viral rebounds. CONCLUSION: Long-acting nanoART has translational potential with sustained and targeted efficacy and with limited systemic toxicities. Such success in drug delivery and distribution could improve drug adherence and reduce viral resistance in infected people.",
keywords = "HIV-1, HIV-associated neurocognitive disorders, central nervous system, drug biodistribution, humanized mice, nanoformulated antiretroviral therapy",
author = "Dash, {Prasanta K.} and Gendelman, {Howard Eliot} and Upal Roy and Shantanu Balkundi and Yazen Alnouti and Mosley, {R Lee} and Gelbard, {Harris A.} and McMillan, {JoEllyn M} and Santhi Gorantla and Poluektova, {Larisa Y}",
year = "2012",
month = "11",
day = "13",
doi = "10.1097/QAD.0b013e328357f5ad",
language = "English (US)",
volume = "26",
pages = "2135--2144",
journal = "AIDS",
issn = "0269-9370",
publisher = "Lippincott Williams and Wilkins",
number = "17",

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TY - JOUR

T1 - Long-acting nanoformulated antiretroviral therapy elicits potent antiretroviral and neuroprotective responses in HIV-1-infected humanized mice

AU - Dash, Prasanta K.

AU - Gendelman, Howard Eliot

AU - Roy, Upal

AU - Balkundi, Shantanu

AU - Alnouti, Yazen

AU - Mosley, R Lee

AU - Gelbard, Harris A.

AU - McMillan, JoEllyn M

AU - Gorantla, Santhi

AU - Poluektova, Larisa Y

PY - 2012/11/13

Y1 - 2012/11/13

N2 - OBJECTIVES: Long-acting nanoformulated antiretroviral therapy (nanoART) with improved pharmacokinetics, biodistribution and limited systemic toxicities will likely improve drug adherence and access to viral reservoirs. DESIGN: Atazanavir and ritonavir crystalline nanoART were formulated in a poloxamer-188 excipient by high-pressure homogenization. These formulations were evaluated for antiretroviral and neuroprotective activities in humanized NOD/scid-IL-2Rgc (NSG) mice. METHODS: NanoART-treated NSG mice were evaluated for drug biodistribution, pharmacodynamics and toxicity. CD34 human hematopoietic stem cells were transplanted at birth in replicate NSG mice. The mice were infected with HIV-1ADA at 5 months of age. Eight weeks later, the infected animals were treated with weekly subcutaneous injections of nanoformulated ATV and RTV. Peripheral viral load, CD4 T-cell counts and lymphoid and brain histopathology and immunohistochemistry tests were performed. RESULTS: NanoART treatments by once-a-week injections reduced viral loads more than 1000-fold and protected CD4 T-cell populations. This paralleled high ART levels in liver, spleen and blood that were in or around the human minimal effective dose concentration without notable toxicities. Importantly, examination of infected brain subregions showed that nanoART elicited neuroprotective responses with detectable increases in microtubule-associated protein-2, synaptophysin and neurofilament expression when compared to untreated virus-infected animals. Therapeutic interruptions produced profound viral rebounds. CONCLUSION: Long-acting nanoART has translational potential with sustained and targeted efficacy and with limited systemic toxicities. Such success in drug delivery and distribution could improve drug adherence and reduce viral resistance in infected people.

AB - OBJECTIVES: Long-acting nanoformulated antiretroviral therapy (nanoART) with improved pharmacokinetics, biodistribution and limited systemic toxicities will likely improve drug adherence and access to viral reservoirs. DESIGN: Atazanavir and ritonavir crystalline nanoART were formulated in a poloxamer-188 excipient by high-pressure homogenization. These formulations were evaluated for antiretroviral and neuroprotective activities in humanized NOD/scid-IL-2Rgc (NSG) mice. METHODS: NanoART-treated NSG mice were evaluated for drug biodistribution, pharmacodynamics and toxicity. CD34 human hematopoietic stem cells were transplanted at birth in replicate NSG mice. The mice were infected with HIV-1ADA at 5 months of age. Eight weeks later, the infected animals were treated with weekly subcutaneous injections of nanoformulated ATV and RTV. Peripheral viral load, CD4 T-cell counts and lymphoid and brain histopathology and immunohistochemistry tests were performed. RESULTS: NanoART treatments by once-a-week injections reduced viral loads more than 1000-fold and protected CD4 T-cell populations. This paralleled high ART levels in liver, spleen and blood that were in or around the human minimal effective dose concentration without notable toxicities. Importantly, examination of infected brain subregions showed that nanoART elicited neuroprotective responses with detectable increases in microtubule-associated protein-2, synaptophysin and neurofilament expression when compared to untreated virus-infected animals. Therapeutic interruptions produced profound viral rebounds. CONCLUSION: Long-acting nanoART has translational potential with sustained and targeted efficacy and with limited systemic toxicities. Such success in drug delivery and distribution could improve drug adherence and reduce viral resistance in infected people.

KW - HIV-1

KW - HIV-associated neurocognitive disorders

KW - central nervous system

KW - drug biodistribution

KW - humanized mice

KW - nanoformulated antiretroviral therapy

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