As we were reminded not long ago by Prof. Marco Ruggiero, virology is a blessedly rule-free science, and HIV has come to define and redefine this rulelessness as it gathers to itself every arcane power ever attributed to any virus of any class in the service of novel teleologies. In the following we will look at just two new HIV phenotypes that have grown out of what was until recently considered one of HIV’s waste products, unintegrated viral DNA.
Luc Montagnier redefined mainstream HIV/AIDS rethinking as well as retroviral infection with his remarks in the documentary House of Numbers that a good immune system can clear the body of (at least early) HIV infection. Perhaps the mainstream rethinkers’ fixation on sound bites and accessible media is the reason why equally remarkable comments made in serious publications have gone unnoticed. The passages below are taken from two of Montagnier’s latest papers, Electromagnetic Detection of HIV DNA in the Blood of AIDS Patients Treated with Antiretroviral Therapy and DNA Waves and Water .
We therefore will favor a third hypothesis. The antiretroviral therapy works efficiently to prevent reverse transcription of viral RNA into DNA and therefore blocks any productive infection of susceptible cells. However, it will not prevent DNA-DNA replication in a non-integrated state. In other words, we hypothesize that the ART treatment will push the virus towards an alternate way of replication, probably minor and depending on a cellular polymerase, but sufficient to maintain the viral genetic information as unintegrated viral DNA and able to resume the normal viral cycle if ART is interrupted for any reason (…) The cells and tissues in which this replication occurs remain to be identified.
(…) it is suggested that the HIV DNA fragments and their nanostructures present in the blood may not originate from cell lysis but, on the contrary, represent pieces of definite size able to recombine in the appropriate recipient cells (lymphocytes) to form whole genomic DNA and finally regenerate infectious virus.
If we can target by specific inhibitors this episomal replication without damaging the cellular processes, we might achieve complete elimination of the HIV reservoir and therefore eradication of HIV infection.
In these passages from Montagnier we learn that HIV can adopt an “alternate” mode in which it:
- has no need of its specific reverse transcriptase, the original defining characteristic of retroviruses; their raison d’etre as an explanatory hypothesis, as it were.
- can replicate in “cells and tissues” that “remain to be identified”.
- can infect without the need to ever become an infectious particle.
Furthermore, and perhaps most extraordinarily, we are given to understand that were it not for this ability of the HI-virus to replicate without ever becoming a virus, antiretrovirals would suffice to eradicate HIV infection. In their commentary to a Montagnier interview in Nexus magazine, the Perth Group state:
According to all the HIV experts, once infected with a retrovirus, always infected. This is because the retroviral RNA is reverse transcribed into DNA which is then incorporated into the host genome (DNA). Once in the host DNA it cannot be removed by any means. This is why HIV infection is incurable. As retrovirologist Harold Varmus said in 1998, “Trying to rid the body of a virus whose genome is incorporated into the host genome may be impossible”. So Montagnier has to explain how “general health measures”, which we assume equate to clean water, sanitation, a good diet and medical services, are able to excise approximately 9 thousand specific bases from the human genome while managing to leave all the rest intact.
We would like to repeat that request only exchanging “general health measures” for “specific inhibitors”.
Montagnier hypothesises that ART treatment has pushed HIV to this alternate existence, but perhaps it is rather the bottomless mysteries of HIV that have pushed its Nobel-recognised inventor to propose a new distinct HIV phenotype. And he is far from the only one. In 2008, a couple of years earlier than the Montagnier paper, Gelderblom et al. had already announced that Viral complementation allows HIV replication without integration. The stage is set elegantly:
Background: The integration of HIV-1 DNA into cellular chromatin is required for high levels of viral gene expression and for the production of new virions. However, the majority of HIV-1 DNA remains unintegrated and is generally considered a replicative dead-end.
But HIV-ologists, and consequently their subject-matter, are not fond of dead ends, so Gelderblom et al. set out to demonstrate experimentally the purposefulness of unintegrated HIV DNA (uDNA):
Most cells which contained only uDNA displayed no detected expression from fluorescent reporter genes inserted into early (Rev-independent) and late (Rev-dependent) locations in the HIV-1 genome. Coinfection with an integrated provirus resulted in a several fold increase in the number of cells displaying uDNA early gene expression and efficiently drove uDNA into late gene expression. We found that coinfection generates virions which package and deliver uDNA-derived genomes into cells; in this way uDNA completes its replication cycle by viral complementation. uDNA-derived genomes undergo recombination with the integrated provirus-derived genomes during second round infection.
Conclusion: This novel mode of retroviral replication allows survival of viruses which would otherwise be lost because of a failure to integrate, amplifies the effective amount of cellular coinfection, increases the replicating HIV-1 gene pool, and enhances the opportunity for diversification through errors of polymerization and recombination.
Gelderblom et al. account for unintegrated intracellular HIV DNA in teleological terms by suggesting a novel method of HIV replication, a novel HIV power and a novel phenotype. “Dead-end” HIV DNA is sublimated, transformed into virions and finally reunified at a higher level of fitness for survival with its already integrated kin.
Gelderblom’s uDNA redemption tale stops short, barely, at concluding that HIV does not need to integrate at all (genomic integration being another defining characteristic of retroviruses) to replicate. But since an external factor, such as previous integration of another HI-virus in the same cell, is sufficient to complete the last step, late gene expression, the door has been opened to further possibilities, including integration-free HIV replication.
Enter Montagnier, whose errand is extracellular as opposed to intracellular unintegrated HIV DNA. The mystery Montagnier seeks to solve is why one marker of productive infection, the “viral load” (HIV RNA), indicates that HIV activity has all but ceased, while another marker, circulating HIV DNA, is still present and indicates ongoing activity. The currently popular explanations of how HIV can continue to stress the immune system and deplete CD4+ cells after it has been effectively put to chromatin sleep usually involve “hidden reservoirs” of HIV where replication can continue to some extent. Circulating viral RNA picked up by the viral load tests seems to confirm this hypothesis, but if the drugs make the viral RNA disappear, why not the circulating DNA? Montagnier’s ingenious answer is that HIV transforms from a retrovirus into an infectious (or rather “transfectious”) DNA being, yet another HIV phenotype.
The idea of infectious DNA carrying all essential viral information is not new, however, and it begs the question why a traditional virus is needed at all. This question has even occurred to virologists, and the answer is that a properly packaged virion is many times more infectious than naked DNA, thus selected for by evolution. Montagnier dutifully includes a version of this virion saver by suggesting that his alternate replication mode is “probably minor”.
But the idea that this alternate mode is what saves the virus from eradication by ARVs is anything but minor. Viral DNA programmed to seek out “unidentified cells and tissues”, borrow their polymerases to replicate as “pieces of a definite size” that can be released and travel intercellularly, while dodging the immune system as well as the drugs, infect and recombine in “appropriate target cells”, finally to regenerate functional virions is hardly what one would call an accidental mechanism in teleological terms. It is a complete and autonomous para-viral operation that could rekindle HIV infection like a phoenix rising from the ashes even after the last virion and the last integrated provirus have been eradicated. It is thus quite possible that the evolution of HIV science at some point in the not so distant future will select for unintegrated viral DNA over virions as the dominant phenotype of HIV generation X.