The concept of the biological principle of innate immunity Pii explains the main functionalities of non-coding repeat elements for their hosts’ genomes.
ERVs, Endogenous Retroviruses, as well as transposons are, according to this concept, a sequence-based virus registry on the host genome for the host’s immune system. One complete ERV is one immune-functional unit IFU on the host genome. It functions as one single unit and is inherited as a single unit to convey and ensure resistance against sequence-homolog exogenous pathogens. In more modern immune systems utilizing immune cells like bony fish and mammals, ERVs are methylated to non-coding ERVs for sequence-comparison-only function. The non-coding virus registry provides immunization against sequence-homologue exogenous invading viruses.
One example is presented here to demonstrate the naturally occurring IFU immunization and how it looks for HIV. IFU immunization is the natural process to provide mammals with a virus-registry-based immunization in collaboration with host’s immune cells. The concept of Pii predicts that we will discover HIV-IFUs on human genomes of surviving babies and children of HIV-infected parents which do not demonstrate AIDS symptoms.
ERV, transposon, HIV, immune functional unit, immunization, natural immunization against HIV
Repeats and viral genomes such as endogenous retrovirus genomes and retrotransposons / transposons on host genomes are typically viewed as junk-DNA [1,2] nd genomic parasites. Vast parts of eukaryote genomes convey these repeat framed genomes, which are usually non-coding sequences. This ‘noncoding’ DNA [3] consists mainly of repeat elements of conserved nature during evolution which is visible by their naming convention such as conserved non-coding regions CNC [4], non-coding conserved regions [5], and conserved non-genic sequences CNG [5,6], conserved DNA [7], highly conserved sequences [8], conserved non-coding sequences [9-11], conserved non-coding elements CNE [12], and easily more. The conserved elements are frequently more accurate inherited than genes.
Scientific research on ERVs and transposons and other repeat types is still unable to explain and demonstrate their functionality. Involvement in self-recognition was suggested for ERVs [13] (Villarreal 2009), albeit not as the biological nature is utilizing it in reality and depicted here as principle of innate immunity Pii [14]. According to the state of the art in science are infections by a retrovirus for retroviral replication the cause of a permanent integration of the viral genome into host cell genomes as well as into germline cells, where they are vertically transmitted. The human genome consists of circa 8% of ERVs [15]. In general, replication function of ERVs was disabled during evolution. Human ERVs are also called HERVs.
The genome of an endogenized provirus is identical or almost identical to the infecting exogenous virus. The concept of the principle of innate immunity Pii explains the central functionality of ERVs and transposons on the host genome, and how they in theory convey immunization against highly sequence-homolog exogenous viruses [14].
AIDS, the human Acquired Immune Deficiency Syndrome caused by the human immunodeficiency virus HIV, is one of the most catastrophic pandemics in the modern human history. The vast amount of global infections add up to 77 million humans [16], 35 million of them already died from AIDS [16]. By the year 2012, the figure was down to 1.6 million deaths per year after peaking in 2005 with 2.3 million deaths per year [16]. The causing pathogen, HIV, is subdivided into HIV-1 and HIV-2, HIV-1 is further divided into several subtypes, of which the subtype HIV-1 group M is the one responsible for the global pandemics, while the others are still largely remaining in Central or Westerns Africa. HIV-1 group M established around the year 1920 in the region of Kinshasa, Central Africa, before expanding globally in the late 1970s.
The concept of immune functional units IFUs and the nature of virus repeats as anti-viral registries: The concept of the biological principle of innate immunity Pii is a natural law about distinguishing self-versus non-self and the identification of pathogens.
Endogenized virus genomes and other types of repeats represent the host’s virus sequence database for the host’s immunization against sequence-similar or sequence-homolog exogenous pathogens. This registry database is the basis for both innate and humoral immune systems. It stores the information about foreign pathogen sequences. Invading pathogen sequences are crosschecked versus this on the host’s genome DNA stored information sequence. When a match is found, the foreign DNA is destroyed. In this concept, ERVs are the basis for the host’s innate immune system. It conveys immunity or resistance against exogenous viruses with similar sequences.
In higher animals it has a sequences-comparison-only function [14]. One respective ERV functions as a single unit despite various numbers of genes on its sequence, therefore, it is one immune functional unit IFU [14]. Methylation of IFUs was a fast and easy inhibition of IFU transcripts. A default methylation was postulated by the Pii concept, neither hyper-methylated nor hypo-methylated, and all cytosines along the IFU sequence are mono-methylated.
The proposed function of an ERV is the storage of sequence information, in the case of viruses the complete genome sequence of the virus, as an immune functional unit IFU on behalf of the host’s immune system [14]. One endogenous retrovirus genome on a host genome functions as one single anti-virus sequence registry, and hence, as one immune functional unit IFU.
The main function of the innate immune system is the capability to distinguish between self and non-self or foreign. The main innate classification basis is the sequence stored in the immune functional units IFUs by which the host can separate a known pathogen by the sequence match of the invading pathogen versus the IFU sequences. When as a result a high sequence match is sensed between detected invading DNA or RNA, then the host identifies this invading sequence as foreign. Thus, the only functionality of IFUs is the sequence-comparison-only function in higher animals [14]. In theory, the immune response after sensing a match with an IFU sequence is managed by immune cells in higher animals with an evolved cellular immune system, though the mechanism of action remains to be identified.
The main immune function of an IFU is to convey immunity to the host against sequence-homologue invaders. Additionally, IFUs inherit the same immunity to future generation by inheriting en block the specific IFU to the next generation. The IFU is inherited, managed, treated, and maintained as one single unit under most circumstance. For this reason, IUFs are the largest informational units on the genome, in strong functional difference to genes. The sequence-comparison function is dependent on the measured similarity between endogenous registry and exogenous virus sequences. The repeat types are identifiers of IFUs, indicating to the immune system that between the repeats are foreign sequences stored. With the evolution of a cellular immune system, all IFUs were switched mandatorily to non-coding. The immune response is not any longer connected with the IFU, therefore, the IFU is only a sequence registry, with the mandatory change of the sequence to a completely methylated IFU, the default methylation of IFUs [14].
All reported repeats on animal genomes are in reality distinct IFU registry types, for example endogenous retrovirus ERV and transposons [14]. Moreover, IFUs are not limited to the two types but encompass all common and rare repeat registries as IFU, for example, long interspersed nuclear elements LINEs, short interspersed nuclear elements SINEs, Alu repeat elements, chicken repeat 1 CR1 and interspersed CR1 repeat elements, intracisternal A-type particle IAP, and many rare repeat types.
The feedback loop to integrate a new IFU into germline cells for endogenization of IFUs to immunize future generations: The concept of the principle of innate immunity Pii includes the function of a feedback loop from adaptive memory immune cells to germline cells [14]. This feedback loop is under the control and management of the host’s immune system, and it is responsible for integrating new future IFUs into the genomes of germline cells. The control of endogenization of a new IFU-to-be is a central function of the innate immune system [14]. The feedback loop requires specialized molecules or immune cells to create a new endogenized IFU in spermatocytes or oocytes.
The required mandatory feedback loop is not proven yet in science, but the result is in any case one more IFU in the form of a methylated pathogen-sequence-IFU registry on the host’s genome. With respect to HIV, these new pathogen-sequence-IFU registries would be one or a few HIV-IFUs, starting per individual with a single new IFU, covering population-wide all relevant subtypes. It seems likely, that it is easier to identify a single HIV-IFU on human survivors’ genomes, than proving the principle in a lab before and after endogenization of an IFU and consequent resistance to the exogenous virus.
How naturally occurring HIV-IFUs would look like: The virus is thought to have spilled over from Chimpanzee, Pan troglodytes troglodytes, as they are carriers of the closely related simian immunodeficiency virus SIV. However, as it appears, all primates such as chimpanzee, Western gorilla, mandrills, and other primates obtained SIV infections from a reservoir species [17]. Sooty mangabeys, Cercocebus torquatus atys, are outstanding among SIV-infected primates as they naturally carry SIV, yet don’t develop AIDS-like symptoms, and don’t produce antibodies against SIVs [18]. HIV-2 originates directly from sooty mangabeys [19], while HIV-1 may have mutated in Chimpanzee during long term epidemic adaptation to chimpanzee, which was seriously reducing chimpanzee HLA-repertoire [20] as a proxy to understand that all other HLA-types in chimpanzee became extinct because they did not survive ancient SIV infection. As sooty mangabeys are producing high SIV virus loads without demonstrating symptoms they appear to be SIV super spreaders as a species. According to the concept of Pii, sooty mangabeys should not produce virus loads when carrying endogenous IFUs sequence homolog SIVs. Strikingly, the gray mouse lemur from Madagascar, Microcebus murinus, carries an ancient form of an endogenized SIV on its genome [21]. This observation illustrates that the gray mouse lemur from Madagascar had experienced the SIV epidemic and consequently endogenized the SIV virus as an IFU into its genome at least 14 million years ago [22]
The gray mouse lemur from Madagascar should be tested for immunity against highly sequence homolog exogenous SIV or HIV types: from the concept of Pii, it should be immune against homolog SIVs or HIVs. It would resemble a natural animal model for SIV infections and immunizations.
Translational science and medicine for HIV-IFUs: Many HIV-infected parents get children, either both parents are HIV-infected or either the father or the mother is infected. According to the concept of Pii, endogenization of new IFUs is managed under the control of the host’s immune system. The new IFU is endogenized as the anti-virus registry of the respective exogenous pathogen.
This new IFU is first visible, in general, in children surviving an epidemic. Or better describes, on their genome, and they should be immune against HIV infections homolog to the new IFU sequence.
With the HIV pandemic, we have a devastating epidemic with no real cure of the infection. Therefore, it would be possible to see how nature is dealing with this infection on its own. This means, according to the concept of Pii and based on the observations of repeats on host genomes, that the natural way of HIV-immunization will be the germline endogenization of the complete HIV genome.
This will in principle be first visible on the genome of surviving children from HIV-infected parents. During their parents’ infections, a few of them are able to hand over the HIV sequence in the mentioned feedback loop to their germline cells, either a spermatocyte or an oocyte, into whose cell’s genome the new HIV-IFU is integrated, likely by a memory immune cell of one of their parents. The children carrying the new HIV-IFU should be immune to the sequence-homolog HIV virus. And these children should carry the new HIV-IFU in all their cell genomes.
To discover the new HIV-IFU, whole-genome sequencing is necessary of children from HIV-infected parents surviving virus-free. There will be only one single copy of the new HIV-IFU on a few children genomes, integrated anywhere into the genome, the enHIV. According to the concept of Pii, a single HIV-IFU is sufficient to induce immunity against highly sequence-homolog exogenous HIVs. Depending on the origin of the children, this HIV-IFU will be homolog to the predominant pandemic exogenous HIV-1 group M, the IFU is then enHIV-1_group_M, when the surviving child is from outside of Africa. The new HIV-IFU can be homolog to any existing subtype, when the child originates from Central or West Africa as mostly the group M subtype has been casing the global pandemic while the other subtypes still mostly relate to African regions.
Main limitations
The here presented concept provides the rational why junk DNA exists. The main drawback of the concept is that it lacks a laboratory proof in an animal model. Future research should identify surviving children with newly integrated HIV-IFUs. Then we will have a basis for translational medicine by identifying how the new HIV-IFU functions.
No conflicts of interests for this manuscript.
- Doolittle WF (2013) Is junk DNA bunk? A critique of ENCODE. Proc Natl Acad Sci U S A 110: 5294-5300. [Crossref]
- Pennisi E (2012) Genomics. ENCODE project writes eulogy for junk DNA. Science 337: 1159-1161. [Crossref]
- Bromham L (2002) The human zoo: endogenous retroviruses in the human genome. Trends in ecology & evolution 17: 91-97.
- Kryukov GV, Schmidt S, Sunyaev S (2005) Small fitness effect of mutations in highly conserved non-coding regions. Human molecular genetics 14: 2221-2229
- Dermitzakis ET, Reymond A, Antonarakis SE (2005) Conserved non-genic sequences - an unexpected feature of mammalian genomes. Nature reviews genetics 6: 151-157.
- Dermitzakis ET, Reymond A, Lyle R, Scamuffa N, Ucla C, et al. (2002) Numerous potentially functional but noon-genic conserved sequences on human chromosome 21. Nature 420: 578-582.
- Hovel-Miner G, Mugnier MR, Goldwater B, Cross GAM, Papavasiliou FN (2016) A Conserved DNA Repeat Promotes Selection of a Diverse Repertoire of Trypanosoma brucei Surface Antigens from the Genomic Archive. PLOS Genetics 12: e1005994.
- Zhang J, Yang J-R (2015) Determinants of the rate of protein sequence evolution. Nature reviews genetics 16:409.
- Drake JA, Bird C, Nemesh J, Thomas DJ, Newton-Cheh C, et al. (2006) Conserved noncoding sequences are selectively constrained and not mutation cold spots. Nature Genetics 38: 223-227.
- Wicker T, Taudien S, Houben A, Keller B, Graner A, et al. (2009) A whole-genome snapshot of 454 sequences exposes the composition of the barley genome and provides evidence for the parallel evolution of genome size in wheat and barley. The Plant Journal 59: 712-722.
- Woolfe A, Goodson M, Goode DK, Snell P, G.K. M, et al. (2005) Highly conserved non-coding sequences are associated with vertebrate development. PLOS Biology 3: 116-130.
- Benko S, Fantes JA, Amiel J, Kleinjan DJ, Thomas S, et al. (2009) Highly conserved non-coding elements on either side of SOX9 associated with Pierre Robin sequence. Nature Genetics 41: 359.
- Villarreal LP (2009) The source of self: genetic parasites and the origin of adaptive immunity. Ann N Y Acad Sci 1178: 194-232. [Crossref]
- Hammen VC (2018) Ars Immunitas: The Source and Fate of Innate Immunity. The Principle of innate immunity Pii, the concept of the natural law of genomic immune functional units as antiviral registries, the three major pathways of disease, and the 4th pathway of ageing epubli, München, Weilburg, Germany, 580 pp.
- Gifford R, Tristem M (2003) The evolution, distribution and diversity of endogenous retroviruses. Virus Genes 26: 291-315. [Crossref]
- UNAIDS (2018) 2017 GLOBAL HIV STATISTICS. UNAIDS.
- Sharp PM, Hahn BH (2011) Origins of HIV and the AIDS pandemic. Cold Spring Harb Perspect Med 1: a006841. [Crossref]
- Kaur A, Grant RM, Means RE, McClure H, Feinberg M, et al. (1998) Diverse Host Responses and Outcomes following Simian Immunodeficiency Virus SIVmac239 Infection in Sooty Mangabeys and Rhesus Macaques. Journal of Virology 72: 9597-9611.
- Chen Z, Telfier P, Gettie A, Reed P, Zhang L, et al. (1996) Genetic characterization of new West African simian immunodeficiency virus SIVsm: geographic clustering of household-derived SIV strains with human immunodeficiency virus type 2 subtypes and genetically diverse viruses from a single feral sooty mangabey troop. Journal of Virology 70: 3617-3627.
- de Groot NG, Bontrop RE (2013) The HIV-1 pandemic: does the selective sweep in chimpanzees mirror humankind's future? Retrovirology 10: 53. [Crossref]
- Gifford RJ, Katzourakis A, Tristem M, Pybus OG, Winters M, et al. (2008) A transitional endogenous lentivirus from the genome of a basal primate and implications for lentivirus evolution. Proceedings of the National Academy of Sciences 105: 20362-20367.
- Pretorius C, Glaziou P, Dodd PJ, White R, Houben R (2014) Using the TIME model in Spectrum to estimate tuberculosis-HIV incidence and mortality. AIDS 28 Suppl 4: 477-487. [Crossref]
