So far, I've covered several stages in the life cycle of a retrovirus infecting mammals. Transmission via body fluids, blood, saliva, semen in horizontal transmission, milk in vertical transmission are typical. This could apply to a beta or gamma retrovirus. As it happens, both groups are well represented as human endogenous retroviruses (HERV). The "junk DNA" left by HERVs over periods of up to many millions of years forms about 8% of current human genomes. We can set upper bounds on age, but setting lower bounds gets us into problems. Some of them could have been inserted recently. Sequencing genomes has not gone far enough among billions of people to have much idea of all the junk we may yet find. We are still looking at variations in regions coding for normal human DNA.
In fact, sequences which have totally lost the ability to form exogenous virions can continue to insert themselves at new places in a genome, these are called retrotransposons. In mice, which have been extensively studied, these can generate particles that don't make it out of cells, intracisternal A-type Particles (IAP). There are typically some 2,000 copies of these defective viral sequences in a mouse genome.
This provides a quick check for contamination by mouse cells, as does testing for mouse mitochondrial DNA, which is significantly different from human mitochondrial DNA and more common than nuclear DNA. Still, some caution is needed. Long persistent retroviral infections generate similar IAP particles in other species. If the infecting virus closely resembles a mouse virus, and it generates IAP particles, there may be a few IAP-like sequences in hosts. The difference is a matter of numbers.
As said above, those HERV sequences tell a story of infection of human ancestors. We are not talking about one or two events, but dozens of distinct viruses which made the full transition from exogenous to endogenous. Delta retroviruses and lenti viruses, like HIV-1 and HIV-2 are less well represented, indicating these are recent additions, in evolutionary time. In the case of HIV-1 there is good reason to put case zero around 1910, very recent by evolutionary standards. HTLV-1 appears to have been around longer, though we don't know much about this. HIV-2 and HTLV-2 are likely older than their counterparts, and better adapted (less lethal) to human hosts.
To become fully endogenous a retrovirus must insert its genes in germ-line cells without damaging their ability to reproduce. When gametes meet to form zygotes, these genes must not become active early in gestation, or the infected embryo will likely die. Carrying these extra genes must not handicap the host to the extent of reducing differential reproductive success, or the genes will not spread throughout a breeding population. These are tough requirements. For every exogenous retrovirus which becomes endogenous there must be many that infect some host populations without becoming widespread and endogenous throughout the entire species. This is where we should find chronic infectious diseases which handicap, but seldom kill, hosts.
Where we see definite remains of perhaps 60 distinct viruses, we are probably looking at the residue of many thousands of epidemics spread over millions of years. Estimates of ages for these sequences are reassuring, in the sense of suggesting present infections are rare. All such complete sequences are replication defective, so considered inactive.
The problem with the reassuring arguments is that almost all human population growth has taken place very recently. Human numbers during most human evolution were generally below 100 million, or even 10 million. Even these populations were often fragmented into smaller unconnected groups. More likely than not, an epidemic which doesn't drive an isolated population to extinction will burn itself out there without becoming a HERV. If the rate of appearance of new retroviral epidemics were only one in six thousand years, in a population of one million, for a single connected population of six billion we might expect one new epidemic every year.
With the exception of dogs, nearly all domesticated animals were bred in the last 5,000 years. Huge populations of people living together with huge populations of domesticated animals are biologically recent phenomena. We need to consider possible transmission from those animals to humans very carefully. When many of those animals, included those domesticated by accident, like mice, are hosts to retroviruses we have to ask what makes humans immune? So far, we have no good answer.
There is one other meaning to the retroviral endgame, the death of individual hosts. This is a case where slow replication does the virus no good whatsoever. If the virus can tell the host is dying, it would make sense for it to abandon any restraint about replicating rapidly. It just might get lucky and infect a care-giver or predator. Illnesses thought long-gone will reemerge near the time of death. This gives another clue about what characteristics to look for in a retrovirus causing chronic illness. The illnesses caused by defective virus or poor pathogen adaptation will resemble the results of premature aging.
Does any of this sound familiar to people with ME/CFS?
In fact, sequences which have totally lost the ability to form exogenous virions can continue to insert themselves at new places in a genome, these are called retrotransposons. In mice, which have been extensively studied, these can generate particles that don't make it out of cells, intracisternal A-type Particles (IAP). There are typically some 2,000 copies of these defective viral sequences in a mouse genome.
This provides a quick check for contamination by mouse cells, as does testing for mouse mitochondrial DNA, which is significantly different from human mitochondrial DNA and more common than nuclear DNA. Still, some caution is needed. Long persistent retroviral infections generate similar IAP particles in other species. If the infecting virus closely resembles a mouse virus, and it generates IAP particles, there may be a few IAP-like sequences in hosts. The difference is a matter of numbers.
As said above, those HERV sequences tell a story of infection of human ancestors. We are not talking about one or two events, but dozens of distinct viruses which made the full transition from exogenous to endogenous. Delta retroviruses and lenti viruses, like HIV-1 and HIV-2 are less well represented, indicating these are recent additions, in evolutionary time. In the case of HIV-1 there is good reason to put case zero around 1910, very recent by evolutionary standards. HTLV-1 appears to have been around longer, though we don't know much about this. HIV-2 and HTLV-2 are likely older than their counterparts, and better adapted (less lethal) to human hosts.
To become fully endogenous a retrovirus must insert its genes in germ-line cells without damaging their ability to reproduce. When gametes meet to form zygotes, these genes must not become active early in gestation, or the infected embryo will likely die. Carrying these extra genes must not handicap the host to the extent of reducing differential reproductive success, or the genes will not spread throughout a breeding population. These are tough requirements. For every exogenous retrovirus which becomes endogenous there must be many that infect some host populations without becoming widespread and endogenous throughout the entire species. This is where we should find chronic infectious diseases which handicap, but seldom kill, hosts.
Where we see definite remains of perhaps 60 distinct viruses, we are probably looking at the residue of many thousands of epidemics spread over millions of years. Estimates of ages for these sequences are reassuring, in the sense of suggesting present infections are rare. All such complete sequences are replication defective, so considered inactive.
The problem with the reassuring arguments is that almost all human population growth has taken place very recently. Human numbers during most human evolution were generally below 100 million, or even 10 million. Even these populations were often fragmented into smaller unconnected groups. More likely than not, an epidemic which doesn't drive an isolated population to extinction will burn itself out there without becoming a HERV. If the rate of appearance of new retroviral epidemics were only one in six thousand years, in a population of one million, for a single connected population of six billion we might expect one new epidemic every year.
With the exception of dogs, nearly all domesticated animals were bred in the last 5,000 years. Huge populations of people living together with huge populations of domesticated animals are biologically recent phenomena. We need to consider possible transmission from those animals to humans very carefully. When many of those animals, included those domesticated by accident, like mice, are hosts to retroviruses we have to ask what makes humans immune? So far, we have no good answer.
There is one other meaning to the retroviral endgame, the death of individual hosts. This is a case where slow replication does the virus no good whatsoever. If the virus can tell the host is dying, it would make sense for it to abandon any restraint about replicating rapidly. It just might get lucky and infect a care-giver or predator. Illnesses thought long-gone will reemerge near the time of death. This gives another clue about what characteristics to look for in a retrovirus causing chronic illness. The illnesses caused by defective virus or poor pathogen adaptation will resemble the results of premature aging.
Does any of this sound familiar to people with ME/CFS?
