CBF-1 induces both establishment and maintenance of HIV latency via recruiting
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CBF-1 induces both establishment and maintenance of HIV latency via recruiting PcG corepressor complex at HIV LTR. Mudit Tyagi George Mason University, Manassas, Virginia, USA. Multiple mechanisms are involved in establishing HIV latency.

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Mudit Tyagi George Mason University, Manassas, Virginia, USA

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Mudit tyagi george mason university manassas virginia usa

CBF-1 induces both establishment and maintenance of HIV latency via recruiting PcGcorepressor complex at HIV LTR

Mudit Tyagi

George Mason University,

Manassas, Virginia, USA


Mudit tyagi george mason university manassas virginia usa

Multiple mechanisms are involved in establishing HIV latency

  • Quiescent T cells show an absence of transcription factors such as NF-kB and NF-AT restricting initiation (Nabel, Kinoshita)

  • Quiescent T cells show reduced levels of P-TEFb, limiting transcription elongation and Tat activity (Rice, Karn)


Mudit tyagi george mason university manassas virginia usa

Are there specific repressors of HIV LTR promoter, which are higher in resting T cells than their active counterparts.


Mudit tyagi george mason university manassas virginia usa

CBF-1 Levels Rapidly Fall after T-cell Activation

B. HIV (mRNA)

A. CBF-1 (mRNA)


Mudit tyagi george mason university manassas virginia usa

CBF-1 facilitates HIV latency in both transformed and primary CD4+ T cells

CBF-1 plays important role in HIV latency, as its knockdown in latently infected T cells reactivates latent HIV proviruses

CBF-1 inhibits HIV transcription by recruiting histonedeacetylases (HDAC) containing corepressorcomplexes


Mudit tyagi george mason university manassas virginia usa

CBF-1 recruited PcG corepressor complex

facilitate HIV latency establishment

Nucleosome-1 (+30 to +134)

Scrambled shRNA

CBF-1 shRNA

Input DNA %


Mudit tyagi george mason university manassas virginia usa

Polycomb Group corepressor complex

  • PcG complex carry variety of enzymes known to induce different repressive epigenetic modifications. Thus, PcG complex induce several layers of repressive epigenetic modifications involving both histones and DNA.

    PcG complex is known to play important role in both inducingand maintaining the silencing of several cellular genes,including transcriptional repression of the endogenous retroviruses and maintaining the long-term silencing of X chromosome.


Mudit tyagi george mason university manassas virginia usa

CBF-1 recruited PcG corepressor complex

facilitate HIV latency maintenance too

Nucleosome-1 (+30 to +134)

Scrambled shRNA

CBF-1 shRNA

Input DNA %


Mudit tyagi george mason university manassas virginia usa

PcG corepressor complex knockdown results in the reactivation of latent HIV proviruses

Aza-dC (5 uM)

-

+

+

+

+

+

+

+

Luciferase counts


Mudit tyagi george mason university manassas virginia usa

Conclusions

CBF-1 is a potent and specific inhibitor of HIV transcription

CBF-1 performs its function by recruiting PcG corepressor complex at HIV LTR

Like an ideal repressors CBF-1 levels goes down following T cell activation.

Multiple chromatin modifying mechanisms are involved

in regulating gene expression from latent HIV proviruses

Inhibitors of PcG corepressor complex may play useful role for the induction strategies designed to eradicate latent viral pools in HIV patients.


Mudit tyagi george mason university manassas virginia usa

Acknowledgements

Prof. Jonathan Karn


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