BI-2 destabilizes HIV-1 cores during infection and Prevents Binding of CPSF6 to the HIV-1 Capsid
© Fricke et al.; licensee BioMed Central Ltd. 2014
Received: 7 May 2014
Accepted: 2 December 2014
Published: 11 December 2014
The recently discovered small-molecule BI-2 potently blocks HIV-1 infection. BI-2 binds to the N-terminal domain of HIV-1 capsid. BI-2 utilizes the same capsid pocket used by the small molecule PF74. Although both drugs bind to the same pocket, it has been proposed that BI-2 uses a different mechanism to block HIV-1 infection when compared to PF74.
This work demonstrates that BI-2 destabilizes the HIV-1 core during infection, and prevents the binding of the cellular factor CPSF6 to the HIV-1 core.
Overall this short-form paper suggests that BI-2 is using a similar mechanism to the one used by PF74 to block HIV-1 infection.
The ability of the novel HIV-1 inhibitor BI-2 to potently block HIV-1 infection has been correlated with stabilization of in vitro assembled HIV-1 CA-NC complexes -. Crystal structure of the drug with the N-terminal domain of capsid (CANTD) revealed that BI-2 binds in the site 2 pocket , as it has been shown for the small-molecule inhibitor PF74 ,,. Using a novel capsid stability assay, we have demonstrated that BI-2 and PF74 stabilize in vitro assembled HIV-1 capsid-nucleocapsid (CA-NC) complexes . Counter intuitively, PF74 destabilizes the HIV-1 core during infection of cells . In addition, several reports have demonstrated that PF74 prevents the binding of the cellular factor cleavage and polyadenylation specific factor 6 (CPSF6) to the viral capsid ,. Previous observations have shown that BI-2 stabilizes in vitro assembled HIV-1 CA-NC complexes by using two different assays ,. Because BI-2 has been suggested to inhibit HIV-1 infection, at least in part, by stabilizing the viral capsid ,, we investigated the effects of BI-2 in infection by analyzing 1) HIV-1 DNA metabolism, 2) the fate of the HIV-1 capsid, 3) binding of CPSF6 to HIV-1 capsid, and 4) the ability of BI-2 to block infection by other retroviruses.
BI-2 blocks infection of HIV-1 after reverse transcription but prior to nuclear import
BI-2 destabilizes the HIV-1 core during infection
BI-2 prevents the binding of CPSF6 to in vitro assembled HIV-1 CA-NC complexes
Ability of BI-2 to block infection by different retroviruses
This short-form article thoroughly examined and compared the effects of BI-2 and PF74 on HIV-1 infection. Our novel findings demonstrate that BI-2, similar to PF74, destabilizes the HIV-1 core during infection and prevents the binding of CPSF6 to the HIV-1 core.
NIH R01 AI087390 and R21 AI102824 grants to F.D.-G funded this work. C.B. would like to acknowledge support from the National Institutes of Health grant T32 AI07501. We are grateful to the NIH HIV-1/AIDS repository for providing reagents such as antibodies and small-molecule inhibitors that were crucial for this work. We are also very thankful to the technical service of Abcam for providing antibodies against CPSF6.
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