P51.04
Background: Previous studies have suggested that the central nervous system (CNS) is an important reservoir for HIV and that proviral DNA and productive infections can be detected in this region. In particular, the brain represents a sanctuary for HIV-1 latency because the provirus can persist in this area due to the variable and poor penetration of antiretrovirals (ARV). Despite an undetectable viral load in patients treated with potent ARV, current therapies are unable to purge the virus from these latent reservoirs. Combinatory strategies to eliminate HIV-1 reservoirs using selective activators of viral expression could lead to a decline in HIV-1 levels in reservoirs that would be sufficient to efficiently control the infection.
Methods: Human primary astrocytes (NHA) isolated from the cerebrums of 5-month-old human foetuses and astrocytic cell line U-87 were used in all experiments.
Results: To broaden the inhibitory range and effectiveness of current ARV, the potential of bryostatin was investigated as a latent HIV-1 activator. Bryostatin reactivates latent viral infection in NHA and in U-87 via activation of protein kinase C (PKC)-alpha and -delta because the PKC inhibitors rottlerin and GF109203X abrogated the bryostatin effect. We did not find any alteration in cell proliferation. Moreover, bryostatin strongly stimulated LTR transcription by activating the transcription factor NF-κB. The effect of bryostatin could be especially important in a cellular reservoir such as astrocytes because it may be a beneficial adjunct to the treatment of HIV-infection.
Conclusions: Bryostatin can directly increase HIV-1 LTR activity in human astrocytes in vitro via the PKC pathway and an NF-κB-dependent mechanism. Thus, it is plausible that HIV-1-infected astrocyte cells exposed to bryostatin may contribute to HIV-1 latency activation and will provide a foundation for future novel HIV-1-purging strategies from tissue reservoirs such as the CNS.
