© 2006
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 disease process.

     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.