Herpes Simplex Virus types1 and 2 are human viruses which cause cold sores and genital herpes, respectively. Current estimates suggest that 80% of the US population are infected with HSV-1 and 20% with HSV-2. Both viruses establish latency in neurons of the infected individual, and periodically reactivate in response to stress or sunlight. During latency, the virus is asymptomatic but during reactivation, sores reappear at the site of the initial infection.
Current therapies do not prevent reactivation , they only limit the spread of virus once it has already reactivated. We have recently discovered a link between cellular DNA repair proteins and HSV replication, and we have found that this the link is different between lytic and latent infection. During lytic infection, the cellular DNA repair proteins are activated by the virus, whereas during latent infection they are not. Our hypothesis is that DNA repair proteins control the switch between lytic and latent infection and this hypothesis forms the basis of this proposal. If correct, this finding could be exploited therapeutically to force the virus into a permanent state of latency. The natural site of HSV latency is neurons and we have found that the interactions we have observed between DNA repair proteins and HSV are specific to human cells. This finding limits the usefulness of rodent cells for our experiments but we feel that neuronally differentiated human embryonic stem (hES) cells may provide us with a unique opportunity to test our hypothesis in a biologically relevant setting. We propose to establish a model of HSV latency in hES cells which have been differentiated to a neuronal lineage. Modeling latency of a human virus in human neuronal cells will in itself be a significant advance in a field which has been traditionally limited to rodent and rabbit models, which do not recapitulate all aspects of the human disease. We will then use this model to investigate whether inhibiting certain DNA repair proteins can prevent HSV reactivation.
Establishing a link between viral latency and DNA repair proteins may have implications beyond the field of HSV research; this example may turn out to be a paradigm for viral latency in general. If correct, our hypothesis will not only greatly expand our understanding of viral latency but may have important therapeutic applications, potentially leading to novel therapies designed to prevent rather than treat HSV reactivation.
Statement of Benefit to California:
The proposed research will benefit California in two ways. Firstly, it will contribute to our knowledge base of infectious diseases and give new insights into the complex interactions between virus and host cell. Secondly, it may lead to novel therapies to target HSV infections. This will be particularly relevant since the CDC reports that STDs are the most common communicable disease in California and HSV-2 positive individuals have recently been shown to be more likely to acquire and transmit HIV. This proposal represents a novel application of human stem cell technology and could provide a paradigm for studying a range of viruses in the most relevant human cell type.