Herpesviruses: latency and reactivation: the pathway in the body

This page shows the biochemical pathway behind the laboratory value Virus reactivation EBV, CMV, VZV (ELISpot): which stations follow one another, which enzymes carry out each step and which cofactors they use. Every statement has a source. The page describes general textbook knowledge and says nothing about any individual person.

In brief

EBV, CMV and VZV are herpesviruses that remain dormant in particular cells for life after primary infection. If they become active again, virus-specific T cells recognise their proteins, remove infected cells and release interferon-γ.

The pathway step by step

Each station states what the compound does there. Three signs: ↑ supplies — builds up or makes available · ↓ depletes — inhibits, consumes or withholds · ↕ both, depending on amount. Behind it stands what the statement rests on: established physiology, observed in studies, or contested. The signs do not grade; they name the direction.

1. Primary infection → EBV Epstein-Barr virus enters the throat via saliva and infects B cells. Its genome persists for life in resting memory B cells. Source 2↕ both, depending on amount In resting memory B cells EBV makes almost no proteins and so stays invisible to T cells; when the cell divides, the viral genome is copied along with it. established physiology Source 2
   ⚖ When the balance tips

   too much — If many B cells carry the virus, there are more starting points for reactivation, and the T cells have more to monitor.

   too little — If few B cells carry the virus, the number of dormant viruses stays small and stable.

   established physiology · Source 2, 5

2. Primary infection → CMV Cytomegalovirus lies dormant in precursor cells in the bone marrow and in monocytes. Only when these mature into tissue macrophages can it become active again. Source 3↕ both, depending on amount In the precursor cells most viral genes are silent; maturation of the host cell switches them back on, so reactivation is linked to the cell's development. established physiology Source 3
   ⚖ When the balance tips

   too much — If many infected monocytes mature into macrophages, for example during inflammation, more opportunities for reactivation arise.

   too little — If the cells stay immature, the virus stays silent.

   established physiology · Source 3

3. Primary infection → VZV After primary infection, varicella zoster virus travels along the nerves into the ganglia beside the spinal cord and cranial nerves and lies dormant in nerve cells there. Source 4↕ both, depending on amount In the nerve cells VZV makes hardly any proteins; T cells that recognise the virus help maintain this dormant state. established physiology Source 4, 6
   ⚖ When the balance tips

   too much — If VZV becomes active in a ganglion, it travels along the nerve to the skin of the corresponding skin segment.

   too little — If VZV-specific T cells remain numerous, the virus stays silent in the ganglia.

   established physiology · Source 4, 6

4. EBV → Reactivation If control by T cells weakens or the host cell is activated, the viruses switch their replication genes back on. Source 1↓ depletes On reactivation the virus again makes proteins and new viruses; the cell is usually destroyed, and viruses reach saliva, blood or skin. established physiology Source 1
   ⚖ When the balance tips

   too much — If reactivation happens often, virus-specific T cells are stimulated again and again and multiply.

   too little — If reactivation remains rare, most of the T cells rest as memory cells.

   established physiology · Source 1, 5

5. CMV → Reactivation If control by T cells weakens or the host cell is activated, the viruses switch their replication genes back on. Source 1↓ depletes On reactivation the virus again makes proteins and new viruses; the cell is usually destroyed, and viruses reach saliva, blood or skin. established physiology Source 1
   ⚖ When the balance tips

   too much — If reactivation happens often, virus-specific T cells are stimulated again and again and multiply.

   too little — If reactivation remains rare, most of the T cells rest as memory cells.

   established physiology · Source 1, 5

6. VZV → Reactivation If control by T cells weakens or the host cell is activated, the viruses switch their replication genes back on. Source 1↓ depletes On reactivation the virus again makes proteins and new viruses; the cell is usually destroyed, and viruses reach saliva, blood or skin. established physiology Source 1
   ⚖ When the balance tips

   too much — If reactivation happens often, virus-specific T cells are stimulated again and again and multiply.

   too little — If reactivation remains rare, most of the T cells rest as memory cells.

   established physiology · Source 1, 5

7. Reactivation → Viral proteins · MHC molecules The cell breaks viral proteins into fragments and displays them on MHC molecules at its surface. This makes it recognisable to T cells. Source 5↑ supplies The displayed fragments are the signal by which T cells recognise an infected cell; herpesviruses carry genes that slow this display. established physiology Source 5
   ⚖ When the balance tips

   too much — If a cell displays many viral fragments, more T cells recognise it, and faster.

   too little — If it displays few, for example because viral genes slow the display, the infected cell stays unrecognised for longer.

   established physiology · Source 5

8. Virus-specific T cell → Interferon-γ Activated T cells release interferon-γ. It puts surrounding cells on defensive alert. Source 5, 7↕ both, depending on amount Interferon-γ inhibits viral replication in neighbouring cells and increases the display of fragments on MHC molecules; in large amounts it drives inflammation. established physiology Source 5
   ⚖ When the balance tips

   too much — If a lot of interferon-γ is released, more phagocytes are activated and inflammation in the tissue increases.

   too little — If little is released, neighbouring cells display fewer fragments and viral replication is checked less strongly.

   established physiology · Source 5

9. Virus-specific T cell → Cell is removed · perforin, granzyme Cytotoxic T cells deliver perforin and granzymes to the infected cell. The cell dies before new viruses are released. Source 5↓ depletes Removing infected cells deprives the virus of its sites of replication and so ends a reactivation. established physiology Source 5
   ⚖ When the balance tips

   too much — If many infected cells are removed, the reactivation ends quickly.

   too little — If few are removed, the virus multiplies for longer and spreads further.

   established physiology · Source 5

10. Interferon-γ → Spot in the ELISpot · capture antibody In the ELISpot, blood cells are stimulated with viral proteins. Each T cell that releases interferon-γ leaves a spot on the bottom of the plate, which is counted. Source 7↑ supplies The number of spots shows how many cells in the sample respond to the respective virus. established physiology Source 7
    ⚖ When the balance tips

    too much — Many spots show many responding T cells; whether they come from an ongoing reactivation or from the memory of earlier contacts cannot be told from the test alone.

    too little — Few spots show few responding cells; this may be due to no contact with the virus or to damped T cells.

    contested · Source 7, 5

Further stations

• Primary infection — each virus separately EBV, CMV and VZV are herpesviruses. At first infection they multiply until the immune system contains them; afterwards they are never completely removed. Source 1↓ depletes In the first phase the viruses make new viruses in infected cells and destroy many of these cells; at the same time virus-specific T and B cells build up. established physiology Source 1
  ⚖ When the balance tips

  too much — If a virus multiplies strongly, it reaches more cells, and more cells carry it in dormant form afterwards.

  too little — If multiplication is checked early, the number of cells that carry the virus permanently stays small.

  established physiology · Source 1

• Virus-specific T cell — recognises the fragment T cells with a matching receptor recognise the viral fragment on the cell. They become active and release messengers. Source 5, 6↓ depletes Activated T cells remove infected cells and keep the dormant viruses in check; for EBV and CMV, a considerable share of memory T cells forms this guard. established physiology Source 5
  ⚖ When the balance tips

  too much — If many T cells are stimulated, they multiply and fill a large part of the T-cell pool with virus-specific cells.

  too little — If few virus-specific T cells are present or they work in a damped way, reactivations are contained more slowly.

  established physiology · Source 5

Cofactors in this pathway

• MHC molecules — Display viral fragments on the cell surface so that T cells can recognise them Source 5
• Perforin and granzymes — Tools of the cytotoxic T cell with which it removes infected cells Source 5
• Interferon-γ — Messenger of the activated T cell that the ELISpot makes visible as a spot Source 7
• Viral proteins (antigens) — Stimulate, in the test, the T cells that recognise exactly this virus Source 7

Sources

1. Cohen JI. Herpesvirus latency. J Clin Invest 2020 · PubMed 32364538
2. Thorley-Lawson DA. EBV Persistence--Introducing the Virus. Curr Top Microbiol Immunol 2015 · PubMed 26424647
3. Sinclair J, Sissons P. Latency and reactivation of human cytomegalovirus. J Gen Virol 2006 · PubMed 16760381
4. Gershon AA, Breuer J, Cohen JI et al. Varicella zoster virus infection. Nat Rev Dis Primers 2015 · PubMed 27188665
5. Taylor GS, Long HM, Brooks JM et al. The immunology of Epstein-Barr virus-induced disease. Annu Rev Immunol 2015 · PubMed 25706097
6. Laing KJ, Ouwendijk WJD, Koelle DM, Verjans GMGM. Immunobiology of Varicella-Zoster Virus Infection. J Infect Dis 2018 · PubMed 30247598
7. Slota M, Lim JB, Dang Y, Disis ML. ELISpot for measuring human immune responses to vaccines. Expert Rev Vaccines 2011 · PubMed 21434798

Related pathways

• Neopterin — interferon-γ

As of 2026-10-05. Draft written by Claude to schema v2; sources checked in PubMed; expert review pending
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