The Human Herpesviruses: Much more than you wanted to know
The Human Herpesviruses: Much more than you wanted to know
Part 1: Introduction to herpesvirus biology
1. Introduction
Despite infecting the vast majority of humanity, herpesviruses receive surprisingly little attention. For most people, the term “herpesvirus” is equivalent to herpes simplex, a disease mainly spread through kissing or sex that causes recurrent outbreaks of painful blisters. The many other herpesviruses that infect humans remain relatively obscure, at least to non-virologists. However, given their links to things like cancer1, birth defects2, aging3, and autoimmune disease4, I believe that they deserve more awareness.
This is the first post in a series that will explore the biology and epidemiology of human herpesviruses, and why you should care about them.
Series Outline:
Part 9: Conclusions
The intended audience is people with a high-school level of biology knowledge (i.e., you should know what DNA, RNA, and proteins are). Any more advanced concepts will be explained.
2. What is a herpesvirus?
Although there are many different kinds of herpesviruses, they all share some common characteristics5:
Their genomes consist of double-stranded DNA (instead of single-stranded DNA or RNA). Their genome size (ranging from 125 – 290 kilobasepairs) is relatively large for a virus, enabling them to encode many genes6. This DNA replicates within the nucleus of the host cell (instead of the cytoplasm).
The DNA is contained within an icosahedral protein shell (known as a capsid).
The capsid is further enclosed within a lipid envelope, which is a stolen piece of the host cell membrane.
The surface of the envelope contains viral glycoproteins, which mediate infection of cells and evasion of the immune system.
Herpesviruses infect animals (instead of plants, bacteria, or fungi). Most types infect vertebrates, although there is at least one that infects mollusks.
They establish latent infections, where the viral DNA is present in host cells, but inactive.
Human herpesviruses fall into three taxonomic categories:
Alpha:
Herpes simplex virus 1 and 2 (HSV1 and 2). Causes classic herpes, and fatal encephalitis in rare cases.
Varicella-zoster virus (VZV). Causes chickenpox and shingles.
Beta:
Cytomegalovirus (CMV). Causes birth defects and immune aging.
Human herpesviruses 6A, 6B, and 7. Cause rashes and fevers in infants; may be linked with neurological disease.
Gamma:
Epstein-Barr virus (EBV). Causes mononucleosis, several types of cancer, and maybe some autoimmune diseases.
Kaposi’s sarcoma virus (KSHV). Causes Kaposi’s sarcoma.
3. Herpesvirus replication and latency
Figure source: Swiss Institute of Bioinformatics, https://viralzone.expasy.org/5836
Understanding the viral replication cycle is key to evaluating potential therapies for herpesvirus infections. Of the nine human herpesviruses, all follow the same basic plan7:
The envelope glycoprotein binds to the surface of the target cell.
The viral membrane fuses with the target cell membrane, releasing the contents into the target cell.
The viral DNA is transported into the nucleus.
Some viral genes (“immediate-early genes”) are transcribed into mRNA by the host cell’s RNA polymerase, and translated into proteins by the host cell’s ribosomes.
At this point, the virus can establish latent infection, its genome remaining dormant within the host nucleus. Eliminating latent herpesviruses is extremely difficult, both for the host immune system and for medical treatments. This is because during latency, the herpesvirus is basically just a piece of DNA. Eliminating this would require a 100% effective method of destroying the viral DNA while leaving the host DNA unharmed. Even the best gene editing methods can’t reach 100% efficacy.
The choice between latency and active replication is determined by a complicated interaction between the host cell and the virus. Whether the virus immediately starts replicating, or reactivates after latency, in both cases the subsequent steps of replication are the same:
The virus has a gene encoding a DNA polymerase, which it uses to replicate its own genome.
The virus also has genes encoding structural proteins, including those for its capsid and envelope glycoproteins.
The capsid proteins assemble around the newly replicated viral genomes within the host cell nucleus, forming nucleoprotein complexes.
These complexes are transported out of the nucleus and associate with viral tegument proteins and envelope glycoproteins. Together with host membranes, these form complete viral particles.
The viral particles are transported to the cell surface and released.
Notably, viral replication doesn’t kill the cell by itself (it’s not like some viruses which literally burst the host cell open). However, the massive hijacking of host cell resources during active viral replication tends to lead to the death of the host cell, and the host immune system can also kill infected cells.
Although replication is the most important function of the virus, herpesviruses also do many other interesting things related to suppressing host cell activities and evading the immune response. These are more varied, and will be discussed individually.
4. Prevalence of human herpesviruses
Interestingly, the classic “herpes” viruses (herpes simplex virus 1 and 2) actually infect a smaller fraction of the human population compared to the other herpesviruses. Since latent viral genomes can be difficult to detect, testing is usually performed by analyzing blood serum samples for antibodies against the particular virus. Infection is lifelong, so having antibodies (also known as being “seropositive”) means the person is latently infected. This is similar to how HIV tests work.
The rates of infection differ between populations, but typical numbers are8:
HSV1: ~50%
HSV2: ~15%
VZV: (this one is tricky since the vaccine also causes seropositivity, but it’s high)
EBV: 80% – 100%
CMV: ~50% to 100% in some populations
HHV6A/B: 90% – 100%
HHV7: 75% – 100%
KSHV: 0 – 30%
5. Conclusions
Herpesviruses infect nearly all of humanity, and are associated with negative effects such as cancer, autoimmune disease, birth defects, and aging. Therefore, developing new treatments and preventions for herpesvirus infections is important. This post series will explore the biology and epidemiology of human herpesviruses, with the goal of raising awareness.
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