Basal shuttle of NF-kappaB/I kappaB alpha in resting T lymphocytes regulates HIV-1 LTR dependent expression.
BACKGROUND
In HIV-infected T lymphocytes, NF-kappaB/Rel transcription factors are major elements involved in the activation of LTR-dependent transcription from latency. Most NF-kappaB heterodimer p65/p50 is sequestered as an inactive form in the cytoplasm of resting T lymphocytes via its interaction with I kappaB inhibitors. In these cells, both absolute HIV latency and low level ongoing HIV replication have been described. These situations could be related to differences in the balance between NF-kappaB and I kappaB alpha ratio. Actually, control of I kappaB alpha by cellular factors such as Murr-1 plays a critical role in maintaining HIV latency in unstimulated T lymphocytes. Formerly, our group demonstrated the presence of nuclear I kappaB alpha in T cells after PMA activation. Now we attempt to determine the dynamics of NF-kappaB/I kappaB alpha nucleocytosolic transport in absence of activation as a mechanism to explain both the maintenance of latency and the existence of low level ongoing HIV replication in resting CD4+ T lymphocytes.


CONCLUSIONS
We show that the inhibition of the nuclear export by leptomycin B in resting CD4+ T cells resulted in nuclear accumulation of both I kappaB alpha and p65/RelA, as well as formation of NF-kappaB/I kappaB alpha complexes. This proves the existence of a rapid shuttling of I kappaB alpha between nucleus and cytosol even in absence of cellular activation. The nuclear accumulation of I kappaB alpha in resting CD4+ T lymphocytes results in inhibition of HIV-LTR dependent transcription as well as restrains HIV replication in CD4+ T lymphocytes. On the other hand, basal NF-kappaB activity detected in resting CD4+ T lymphocytes was related to low level HIV replication in these cells.
Coiras
Mayte
M
AIDS Immunopathology Unit, National Center of Microbiology, Instituto de Salud Carlos III, Majadahonda, Madrid, Spain. mcoiras@isciii.es
López-Huertas
María Rosa
MR
Rullas
Joaquín
J
Mittelbrunn
Maria
M
Alcamí
José
J
D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology*; D002467:Cell Nucleus / Q000378:metabolism; D002478:Cells, Cultured; D003600:Cytosol / Q000378:metabolism; D004279:DNA, Viral / Q000235:genetics; D015967:Gene Expression Regulation, Viral; D015658:HIV Infections / Q000378:metabolism* / Q000821:virology; D016325:HIV Long Terminal Repeat / Q000235:genetics*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D016328:NF-kappa B / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D014779:Virus Replication
D004279:DNA, Viral; D020672:I-kappa B Proteins; D016328:NF-kappa B