by Alan Cocchetto, NCF Medical Director
The NCF has believed that it was possible that Dr. Yoshitsugi Hokama's
monoclonal antibody for ciguatera reacted with the paramyxovirus PIV-5
in some manner. As such, the background for this inquiry is provided.
First some previous history is required. Dr. W. John Martin made an
important discovery for his "stealth virus" that he had isolated from
the blood of CFIDS patients. He learned that these blood samples reacted
with okadaic acid, a phosphatase inhibitor. In fact, he found that this
compound inhibited viral replication in his in-vitro experiments. From
there, Dr. Martin recognized that CFIDS/ME patients mimicked ciguatera
poisoning to at least some degree. Furthermore, he knew that there was a
scientific association between okadaic acid and ciguatera from a
compound perspective. As such, he obtained Dr. Hokama's monoclonal
antibody for ciguatera from a research associate at another university.
(Dr. Hokama was unaware of this connection with the use of his
monoclonal antibody with Dr. Martin's research.) Dr. Martin found that
blood from CFIDS/ME patients did react with Dr. Hokama's antibody. As
such, once the NCF had identified this fact, we provided research
funding to Dr. Hokama to confirm or deny the ciguatera monoclonal
antibody reactivity in patient blood samples. Dr. Hokama subsequently
confirmed this fact after having looked at many different blood samples
from various illnesses. He found and published that CFIDS patients
exhibited much higher levels of antibody reactivity than other illnesses
which primarily included hepatitis and some cancers. In fact, Dr. Hokama
found that his monoclonal antibody for ciguatera reacted in over 95% of
all CFIDS/ME patient blood samples.
From the NCF's many discussions with Dr. Hokama, we learned that
there is an overlap in detection between okadaic acid and his monoclonal
antibody. From what we understand, okadaic acid, which is another marine
toxin, reacts with the east end of the molecule for ciguatera and that
is the apparent reason for detection by the monoclonal antibody. The
west end of the ciguatera molecule is apparently tied to the sodium
channel activation. As you may recall, Dr. Teri Mitchell published on
okadaic acid reactivity in the blood of patients with systemic lupus.
Dr. Hokama's team has reviewed this work and they determined that the
monoclonal would also react to lupus patient blood.
What the NCF then postulated was the following. Was it possible
that the ciguatera monoclonal antibody represented an "indirect"
measurement for viral load for PIV-5? In fact, the NCF wondered if Dr.
Hokama's monoclonal reacted with one of the envelope-based viral
proteins for PIV-5?
The NCF believed this was possible for the following reasons.
Okadaic acid is a
serine-threonine phosphatase inhibitor. Lab experiments suggest that
okadaic acid affects phosphorylation in RNA viruses. ("Inhibition of
vesicular stomatitis virus RNA synthesis by protein hyperphosphorylation"
by Chang TL, J. Virol 1994). Furthermore, results suggest that
phosphorylation plays an important role in the regulation between viral
transcription and viral RNA replication as well as the turning off of
RNA replication. Thus, phosphatase inhibitors, such as okadaic acid,
promise to be a valuable tool for dissecting the regulatory mechanisms
involving phosphorylated viral proteins. In addition, in Sendai virus, a
paramyxovirus, okadaic acid was found to cause a six-fold increase in
the P protein phosphorylation in virus-infected cells. ("Intracellular
phosphorylation of the Sendai virus P protein" by Byrappa S, Virology
1995). The phosphoproteins (P) of nonsegmented negative strand RNA
viruses are viral RNA polymerase subunits involved in both transcription
and replication during the virus life cycle. ("Phosphorylation of Sendai
virus phosphoprotein by cellular protein kinase C zeta" by Huntley CC,
J Biol Chem 1997).
Therefore, it is possible that Dr. Hokama's monoclonal antibody
reacts with a viral component associated with the lipid envelope of
PIV-5? Is it also possible that this specific antibody and its
reactivity in CFIDS/ME sera provides us with an important scientific
hint as to potential viral replication? The NCF believed that the signal
transduction association of okadaic acid and phosphatase inhibition
could turn out to an important component in understanding the CFIDS/ME
To investigate this possibility, the NCF believed that an
experiment, using Dr. Hokama's monoclonal antibody for ciguatera on
PIV-5 infected cells, would serve to acknowledge or deny direct
involvement with a paramyxovirus or PIV-5 based viral component. As
such, Dr. Hokama recently sent his monoclonal antibody to two research
groups for their assessment as formally requested by the NCF. Dr. Konnie
Knox and Dr. Donald Carrigan had previously expressed an interest in
evaluating this monoclonal so the NCF arranged for them to receive it.
In addition, Dr. Thomas Kraus along with Dr. Curt Horvath, both from
Northwestern University and associated with the Horvath Laboratory, have
agreed to screen Dr. Hokama's monoclonal antibody against several
paramyxoviruses that they have readily available in their lab. The NCF
is grateful for these collaborations and the subsequent knowledge that
will be gained by these research experiments.