The Infectious Dose of Cytomegalovirus Determines the Degree of Resulting Age-Related Immune Dysfunction

Here researchers show that, in mice at least, a greater infectious dose of cytomegalovirus (CMV) causes a larger degree of age-related immune dysfunction. This is a useful paper that might go some way to answering one class of objection to the existing data on the contribution of CMV to immune system aging, in that not everyone who shows the markers of infection is impacted to the same degree. It seems that the level of exposure may be an important factor. The evidence for CMV to be a major issue for immune health is quite compelling: near everyone is infected by the time they are old; the immune system cannot effectively clear CMV; older people are characterized by a rapid increase in the proportion of immune cells uselessly specialized to CMV, and thus unable to contribute to any of the other responsibilities of the immune system.

The best way forward towards effective therapies is probably some form of targeted destruction of these cells, perhaps augmented by a cell therapy to deliver fresh immune cells to renew the defenses more rapidly than would otherwise be the case. There are groups working on vaccines or other medical approaches to clearing CMV, but my impression has been that this won't really help older people who are already greatly impacted: the degraded state of the immune system will remain, and must still be addressed separately. The researchers here think that clearing out the virus may be useful enough to try, however. The question is always the size of the resulting benefit, and it is unlikely that any method other than trying it out will give an acceptably robust answer in an acceptably short period of time.

The relationship between human cytomegalovirus (HCMV) infections and accelerated immune senescence is controversial. Whereas some studies reported a CMV-associated impaired capacity to control heterologous infections at old age, other studies could not confirm this. We hypothesized that these discrepancies might relate to the variability in the infectious dose of CMV occurring in real life. Here, we investigated the influence of persistent CMV infection on immune perturbations and specifically addressed the role of the infectious dose on the contribution of CMV to accelerated immune senescence.

We show in experimental mouse models that the degree of mouse CMV (MCMV)-specific memory CD8+ T cell accumulation and the phenotypic T cell profile are directly influenced by the infectious dose, and data on HCMV-specific T cells indicate a similar connection. Detailed cluster analysis of the memory CD8+ T cell development showed that high-dose infection causes a differentiation pathway that progresses faster throughout the life span of the host, suggesting a virus-host balance that is influenced by aging and infectious dose.

Importantly, short-term MCMV infection in adult mice is not disadvantageous for heterologous superinfection with lymphocytic choriomeningitis virus (LCMV). However, following long-term CMV infection the strength of the CD8+ T cell immunity to LCMV superinfection was affected by the initial CMV infectious dose, wherein a high infectious dose was found to be a prerequisite for impaired heterologous immunity. Altogether our results underscore the importance of stratification based on the size and differentiation of the CMV-specific memory T cell pools for the impact on immune senescence, and indicate that reduction of the latent/lytic viral load can be beneficial to diminish CMV-associated immune senescence.

Link: https://doi.org/10.3389/fimmu.2017.01953

Comments

Pineapple Fund donated to Erowid. I want to set up a similar site for geroprotectors but dont have money or knowledge.

Posted by: Norse at January 29th, 2018 7:55 AM

Moderna has an mRNA vaccine against CMV that should be starting clinical trials this year:

https://www.modernatx.com/pipeline

"Our investigational CMV vaccine in development, mRNA-1647, combines six mRNAs encoding for six viral proteins, including five proteins that comprise the CMV gH Pentamer complex (gH, gL, UL128, UL130 and UL131A), as well as another CMV antigen, the herpesvirus glycoprotein (gB) protein. The mRNAs direct cells in the body to produce and express all six proteins on the cell surface, including the expression of gB and a fully formed Pentamer complex, or five proteins expressed as a single antigen, much like a native infection would do but without the ability to cause disease or spread. As a result, the body's immune system responds as if the actual virus in present. The immune system produces antibodies against the Pentamer and gB that have the potential to neutralize the virus and prevent infections in the event the vaccinated person is exposed to the actual CMV virus in the future."

Posted by: Jim at January 29th, 2018 5:44 PM

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