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HHV-6 and a syndrome: a follow up

Lee R. Martin LRM at zeus.ahabs.wisc.edu
Thu Aug 10 13:28:06 EST 1995

Thanx to all who emailed me or posted in re my questions about HHV-6.
Frank Neipel from the University of Erlangen, Germany, sent me a most
informative email, that with his permission I'd like to post here:


As you are certainly aware, HHV-6 is very widespread in the healthy population
with seroconversion occuring in early childhood (almost always within the first
two years of life). The only disease HHV-6 so far is clearly associated with is
a mild (benign and self-limiting) fever called "Exanthema subitum" or
"Roseola infantum". However, there are a few reports more severe (occasionally
fatal) diseases associated with HHV-6 infection or reactivation. Lymphadeno-
pathy, hepatitis and signs of bone-marrow supression were usually observed in
these cases. Please note: I wrote "associated with", i.e. active HHV-6 
replication occured at the same time and (in some cases) could be shown
in tissues involved. This doesn't necessarily mean that the condition was
caused by HHV-6, as - like presumably all herpesviruses - HHV-6 stays latent
in its host after primary infection and may be reactivated later during
his / her life - for example in the course of a severe illness caused by
something else. So - disease association is difficult to prove for any new
herpesvirus. Although I agree that a condition like your friends
friend suffers from  has never been attributed to HHV-6 unequivocally,
it remains a possibility as (usually more acute) forms of lymphadenopathy
have been observed in the context of HHV-6 infection. BUT: I have a few 

1. how did the doctors show HHV-6 infection? Serology alone is hardly as:
   - positive IgG is a normal finding
   - increases in IgG observed in consecutive samples is better, but HHV-6
is immunologically crossreactive with HHV-7 and (to a lesser extent) HCMV; 
the same is true for IgM; so I wouldn't consider serology sufficient to prove
ACTIVE HHV-6 infection:

Similar caveats are necessary for the widely used PCR: HHV-6 is (most likely) 
latent in mononuclear cells; by PCR HHV-6 can be found in 15 to 25% of the
healthy adult population (or may be more, depending on the amount of DNA used
and the sensitivity of the PCR): so, HHV-6 DNA in the peripheral blood (or 
in lymphnodes or almost any organ you want to look at) is also a normal finding.

If one wants to show a POSSIBLE association btw. HHV-6 and diseases one needs
to show active replication. This can be done by:
   -PCR from cell free serum (not very good, as the DNA could have been 
released from lysed cells harbouring latent HHV-6 genomes)
   -show HHV-6 structural proteins in lymph node biopsies (the doctors 
have certainly taken some biopsies - if not: GET THEM TO DO THIS!)
   - if HHV-6 Ag can be detected in the lymphnodes: repeat with a second
antibody, just to be sure, or use electron microscopy.

If this is positive, than your friends friend has really active HHV-6 
replication. Is this the cause of his disease? Don't know (see above),
 but I think it is possible. 
AND: the doctors should know that something can be done against HHV-6: 


 inhibits HHV-6 replication. Ganciclovir
is used with good success against Cytomegalovirus (CMV), a close relative of
HHV-6. In vitro HHV-6 is about as susceptible to ganciclovir as
CMV is - so I would (and everybody else in the field does) expect that 
ganciclovir is also effective against HHV-6 in vivo. That this has not
been shown conclusively  so far is only due to the fact that severe 
diseases associated with HHV-6 are rarely observed.

Hope this helps
If there are any further questions, don't hesitate to contact me.

Frank Neipel
Institut for Virology
University of Erlangen
Schlossgarten 4
D-91054 Erlangen

Lee R. Martin
LRM at zeus.ahabs.wisc.edu

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