New Methods to Reverse HIV Latency
By Jeffrey Laurence, M.D.
HIV persists in a dormant state primarily in T cells expressing surface proteins known as immune checkpoint (IC) molecules. These surface molecules act as brakes that prevent an overly reactive immune response. In the setting of HIV, ICs might also help keep the virus in immune cells in a latent state.
One approach to eliminating latently infected cells in people living with HIV is to activate the latent virus, and thus induce the death of the infected cell. This led the authors to investigate whether blocking IC proteins might serve as just such a potent activator.
Four prominent IC proteins were identified on T cells in a test-tube model for HIV latency: PD-1, TIM-3, LAG-3, and TIGIT. These same proteins had previously been identified on T cells taken directly from HIV-positive individuals on antiretroviral therapy.
When an artificial stimulus was used to promote T cell growth, antibodies to two T cell surface proteins—PD-1 and CTLA-4—reversed latency. In the absence of an artificial stimulus, a cocktail of antibodies to PD-1, CTLA-4, TIM-3, and TIGIT reversed latency. The potency of this mixture was as high as other previously used latency-reversing agents.
FDA-approved drugs that interact with PD-1 and CTLA-4 are currently used in the treatment of some types of cancer. Their availability could speed up the time to determine in clinical trials whether the combined IC blocking approach to latency reversal is effective.
According to the authors, immune checkpoint blockade is “an attractive option” to move into the clinic, as both a potential method of reversing the latent state of HIV and a strategy to boost T cell activity against HIV.
amfAR funds several researchers involved in this study.
Dr. Laurence is amfAR’s senior scientific consultant.