Viruses achieve latency by immune-suppressing mechanisms

The majority of people will be exposed to a virus in the Herpes family at some point that will remain in their body for the rest of their life.  The Herpes family is an example of viruses that can establish latency, which is when the virus remain dormant within the host cell and are no longer proliferating, but their viral genome is still present and is being replicated along with the host genome.  In their publication, Human Cytomegalovirus Latency-Associated Proteins Elicit Immune-Suppressive IL-10 Producing CD4 T Cells, Mason et al. examined the mechanism of how these viruses establish latency.  The group focused on a member of the Herpes family, Human cytomegalovirus (HCMV).

HCMV infection is typically asymptomatic, unless the infected person has a compromised immune system.  During the initial infection, there is an extensive CD4+ and CD8+ T cell response (general information on T cells), which controls the active virus.  However, despite the initial immune response, the virus is unable to be cleared and it establishes latency within the host.  The virus establishing latency within the host is problematic because the virus is able to become active (lytic) again, and if this occurs at a time when the immune system is compromised, the individual will experience disease-like symptoms.  In order to clear these viruses from our body, it is important to understand how they are evading our immune system during latency. 

There are different proteins expressed at different stages of HCMV infection.  During the lytic (active) phase, one of the major viral proteins that are recognized by the T cells is gB which is considered one of the immediate early (IE) genes.  When IE genes are absent, this indicates that the virus is latent.  A small amount of HCMV viral genes are expressed during latency, namely UL138 and LUNA.  Interestingly, the viral genes expressed during latency are also expressed during lytic infection.  If there is a T cell response against UL138 and LUNA in both lytic and latent infections, why is it that the infection unable to be cleared in latency?

First, in order to confirm that there is a T cell response (characterized by IFNgamma production) against UL138 and LUNA, the group isolated T cells from the blood of HCMV positive donors and stimulated them with UL138 or LUNA peptides.  The found that both UL138 and LUNA were able to generate a CD4+ T cell response.  They then wanted to determine whether cells that were lytically infected with HCMV would generate the same CD4+ T cell response against UL138 and LUNA.  They infected dendritic cells with HCMV and measured IFNgamma secretion (T cell activation) from CD4+ T cells specific for UL138 and LUNA.  CD4+ T cells specific for gB was also used as a control.  All CD4+ T cells were activated according to their specificity.  These results demonstrate that during HCMV lytic infection, MCH class II is able to present UL138 and LUNA peptides for CD4+ T cell recognition.  Interestingly, when they repeated the assay in monocytes that were latently infected with HCMV, gB specific CD4+ T cells did not show an immune response (as expected since gB isn’t expressed in latent HCMV infections), but UL138 specific CD4+ T cells still secreted IFNgamma.  This suggests that an immune response is occurring.  So, why can’t we get rid of this virus?

The group then analyzed the profile of cytokines secreted by UL138 and LUNA specific CD4+ T cells in comparison to the cytokines secreted by gB specific CD4+ T cells.  The gB, UL138, and LUNA specific CD4+ T cells secrete typical Th₁ type cytokines as expected.  However, the UL138 and LUNA specific CD4+ T cells also secrete high levels of IL-10, which is a regulatory cytokine that halts the immune response.  This is interested because IFNgamma (a Th₁ cytokine) and IL-10 have opposing functions.  The authors wanted to determine whether two, separate T cell populations were secreting these very different cytokines, or if multi-functional T was secreting them both. 

In order to determine this, the group analyzed the cytokines being secreted using cytokine staining and flow cytometry.  They were looking for production and co-expression of IFNgamma and IL-10 from CD4+ T cells.  They found that stimulation of T cells with UL138 peptide generated IFNgamma and IL-10 producing T cells, but the T cells could only secrete one or the other, not both.  This suggests that somehow, the virus is including IL-10 producing CD4+ T cells to prevent latently infected cells from being recognized by the immune system.

The group then sought to demonstrate that the regulatory cytokines (IL-10) secreted from UL138 specific CD4+ T cells would suppress the host T cell response.  They incubated activated CD4+ T cells in supernatant of UL138 specific T cells, stimulated with UL138 peptide.  Using flow cytometry to measure CD4+ T cell proliferation, they found that proliferation was suppressed.  In order to ensure that the regulatory cytokines were having this effect, they added an antibody specific to IL-10, thus inhibiting its function.  They found that proliferation was restored with the addition of the antibody, which indicates that IL-10, produced by UL138 specific CD4+ T cells, is suppressing the immune response. 

This study by Mason et al. demonstrates a new immune suppressive mechanism that HCMV virus uses to maintain latency.  Latent viral antigens that are recognized by CD4+ T cells are inducing IL-10 secretion, which suppresses the antiviral response and allows the virus to remain undetected in the host.  If we could find a way to neutralize IL-10, Th₁ response would likely predominate.  Then the latently infected cells would be recognized and destroyed, thus completely eradicating the virus from our bodies.  The virus will likely reactivate at some point during an infected individual's life time, and if this occurs at a time when the immune system is not equipped to generate an strong immune response, like in old age for example, the virus will cause disease like symptoms.

Primary Article:  Mason GM, Jackson S, Okecha G, Poole E, Sissons JGP, et al. (2013) Human Cytomegalovirus Latency-Associated Proteins Elicit Immune-Suppressive IL-10 Producing CD4+ T Cells.  PLoS Pathog 9(10): e1003635. doi:10.1371/journal.ppat.1003635

Secondary sources (hyperlinks): 

1. http://www.mayoclinic.com/health/cmv/DS00938

2. http://www.niaid.nih.gov/topics/immunesystem/immunecells/pages/tcells.aspx

Images:

1. http://us.123rf.com/400wm/400/400/alila/alila1203/alila120300002/12497991-latent-and-active-infection-by-hiv.jpg

2. http://static.someecards.com/someecards/usercards/MjAxMi01M2FkNTJkYWM3ZWZjZTRl.png