BI-2 destabilizes HIV-1 cores during infection and Prevents Binding of CPSF6 to the HIV-1 Capsid

Abstract

Background: 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. Findings: 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. Conclusions: 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.

X-ray crystal structures of native HIV-1 capsid protein reveal conformational variability

“…Following viral entry, the capsid undergoes controlled disassembly (uncoating), which seems coordinated with reverse transcription (7,9). Antivirals targeting CA (12)(13)(14)(15)(16)(17) include PF-3450074 (PF74), which has a bimodal mechanism of action (18)(19)(20)(21). At lower concentrations (nanomolar to ~2 mM), it competes with binding of host factors CPSF6 and NUP153, affecting nuclear entry.…”

“…At lower concentrations (nanomolar to ~2 mM), it competes with binding of host factors CPSF6 and NUP153, affecting nuclear entry. At higher concentrations, PF74 blocks uncoating and reverse transcription (18)(19)(20)(21)(22)(23). Crystal structures of PF74 with CA NTD (CA NTD -PF74 ) (14) or cross-linked CA hexamers (CA XL-PF74 ) (18,19) have shown that PF74 binds at the same site as CPSF6 and NUP153.…”

The small‐molecule 3G11 inhibits HIV‐1 reverse transcription

“…As shown in Figure a, 3G11 did not change the stability of the HIV‐1 core during infection. As controls, we used the small‐molecule HIV‐1 inhibitors PF74 and Bi‐2, which are known to destabilize the core during infection . As shown in Figure a, 3G11 did not change the stability of the HIV‐1 core during infection when compared to the use of PF74 or BI‐2.…”

“…Over the years, several proteins, drugs, and peptides that target capsid have been discovered: rhesus TRIM5α, owl monkey TRIMCyp, PF74, BI‐2, CAP‐1, Ebselen, the peptide CAI, and others. From studies using these proteins, drugs, and peptides, we have learned much about the early steps of HIV‐1 replication: (i) reverse transcription occurs before or during uncoating, (ii) the decreased stability of the HIV‐1 core, acceleration of uncoating, caused by rhesus TRIM5α, owl monkey TRIMCyp, the small‐molecule PF‐74, or the small‐molecule Bi‐2, prevents HIV‐1 infection, (iii) the increased stability of the HIV‐1 core, inhibition of uncoating, caused by the cytoplasmic expression of human CPSF6 or human MxB, similarly prevents HIV‐1 infection, and (iv) inhibition of reverse transcription increases stability of the HIV‐1 core . Altogether this evidence indicates that the HIV‐1 uncoating process is fundamentally linked to reverse transcription.…”