Herpesvirus vs. Retrovirus

We have already mentioned that herpesvirus and retrovirus are two types of viruses that typically induce chronic infections. You probably are asking why. In this step we will give you some clues to answer your question. Chronic infections can be persistent or latent. In persistent infections, which include slow and progressive infections, the infected cells constantly produce more infectious virus. To the contrary, in latent infections, infectious viruses are not produced because the viral genome is not expressed or only certain genes are expressed. When the symptoms associated with the primary infection disappear, both retroviruses and herpesviruses may remain “hidden” long periods without clinical manifestations.

The strategy of the retrovirus is to stay integrated in the genome of the host cell as a provirus, while herpesviruses remain hidden as non-integrated circular plasmids, known as episomes. We are going to see in detail how these processes are established. To understand why retroviral infections are chronic, we need to briefly review their replication cycle, especially from the point in which the provirus is integrated into the genome of the host cell. The provirus state can persist a long time. At a given point, the proviral genome is expressed, i.e. viral DNA is transcribed into RNA, which will be translated by ribosomes into viral proteins, or which will make up the genome of new particles.

This process must occur with low intensity almost constantly, as there are antibodies present from the beginning of the infection, suggesting continuous viral expression. Over time, there are so many infected cells that retrovirus replicate massively, and this leads to the disease. The LTR of the 5’ end commands the order to start the transcription into RNA. Remember that the LTRs are the sequences flanking the proviral DNA at both ends. They are the real control centres of the viral replication. When they are activated, both types of RNA are transcribed. The LTRs are extraordinary, in the sense that they contain sequences that recognize cellular factors, such as hormones in this example.

This triggers a few sequences of the LTR itself, the TATA and CAT promoters, starting transcription. Therefore, the moment when the provirus is transcribed will depend on the generation of certain signals by the cell, which can take a long time to occur. And this determines that retroviral infections are slow and progressive processes. Also remember that once integrated, provirus behave as Mendelian genes, dividing when the cell divides, so that all the progeny of an infected cell is also infected.

That is why it is so difficult to completely eliminate the retroviral infection: it would be necessary to eliminate all the infected cells. The extreme case would be when retrovirus infect germ cells, egg or sperm cells, instead of infecting somatic cells. In that case, the infection not only passes to the progeny of the cells, but also to the next generation of that animal, and during successive generations. These retroviruses lose part of their genome and become defective, becoming embedded forever in the genome of the species. Herpesviruses produce a clinical (local or systemic) disease following the primary infection, but they can then stay silent for long periods in different body sites, depending on the subfamily of herpesvirus.

Alphaherpesvirus ascend along the nerve endings of the sensory neurons by retrograde transport up to the trigeminal nodes or to the dorsal root. In the case of betaherpesvirus, the latency is produced in lymphoid organs. In both cases, the genome of the virus remains as an episome, expressing only a few viral genes known as “latency-associated genes”. The genes that are expressed are related to the basic functions of replication of the viral episome and often also cause the immortalization of infected cells. As opposed to retrovirus, the reactivation of herpesvirus happens occasionally and is associated to factors such as the immune state or the age of the host. All the genes of the virus are expressed simultaneously, which translates into a productive infection.

In alphaherpesvirus, reactivation occurs in the body of the sensory neuron (trigeminal ganglion or of the dorsal root) and viral particles descend by anterograde transport along the axons up to the epidermis, generating skin lesions and/or disseminated infection. In betaherpesvirus, reactivation occurs in lymphoid organs, causing a systemic infection. If you suffer from cold sores, their origin is precisely the reactivation of an old infection by herpesvirus. Therefore, although retrovirus and herpesvirus determine chronic infections, you see that the mechanisms are very different. In the case of retroviruses, they are due to their ability to remain integrated in the genome and to the low level of expression, while herpesvirus can hide from the immune system.

It is surprising that such small agents are capable of teasing organisms as evolved as animals or humans.