Combined antiretroviral therapy reduces brain viral load and pathological features of HIV encephalitis in a mouse model

Rajeth Koneru, Michael Olive, William R. Tyor

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

The role of brain HIV load in the pathogenesis of HIV-associated neurocognitive disorders (HAND) is unclear. To try and determine if the amount of HIV drives the severity of pathology, a severe combined immunodeficient (SCID) mouse model of HIV encephalitis (HIVE) was utilized to determine the effectiveness of a systemically administered combined antiretroviral (cART) regimen. SCID mice were inoculated intracerebrally with HIV-infected or uninfected (control) human macrophages and treated subcutaneously with cART or saline for 10 days. Immunohistochemistry was then used to examine gliosis and neuronal damage. Drug levels were measured in brain and plasma using high-performance liquid chromatography. Peak plasma and brain levels of atazanavir, tenofovir, and emtricitabine were determined to be 1 h post-injection of cART therapy. cART significantly reduced neuropathological features of HIVE, including astrogliosis and the presence of mononuclear phagocytes, and ameliorated reduced MAP2 (neuronal integrity) staining. However, cART did not eradicate HIV from the brain. Using this animal model of HIVE, these data indicate effective penetration of cART reduces brain viral loads and HIV pathology, possibly by eliminating the production of HIV proteins, virus infected cells, or both. Importantly, these data suggest that viral load directly affects the extent of pathology seen in the brain, particularly neuronal damage, which implies that more effective suppression of HIV in the CNS could reduce currently highly prevalent forms of HAND. However, these data also strongly suggest that cART will not eliminate HIV from the brain and that adjunctive therapies must be developed.

Original languageEnglish (US)
Pages (from-to)9-17
Number of pages9
JournalJournal of NeuroVirology
Volume20
Issue number1
DOIs
StatePublished - Feb 2014

Fingerprint

Encephalitis
Viral Load
HIV
Brain
Therapeutics
SCID Mice
Tenofovir
Pathology
Human Immunodeficiency Virus Proteins
Gliosis
Phagocytes
Animal Models
Immunohistochemistry
Macrophages
High Pressure Liquid Chromatography
Staining and Labeling
Viruses

Keywords

  • Combined antiretroviral therapy
  • HIV encephalitis
  • HIV-associated neurocognitive disorders
  • Neuropathology

ASJC Scopus subject areas

  • Virology
  • Clinical Neurology
  • Cellular and Molecular Neuroscience
  • Neurology

Cite this

Combined antiretroviral therapy reduces brain viral load and pathological features of HIV encephalitis in a mouse model. / Koneru, Rajeth; Olive, Michael; Tyor, William R.

In: Journal of NeuroVirology, Vol. 20, No. 1, 02.2014, p. 9-17.

Research output: Contribution to journalArticle

@article{9c2f0882479d4a258feff1b34f96c15d,
title = "Combined antiretroviral therapy reduces brain viral load and pathological features of HIV encephalitis in a mouse model",
abstract = "The role of brain HIV load in the pathogenesis of HIV-associated neurocognitive disorders (HAND) is unclear. To try and determine if the amount of HIV drives the severity of pathology, a severe combined immunodeficient (SCID) mouse model of HIV encephalitis (HIVE) was utilized to determine the effectiveness of a systemically administered combined antiretroviral (cART) regimen. SCID mice were inoculated intracerebrally with HIV-infected or uninfected (control) human macrophages and treated subcutaneously with cART or saline for 10 days. Immunohistochemistry was then used to examine gliosis and neuronal damage. Drug levels were measured in brain and plasma using high-performance liquid chromatography. Peak plasma and brain levels of atazanavir, tenofovir, and emtricitabine were determined to be 1 h post-injection of cART therapy. cART significantly reduced neuropathological features of HIVE, including astrogliosis and the presence of mononuclear phagocytes, and ameliorated reduced MAP2 (neuronal integrity) staining. However, cART did not eradicate HIV from the brain. Using this animal model of HIVE, these data indicate effective penetration of cART reduces brain viral loads and HIV pathology, possibly by eliminating the production of HIV proteins, virus infected cells, or both. Importantly, these data suggest that viral load directly affects the extent of pathology seen in the brain, particularly neuronal damage, which implies that more effective suppression of HIV in the CNS could reduce currently highly prevalent forms of HAND. However, these data also strongly suggest that cART will not eliminate HIV from the brain and that adjunctive therapies must be developed.",
keywords = "Combined antiretroviral therapy, HIV encephalitis, HIV-associated neurocognitive disorders, Neuropathology",
author = "Rajeth Koneru and Michael Olive and Tyor, {William R.}",
year = "2014",
month = "2",
doi = "10.1007/s13365-013-0223-5",
language = "English (US)",
volume = "20",
pages = "9--17",
journal = "Journal of NeuroVirology",
issn = "1355-0284",
publisher = "Springer New York",
number = "1",

}

TY - JOUR

T1 - Combined antiretroviral therapy reduces brain viral load and pathological features of HIV encephalitis in a mouse model

AU - Koneru, Rajeth

AU - Olive, Michael

AU - Tyor, William R.

PY - 2014/2

Y1 - 2014/2

N2 - The role of brain HIV load in the pathogenesis of HIV-associated neurocognitive disorders (HAND) is unclear. To try and determine if the amount of HIV drives the severity of pathology, a severe combined immunodeficient (SCID) mouse model of HIV encephalitis (HIVE) was utilized to determine the effectiveness of a systemically administered combined antiretroviral (cART) regimen. SCID mice were inoculated intracerebrally with HIV-infected or uninfected (control) human macrophages and treated subcutaneously with cART or saline for 10 days. Immunohistochemistry was then used to examine gliosis and neuronal damage. Drug levels were measured in brain and plasma using high-performance liquid chromatography. Peak plasma and brain levels of atazanavir, tenofovir, and emtricitabine were determined to be 1 h post-injection of cART therapy. cART significantly reduced neuropathological features of HIVE, including astrogliosis and the presence of mononuclear phagocytes, and ameliorated reduced MAP2 (neuronal integrity) staining. However, cART did not eradicate HIV from the brain. Using this animal model of HIVE, these data indicate effective penetration of cART reduces brain viral loads and HIV pathology, possibly by eliminating the production of HIV proteins, virus infected cells, or both. Importantly, these data suggest that viral load directly affects the extent of pathology seen in the brain, particularly neuronal damage, which implies that more effective suppression of HIV in the CNS could reduce currently highly prevalent forms of HAND. However, these data also strongly suggest that cART will not eliminate HIV from the brain and that adjunctive therapies must be developed.

AB - The role of brain HIV load in the pathogenesis of HIV-associated neurocognitive disorders (HAND) is unclear. To try and determine if the amount of HIV drives the severity of pathology, a severe combined immunodeficient (SCID) mouse model of HIV encephalitis (HIVE) was utilized to determine the effectiveness of a systemically administered combined antiretroviral (cART) regimen. SCID mice were inoculated intracerebrally with HIV-infected or uninfected (control) human macrophages and treated subcutaneously with cART or saline for 10 days. Immunohistochemistry was then used to examine gliosis and neuronal damage. Drug levels were measured in brain and plasma using high-performance liquid chromatography. Peak plasma and brain levels of atazanavir, tenofovir, and emtricitabine were determined to be 1 h post-injection of cART therapy. cART significantly reduced neuropathological features of HIVE, including astrogliosis and the presence of mononuclear phagocytes, and ameliorated reduced MAP2 (neuronal integrity) staining. However, cART did not eradicate HIV from the brain. Using this animal model of HIVE, these data indicate effective penetration of cART reduces brain viral loads and HIV pathology, possibly by eliminating the production of HIV proteins, virus infected cells, or both. Importantly, these data suggest that viral load directly affects the extent of pathology seen in the brain, particularly neuronal damage, which implies that more effective suppression of HIV in the CNS could reduce currently highly prevalent forms of HAND. However, these data also strongly suggest that cART will not eliminate HIV from the brain and that adjunctive therapies must be developed.

KW - Combined antiretroviral therapy

KW - HIV encephalitis

KW - HIV-associated neurocognitive disorders

KW - Neuropathology

UR - http://www.scopus.com/inward/record.url?scp=84896711212&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84896711212&partnerID=8YFLogxK

U2 - 10.1007/s13365-013-0223-5

DO - 10.1007/s13365-013-0223-5

M3 - Article

C2 - 24415129

AN - SCOPUS:84896711212

VL - 20

SP - 9

EP - 17

JO - Journal of NeuroVirology

JF - Journal of NeuroVirology

SN - 1355-0284

IS - 1

ER -