The HIV application of bryostatin-1 holds significant promise as the “kick” component of the “kick and kill” approach to HIV cure. Current antiretroviral therapy (ART) for HIV targets only actively replicating virus, and thus, it is not a curative approach to HIV. ART has been transformative in treating HIV infection, and has reduced morbidity, mortality and transmission of the infection worldwide. However, ART is unable to target HIV resident in latently infected, and resting T-cells. These cells are long-lived, with a residence time of over 70 years, are not visible to host immune function. These cells constitute a reservoir of HIV, and represent the source of virus that recurs when ART is stopped. Accordingly, ART is required life-long, and must be taken with exceptionally high levels of adherence in order to prevent the emergence of ART-resistant viral variants.
A curative approach to HIV infection cannot be considered until these latently infected cells can be activated (“kick”) and cleared (“kill”) by immune effector mechanisms and immunotherapeutics. If successful, such an approach could allow the discontinuation of ART.
Bryostatin-1 has been shown to activate the cellular reservoir through the PKC system’s induction of viral transcription. Activation and HIV transcription with bryostatin-1 considerably exceeds that of the HDACi class of agents, once considered the lead candidate to affect latency reversal. The clinical use of bryostatin-1 is considered a top priority in the HIV cure field.
The importance of transformative approaches, such as cure, as a treatment option for those infected with HIV cannot be overstated. At present the entire global allocation of funding for HIV treatment and care is consumed by the treatment of only slightly more than half of those in need of ART (source UNAIDS, 2017). In addition, funding for HIV has been flat, or declining, since 2009 (source Kaiser Family Foundation, 2017), which means that needed treatment expansion must occur within the constraints of existing monies. This will not likely be achievable or sustainable, and thus motivates consideration of innovative approaches for long-term control of the epidemic.
BryoLogyx will test bryostatin-1 in a multi-dose study in HIV-infected individuals in the next 12-15 months, using the original marine source, generously provided by the NCI. Additional clinical studies of bryostatin-1, in combination with other agents in a kick and kill approach, are in the planning stages with the NIH and academic centers.