Another Paradigm shifted

During my last year of struggle at TJU when I was investigating the potential scientific misconducts according to the mandate given to me by the TJU president, counsel and other administrators, I started to observe that there may be a third type of immunity besides innate and classical immunities.  I reasoned that the classical immunity is only 35 million years old and in realty is a new kid in the block.  There must be something else. I began to explore the alternate possibilities and at the end of my tenure at TJU I wrote a book describing this old immunity- that I named molecular immunity[1].

This was beautifully described a journalist in Australia in 1999, just after the book was published. Here is his short account.

Omar Bagasra, HIV and Molecular Immunity: Prospects for the AIDS Vaccine (Eaton Publishing, Inc. Natic, MA, USA, 1999); ISBN 1-881299-10-4

A commentary by Julian Cribb, May 1999

This commentary is part of a collection of material on

Polio vaccines and the origin of AIDS

which in turn is part of Brian Martin’s website on suppression of dissent.

“Bagasra is a distinguished Indian-born US scientist, whose main claim to fame – prior to this – was the invention of the in situ PCR technique, enabling single copies of a gene to be amplified inside a cell. This led to quite a few new insights into the behaviour of HIV.

In the book, most of which I won’t comment on because it’s pretty high science, he argues the case for a new form of immunity, molecular immunity, which he says has protected humans against retroviruses and lentiviruses for eons.

As I understand it, he argues there are “repertoires” of RNAs present in CD8 cells, which arose as a result of our long evolutionary symbiosis with retroviruses. When they encounter a retro (viruses), these RNAs link up to form a triple helix which blocks the entry of the retro(viruses) to the cell nucleus. As soon as blocking takes place, millions more copies of RNAs are made throughout the body which block any other retro(viruse) they can find. This is why, until HIV developed, retro(viruses) made so little disease impact on humans

Bagasra says AIDS is the race between the ability of the retrovirus to slip past the RNAs and begin copying itself, and the ability of the RNAs to mass-copy and block it all round. In rapid-onset cases the virus gets on top first, in slow-onset cases the RNAs have got ahead of the game.

It’s a provocative idea, and Luc Montagnier who wrote the foreward, was suitably cautious.

But more important even than this, Bagasra argues a vaccine against AIDS already exists.

He accepts that AIDS probably began in the CHAT-1 polio vaccine (because it would take a mass experiment like this to break down the long-established molecular immunity which kept humans comparatively safe from retroviral invasion).

He argues that monkey kidney cultures probably contained numerous strains of SIVs, and that during the vaccine process these were able to recombine with another – and maybe with native human retroviruses – to give rise to new kinds of deadly virus, the HIVs. “Therefore the introduction of recombinant SIVs, developed during the culture of different SIV strains or pre-HIVs, into humans could potentially have formed HIVs.” (p27) He cites quite a lot of scientific evidence for so thinking.

Bagasra goes on: if a naive human population were exposed to these recombinants, the initial reaction would have been flu-like symptoms, but after some years the immune system would be undermined and destroyed. People would mostly die of lung and intestinal disorders which were then unremarkable in Africa.

However a proportion would have shown one of the unique symptoms of AIDS: skin lesions from Kaposi’s sarcoma. And sure enough, there is evidence of a huge upsurge in KS cases in the Congo in the 1960s, radiating from the same region as the polio vaccine was used, and the same region which molecular phylogeny points to as the source of most of today’s HIV strains.

Bagasra dismisses the monkey bite hypotheses, arguing there are many cases of monkey bites round the world every year, and these patently do not lead to AIDS.

He considers HIV-1 and HIV-2 were introduced to humans at the same time, probably stemming from different recombinants.

Bagasra presumes that around 3,100-15,500 of the original 310,000 recipients of CHAT-1 may have received recombinant SIVs, of whom a small percentage developed AIDS and gave rise to the epidemic.

But the OPV [oral polio vaccine] theory is less important than the conclusion he draws from it. The vaccine recipients would have been infected with recombinants of varying pathogenicity. The bad ones would have killed their hosts – and died with them. The more weakly pathogenic strains would have outlived their hosts and been passed on as HIV/AIDS. And the nonpathogenic ones would have immunised their recipients.

His punchline: “I believe that the live attenuated vaccine against HIV-1 already exists in the bloodstreams of those individuals who received CHAT-1 live polio vaccine in the Ruzizi valley, near Lake Tanganyika. These individuals carry the sort of viral particles that we can utilize for future AIDS vaccines. If these individuals have survived for over 50 years with a kind of attenuated lentivirus related to HIV-1, we should explore the possibility of using these lentiviruses for mass vaccination.” (p161)

Bagasra also sounds a very strong warning against current AIDS vaccine projects, arguing that using bits of the really pathogenic virus will, owing to its powerful ability to recombine (as seen in the enormous array of HIV strains which have already emerged worldwide), give rise to fresh and maybe even deadlier strains of AIDS.

He also strongly opposes xenografts, pointing out that pigs (as a preferred donor animal) carry many retroviruses which currently do no harm to humans but if innoculated into us in this way could develop killer recombinants.

It’s hot stuff. It’s meticulously scientific, with no fewer than 855 scientific references cited. It is not a book for the general reader, but for virology and immunology specialists.

It demonstrates that there is a darn good reason to hope the OPV theory is correct – because it may also lead to a way to curb the pandemic.”

It has been over three decades since the first report of unusual immunodeficiency diseases came to light. Of course, we now estimate that HIV/AIDS had been around for since early 1960s, two decades before it was noticed in the United States (US) in 1981, but the earliest account of HIV-1 may have found in 1959 in Congo (now Democratic Republic of Congo, or DRC). When the first announcement of an HIV discovery was made in 1983, it was widely expected that we would have a vaccine within a very short time. But, after so many years, it is sad to admit that our understanding of immunity against retroviruses is limited. We are trapped in the tunnel vision of the classical immunity paradigm, where we are trying to develop a vaccine by eliciting antibodies to the HIV-1 envelope or cell-mediated immunity to HIV-1 antigens.  Thus far, we have been unable to see anything beyond the limited boundaries of that paradigm. There are substantial amounts of data emerging from the well regarded laboratories in the US, Canada, and Europe that strongly suggest that anti-HIV-1 neutralizing antibodies and cell mediated immunity (CMI) (both part of the classical immunity) have no significant positive effects in quelling HIV-1.  Data from SIV-infected natural hosts show that disease progression is averted in the presence of relatively high levels of viral replication and detectable, although low, classical immune responses.  It is time to shift our focus towards other immunities that are operational in Homo sapiens, and all other life forms.  It should be realized that HIV-1 is a retrovirus, and adaptive immunity or innate immunity-based vaccines are not the solution, but may be the major problem. Life on earth has been estimated to go back over 4 billion years; Adaptive immunity, by contrast, is only approximately 350 million years old, first arising in Jawed fish. How do life forms protect themselves against retroelements and retroviruses? Obviously, protective immunity against retroelements is different than what we are currently focused on.

In my experience, the transitions from an existing paradigm to the new ones have never been easy or painless— but in many ways, HIV vaccinology is on the cusp of such a period of transition, along with much of cell biology and biomedicine. It all has to do with a growing new understanding of the functions of small double-stranded (ds) RNA and of related epigenetic phenomena known as RNA-interference and microRNAs, which may ultimately prove to be as profound and far-reaching as was the development of recombinant DNA technology over four decades ago. Perhaps this new understanding will even come to rank with the discovery of the structure of DNA itself over five decades ago—yet this new approach lends itself to much more practical application and engineered solutions than the earlier theoretical work ever did.

A noted that Kuhn’s insight into periods of transition was included in the preface of my 1999 book, HIV and Molecular Immunity, and this was in anticipation of impending changes in the understanding of natural defenses against retroviruses and other viral pathogens that appeared imminent at that time. This paradigm shift is taking substantially longer to mature than was expected in 1999, but that is because the shift is far more profound than was ever anticipated, extending across a far larger swath of biology that investigators are only now coming to appreciate.

It was in the 1999 book that I first presented a detailed account of the observations regarding intracellular immunity, and the associated short RNA sequences – although such short sequences were very difficult to discern experimentally de novo, due both to their shortness of sequence and their ubiquity. The theory presented in the HIV and Molecular Immunity grew out of unusual findings that kept popping up in my molecular-immunology laboratory at Thomas Jefferson University in the early- to mid-1990s. Not long thereafter, several notable investigators working with C. elegans and plant genetics published similar results regarding what is now called “RNA interference,” or, more commonly, “RNAi.”

In just a few short years of RNAi analysis, this entirely new field of biology has suddenly grown so extensive that individual investigators can hardly keep up with it; in 2006, it even earned the Nobel Prize for two of its early discoverers, Andrew Fire and Craig Mello, with the prize being awarded just eight years after their first publication on this theory (Fire A 1998). Fire’s and Mello’s concepts were very much akin to my own theory, except I called the concept “molecular immunity,” and related it to defense mechanisms against retroviruses and retroelements, while Fire and Mellow called it “RNAi,” and applied it more broadly to post-transcriptional gene silencing. Curiously, Fire and Mellow did not initially consider the involvement of immunity mechanisms, although this is now thought to be one of the primary and evolutionarily original functions of RNAi in vivo, as I was arguing contemporaneously with my early publications.

Nevertheless, I relate this story mainly to drive home the point that the field of HIV vaccinology has entered a very unusual period in the history of the discipline. We are suddenly getting glimpses of how organisms from archea to bacteria and from plants to primates control their own genomes, along with the utilization of the information contained therein. Previously, we clearly understood that DNA and RNA were intimately involved in these processes, but now we are beginning to understand how the control mechanisms actually work, processes that occur in ways that we might easily (but cautiously) manipulate.

This RNAi and microRNA (miRNA) picture is far from complete, but in many ways this period of transition is comparable to that which accompanied the invention of random access memory (RAM) in computer science, or to the transition that occurred in civil-engineering when concrete gained ascendancy over masonry and mortar technology. With miRNA and RNAi-based silencing and gene regulatory mechanisms, tools are just now becoming available that in the near future should allow HIV vaccine science to extend far beyond what was anticipated just a few years ago, albeit with a requisite paradigm shift. Soon, we believe that preventive vaccines could be available to ward off several types of cancers (e.g. breast cancer, prostate cancer, and blood cancers), infectious diseases such as HCV, HIV-1, Ebola, pox and perhaps the flu. There are miRNA-based therapeutics are currently in clinical trials for several infectious agents, and for cancer.

In the past 30 years, over 46 African nonhuman primate species-specific simian immunodeficiency virus (SIV) strains have been described. These viruses naturally infect African nonhuman primates, and these natural host species do not typically manifest immunodeficiency or AIDS, unlike the progressive immunodeficiency seen in lentiviral infections of humans or Asian macaques infected with SIVmac. The question is why man and only certain species of Asian monkeys are susceptible to specific kinds of SIVs. Do they have similar origins regarding lentiviral pathogens?

Similar to progressive HIV and SIV infections, natural hosts maintain high levels of virus replication after SIV infectionHowever, in contrast to pathogenic lentiviral infections, natural hosts have low levels of immune activation, do not develop mucosal dysfunction or the associated microbial translocation, and most importantly, do not progress to AIDS. However, the species-specific SIV types do not show pathogenicity in their hosts. Heterologous infection by the viruses in other natural hosts or non-natural hosts has been shown to be pathogenic only sometimes. An important difference, thus, between natural hosts and non-natural hosts, is the ability of natural hosts to efficiently avoid disease progression. But, how does that happen?

In a recent book[2] (co-authored by Donald Gene Pace) we explained why the current paradigm of classical-immunity based “vaccination” will not work. Why are only humans and certain Asian monkeys susceptible to HIV-1 or SIVmac? What needs to be done to develop a different type of vaccine against HIV-1? An HIV vaccine is right in front of us but because of our tunnel vision we are unable to “see” it. It is our hope that our efforts to uncover the new frontier in HIV vaccine development will pave the pathways that eventually will lead the way to save millions of lives, mostly in the developing nations, where AIDS has not only created chaos but also encouraged wars, famine, and instability.

[1] HIV and Molecular Immunity: Prospect for AIDS Vaccine. Eaton Publishing, 1999.

[2] Bagasra O and D. Gene Pace.  2013.  Reassessing HIV Vaccine Design and Approaches:

Towards a Paradigm Shift. Nova Scientific Publications, Inc. May 2013.