MEDICAL HYPOTHESES AND RESEARCH
VOL. 1, No. 2 / 3, July 2004


M. Blaud, et al. [2004] Med Hypotheses Res 1: 149-159.

Non-conventional Interactions between the Neuronal
Transcription Factor N-Oct-3 and the HIV-1 TAR and
RRE RNAs: A Rationale for Neuroprotection?

Magali Blaud, Laurent Thion, Xavier Manival, Laurence Nieto,
Robert Alazard, Gérard Joseph, Anne Gatignol and Monique
Erard*

Institut de Pharmacologie et de Biologie Structurale, UMR 5089 - 205, Route de
Narbonne, 31077 Toulouse Cedex 4, France (M.B., L.T., X.M., L.N., R.A., G.J., M.E.)
and McGill University AIDS Centre, Lady Davis Institute for Medical Research,
Montreal, Quebec, Canada (A.G.)


Abstract.  We propose a novel interaction pattern for the neuronal transcription
factor N-Oct-3 which could be of relevance to HIV-1 replication restriction in the central
nervous system. Whereas a significant number of AIDS patients develop a severe form of
neurological impairment known as HIV-associated dementia, neuronal damage in fact
occurs through indirect molecular mechanisms. Indeed, only the brain macrophages and
microglia are sites of productive infection. Bearing in mind the established correlations
between HIV-1 propagation inhibition and neurotypic cell differentiation, we
hypothesized that N-Oct-3, a key-player of neuronal cell differentiation, might be one of
the neuro-specific molecules restricting HIV-1 replication. By using circular dichroism
and molecular modeling, we demonstrate here that N-Oct-3 has the ability to interact with
the HIV-1 TAR and RRE RNAs, in a way which would prevent the binding of their
respective viral protein partners, Tat and Rev, thus impeding the two major regulatory
pathways of HIV-1 replication. The main determinant of specificity in both cases is the
tight fitting of the N-Oct-3 homeodomain rigid arm in the respective RNA minor grooves.
These predictions are a powerful incentive to design peptidomimetics able to
synergistically inhibit HIV-1 Tat and Rev functions.


*Address all correspondence to: Dr. Monique Erard, Institut de Pharmacologie et de
Biologie Structurale, UMR 5089 - 205, Route de Narbonne, 31077 Toulouse Cedex 4,
France. E-Mail:
Monique.Erard@ipbs.fr


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