It might take a 15-year-lag period for a discovery to be recognized as such. In the late 80's, we unexpectedly found that residing in human body most potent xenobiotic dioxin (TCDD) was pretty able to elevate reproduction of HIV-1 viruses in human target cell lines. Thus, dioxin at nanomolar concentrations caused several fold increase of HIV-1 reverse transcriptase activity and viral antigen, and trans-activation of the HIV-LTR-CAT construct. Our pioneer data and an assumption that the Ah receptor (AhR)-mediated transcriptional pathway is involved in mechanism of TCDD activation of the HIV- 1, all have been confirmed in several labs worldwide. However, because of usage TCDD at concentrations about 15 times its human background level in the mid- 90s, and because of lack of any mechanisms of TCDD action on viruses, all the above remained no more than sui generis observations. A mechanistic understanding of how human bodily dioxin transcriptionally up-regulates the HIV-1 came only in 2002, when the viral obligatory component of the suggested TCDD signaling pathway was revealed from the “Species DRE Summary”. Namely, a dioxin response element (DRE) was identified in the 5’-flanking region of the HIV-1 gene, a feature known only for orthologous mammalian genes. However, any practical consideration of the concept was impossible until the basic question as to whether human dioxin body burden is potent enough to up-regulate DRE-containing viruses, was also resolved in 2002. Namely, a strong activation of cytomegalovirus replication in host human cells was shown in the presence of 0.3 pM TCDD, i.e., concentration at least twenty times lower than dioxin background level currently determined in general population of the Unites States. Even though with an extremely low concentration of dioxin, the involvement of the AhR and AhR nuclear translocator (Arnt) in activation of cytomegalovirus replication was demonstrated. So, the discovered current mechanistic concept suggests that in addition to the classic AhR-mediated transcriptional pathway regulating expression of the Ah-battery of mammalian genes dioxin might utilize the same molecular transcriptional machinery to bind viral DREs, and thus trans-activate nucleus-residing viruses,

Thank you so much, Ilya, for your detailed response.  It is an ideal one, because it is based on your own research, not on history books.

Please, allow me a few questions. Although I am ignoramus in this area, I want to understand the logic of your reasoning.  

1. The first discovery was experimental: a strong concentration of TCDD acted positively on HIV-1.  However, it was also accompanied by a hypothesis that at such concentration the activation was due to Ah receptor .  Your data were confirmed by others, who also agreed with your hypothesis.

2. Your finding could not receive a medical application, because concentration of TCDD you used far exceeded the one in human body, and thus you could not have claimed that TCDD creates malignancies in human body.  Since there was no hypothesis of how a low concentration TCDD - such as in a human body - may activate HIV-1, you did not repeat your experiments with low concentrations of TCDD.  Is my interpretation correct?

3. Two critical findings were made in 2002. One showed why dioxin acted on HIV-1 gene: an area was found in this gene sensitive to dioxin (in high concentration?) The other indicated that even  while at  extremely low concentrations,  dioxin is potent, potent enough to activate other viruses (not HIV-1)  in human cells.

4. You concluded from this that i the same mechanism was involved in activating the other virus by a low-concentration dioxin, as was in the case of HIV-1 and high concentration dioxin, namely AhR.  Was this a hypothesis, or you did confirm it by additional experiments?

Please confirm my interpretation or correct it, and then I will ask you how you formulate the meaning (or the content) of the final discovery.

Thank you. Nahum

Dear Nahum,

your interpretation is not correct, as if you would look through my RG bibliography, you should find that “HIV-TCDD” story of the late 80’s was just a pretext of the discovery. The latter was about common human viruses (like EBV, CMV, HSV-1) all possessing multiple DREs in their promotor regions (HIV-1 has the only DRE). So, these inflammation- and malignancy-associated viruses (but not HIV-1) were revealed very susceptible to body burden level of dioxin. The above constitute the matter of our discovery in medicine, which started 15 years earlier with unexpected (and almost unrelated) data on TCCD effects on HIV-1.

Sincerely,

Ilya

Ilya,

Something does not add up.  Did the initial discovery stimulate certain steps which eventually led to 2002 discovery? If yes, the initial event was a part of the final discovery.  A discovery is often a process that takes time, rather than an instantaneous event. 

However, if the findings of the late 1980s did not stimulate any relevant research, and the connection between the events of the 1980s and 2002  was MENTAL,  made after 2002, then the initial event was not a part of the discovery, and you may NOT talk about a 15-year delay of recognition (or acceptance).

Regards,

Nahum