Mechanisms of HIV Entry into the CNS

Increased Sensitivity of HIV Infected CD14+CD16+ Monocytes to CCL2 and Key Roles of CCR2, JAM-A, and ALCAM in Diapedesis

Dionna W. Williams, Tina M. Calderon, Lillie Lopez, Loreto Carvallo-Torres, Peter J. Gaskill, Eliseo Eugenin, Susan Morgello, Joan W. Berman

Research output: Contribution to journalArticle

67 Citations (Scopus)

Abstract

As HIV infected individuals live longer, the prevalence of HIV associated neurocognitive disorders is increasing, despite successful antiretroviral therapy. CD14+CD16+ monocytes are critical to the neuropathogenesis of HIV as they promote viral seeding of the brain and establish neuroinflammation. The mechanisms by which HIV infected and uninfected monocytes cross the blood brain barrier and enter the central nervous system are not fully understood. We determined that HIV infection of CD14+CD16+ monocytes resulted in their highly increased transmigration across the blood brain barrier in response to CCL2 as compared to uninfected cells, which did not occur in the absence of the chemokine. This exuberant transmigration of HIV infected monocytes was due, at least in part, to increased CCR2 and significantly heightened sensitivity to CCL2. The entry of HIV infected and uninfected CD14+CD16+ monocytes into the brain was facilitated by significantly increased surface JAM-A, ALCAM, CD99, and PECAM-1, as compared to CD14+ cells that are CD16 negative. Upon HIV infection, there was an additional increase in surface JAM-A and ALCAM on CD14+CD16+ monocytes isolated from some individuals. Antibodies to ALCAM and JAM-A inhibited the transmigration of both HIV infected and uninfected CD14+CD16+ monocytes across the BBB, demonstrating their importance in facilitating monocyte transmigration and entry into the brain parenchyma. Targeting CCR2, JAM-A, and ALCAM present on CD14+CD16+ monocytes that preferentially infiltrate the CNS represents a therapeutic strategy to reduce viral seeding of the brain as well as the ongoing neuroinflammation that occurs during HIV pathogenesis.

Original languageEnglish (US)
Article numbere69270
JournalPLoS One
Volume8
Issue number7
DOIs
StatePublished - Jul 26 2013
Externally publishedYes

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Activated-Leukocyte Cell Adhesion Molecule
Transendothelial and Transepithelial Migration
monocytes
Monocytes
Brain
HIV
CD31 Antigens
brain
Neurology
blood-brain barrier
Chemokines
HIV infections
Blood-Brain Barrier
HIV Infections
sowing
Antibodies
therapeutics
chemokines
central nervous system
pathogenesis

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Mechanisms of HIV Entry into the CNS : Increased Sensitivity of HIV Infected CD14+CD16+ Monocytes to CCL2 and Key Roles of CCR2, JAM-A, and ALCAM in Diapedesis. / Williams, Dionna W.; Calderon, Tina M.; Lopez, Lillie; Carvallo-Torres, Loreto; Gaskill, Peter J.; Eugenin, Eliseo; Morgello, Susan; Berman, Joan W.

In: PLoS One, Vol. 8, No. 7, e69270, 26.07.2013.

Research output: Contribution to journalArticle

Williams, Dionna W. ; Calderon, Tina M. ; Lopez, Lillie ; Carvallo-Torres, Loreto ; Gaskill, Peter J. ; Eugenin, Eliseo ; Morgello, Susan ; Berman, Joan W. / Mechanisms of HIV Entry into the CNS : Increased Sensitivity of HIV Infected CD14+CD16+ Monocytes to CCL2 and Key Roles of CCR2, JAM-A, and ALCAM in Diapedesis. In: PLoS One. 2013 ; Vol. 8, No. 7.
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