(±)-BI-D is a potent ALLINI(An allosteric IN inhibitor) that binds integrase at the LEDGF/p75 binding site. Approximately 2.4–2.9 μM of BI-D was required to inhibit 50% of HIV-Luc infection of WT and Hdgfrp2 KO cells, while the IC50 decreased dramatically, to 160–200 nM, in Psip1 and double-KO cells.
1. Nucleic Acids Res. 2012 Dec;40(22):11518-30. doi: 10.1093/nar/gks913. Epub 2012
HRP2 determines the efficiency and specificity of HIV-1 integration in LEDGF/p75
knockout cells but does not contribute to the antiviral activity of a potent
LEDGF/p75-binding site integrase inhibitor.
Wang H(1), Jurado KA, Wu X, Shun MC, Li X, Ferris AL, Smith SJ, Patel PA, Fuchs
JR, Cherepanov P, Kvaratskhelia M, Hughes SH, Engelman A.
(1)Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute,
Harvard Medical School, Boston, MA 02215, USA.
The binding of integrase (IN) to lens epithelium-derived growth factor
(LEDGF)/p75 in large part determines the efficiency and specificity of HIV-1
integration. However, a significant residual preference for integration into
active genes persists in Psip1 (the gene that encodes for LEDGF/p75) knockout
(KO) cells. One other cellular protein, HRP2, harbors both the PWWP and
IN-binding domains that are important for LEDGF/p75 co-factor function. To assess
the role of HRP2 in HIV-1 integration, cells generated from Hdgfrp2 (the gene
that encodes for HRP2) and Psip1/Hdgfrp2 KO mice were infected alongside matched
control cells. HRP2 depleted cells supported normal infection, while disruption
of Hdgfrp2 in Psip1 KO cells yielded additional defects in the efficiency and
specificity of integration. These deficits were largely restored by ectopic
expression of either LEDGF/p75 or HRP2. The double-KO cells nevertheless
supported residual integration into genes, indicating that IN and/or other host
factors contribute to integration specificity in the absence of LEDGF/p75 and
HRP2. Psip1 KO significantly increased the potency of an allosteric inhibitor
that binds the LEDGF/p75 binding site on IN, a result that was not significantly
altered by Hdgfrp2 disruption. These findings help to rule out the host factor-IN
interactions as the primary antiviral targets of LEDGF/p75-binding site IN