Proteasomal Inhibition Potentiates Latent HIV Reactivation

Area of Science:

• Virology
• Immunology
• Molecular Biology

Background:

• Antiretroviral therapy (ART) controls HIV but cannot eliminate the latent viral reservoir.
• Latent HIV resides in resting T cells with low expression of essential factors like P-TEFb and NF-κB.
• Proteasome inhibitors (PIs) can increase levels of cyclin T1 (CycT1), a P-TEFb subunit, in resting T cells.

Purpose of the Study:

• To investigate the potential of bortezomib, a clinically approved PI, to reactivate latent HIV.
• To determine if bortezomib can increase CycT1 and activate NF-κB in latently infected cells.
• To assess bortezomib's efficacy as a standalone latency reversing agent (LRA).

Main Methods:

• Treatment of latently HIV-infected primary CD4+ T cells with bortezomib.
• Measurement of CycT1 protein levels and NF-κB activation.
• Assessment of HIV reactivation in the absence of other LRAs.

Main Results:

• Bortezomib treatment significantly increased CycT1 protein levels and activated NF-κB in resting T cells.
• Bortezomib potently reactivated latent HIV as a single agent.
• This reactivation occurred without the need for a second LRA, unlike most current strategies.

Conclusions:

• Bortezomib effectively reactivates latent HIV in primary CD4+ T cells.
• The mechanism involves increasing CycT1 and activating NF-κB.
• Bortezomib represents a potential therapeutic strategy for diminishing the HIV reservoir.