Patogenia de la infección por el VIH-1 en células del sistema nervioso central
Author
Alvarez Losada, SusanaEntity
UAM. Departamento de Biología MolecularDate
2004-09-17Subjects
Infecciones por VIH - Tesis doctorales; Sistema nervioso central - Infecciones - Tesis doctorales; Biología y Biomedicina / BiologíaNote
Tesis doctoral inédita leída en la Universidad Autónoma de Madrid. Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 17-09-2004Abstract
Brain HIV-1-infection may result in a symirome of pmfound cognitive, behavioral and motor
impaiment known as AiDS dementia complex (ADC) in adults and HIV-related encephalopathy in
c h i l h . Although the hduction of HAART has pdonged and impmved the lives of infeUed
individuais, it is clear that HAART does wt pmvide complete prc&ction against neurological
damage in HIVIAiDS. It is assumed tbat HIV in the brain use CCR5 as the. principai coreceptor for
infcd target cells. Although the majority of Wuses in brain are M, it is unlmown the role of X4
strains in development and evolution of ADC. Neurona1 damage is likely to be induced by soluble
fadors UIluding v i d pmtehs, pmhhmatory cytdcines or chemokines released by HIV-1-
infected mcmphages or microglial cells. 'lhese soluble fadors are slso responsible for activation of
uninfeúed cells ami, thus, for spmdhg and perpe(urition of brain damage. Amoq thase fadors it
has been proposed that the gp120 as the main etiologic agent mponsible of the neuronai deatb in
brains of patient with AiDS, since it is able to cause death neurona1 in Miro. in addition, many
accumdated evidentes exist that poht out to COX-2 as a mediator of gp120 induced nairmial
dpúnmon. To analyze whether diffenmt vira1 isdates may have a differentkl behavior in the neural
and glial infection, the receptors involved in this infection, as weU as to study the molecular
mechanism by which gpl20 cootrois COX-2 expmsion in neurons and glial cek. We found that al1
isolates, regardless being SVX4 or NSIm can pmductively infect neurons and glial ceIts in similar
extent. To identify the putative receptor, we tested the cell sur£ace expression of previously described
receptors by cytometry, RT-PCR or iFi. Neurow express variable levels of CCR5, and CXCR4.
Iatercstingly, exogenous heparao wrlfatc alme was able to substantdly inhib't HIV-1-infectioo, an
effect which was patentiated by RANTES or SDF-1 in the HIV-1-infection with R5 or X4-isolates.
Besides, antiCCR5 and antiCXCR4 blocked significantly HIV-1-infection of R5 and X4-
isolates. Our results suggest that HIV-1 entry involves in neurai cells a chemokine receptordependent
but CM-independent entry. in other way, the gpl2O was able to induce COX-2 mRNA
and protein in neumns ami glial ceik, which express CXCR4 and CCR5 but wt CM. Moreover,
gpl20 enhaaced COX-2 pnmota transcription indicahag that pait of the induction takes place at the
transcriptional level. Cctmufection experiments suggest that NF-KB was necessary but nat sufñcient
to cootrol COX-2 hanscriptim induced by gp120 in NB cells. in addition to NF-KB, Ae-1 but mt
NAlTdependent transcription was observesi in this cell type. In giial cells only COX-2 pmmoter
transcnption depedent of NF-KEI was observed.
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