Human herpesvirus replication is activated by apoptosis

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Human herpesvirus replication is activated by apoptosis

A group led by Steven Zeichner, Phd at the Center for Cancer and Immunology Research, Children’s Research Institute, and Children’s National Medical Center has published a study this month in the Journal of Virology that suggests the replication of all human herpesviruses can be activated by apoptosis. This finding comes on the heels of two studies which have recently demonstrated that two of the human herpesviruses, HSV-1 (Du 2011, Du 2012) and HHV-8 (or KSHV) (Prasad 2013), can both initiate replication in response to host cell apoptosis.

A central feature of all herpesviruses is their ability to remain latent within host cells, allowing these viruses to achieve lifelong latency in their host. In addition, it is known that herpesviruses devote considerable genomic resources toward preventing their host cells from undergoing apoptosis, a programmed event that results in the death of the cell. However, Zeichner’s recent studies suggest that an alternative apoptosis-triggered replication program might be a general feature of herpesvirus biology as a way to provide the virus with an “emergency escape pathway” in the event of apoptosis. In addition, the viruses reactivate much faster than they would under normal circumstances, because the cells are somehow intrinsically aware that this is their last chance to reproduce before the death of the host cell.

To explore whether a similar alternative apoptosis-initiated replication program is a common feature of additional human herpesviruses, the group studied HHV-4 (Epstein-Barr virus), HHV-6A, HHV-6B, HHV-7, and HHV-8 (KSHV). They reported that apoptosis does indeed trigger replication for each of the herpesviruses studied, with caspase-3—a protease that play a central role in the execution of apoptosis—being necessary and sufficient to activate replication.

This finding has important clinical implications because it suggests that some treatments designed to promote apoptosis as a mechanism of action may lead to the inadvertent activation of latent herpesviruses. Toxic chemotherapy drugs such as doxorubicin and vincristine, harsh antibiotics and even high dose prednisone could activate herpesvirus due to their high toxicities. Similarly, the herpesvirus reactivation that is common in GVHD and severe DIHS/DRESS may be partially attributed to this newly discovered pathway. Also, this pathway may be one reason why HSV-1 and HHV-6 DNA levels are elevated in the brains of Alzheimer’s Disease patients compared to controls. (Lin 2002, Carbone 2013). Previously, herpesviruses were assumed to reactivate primarily due to immunosuppression.

For more information, read the full paper.