I attended a fascinating talk today by biologist Shari Kaiser. She was presenting results of work she did that generated an interesting hypothesis about why humans are susceptible to HIV when other primate species are not. You can see an abstract of her paper on the subject here. Apparently this work is novel and interesting enough that it will soon be published in Science. I'll paraphrase the abstract and try to fill in some of the background science.
HIV is a retrovirus. Retroviruses work by making parts of the cellular genetic machinery work "backwards". Normally genes (sections of DNA) are transcribed into mRNA, which is then translated into proteins. But a retrovirus is a strand of RNA (plus a protein sheath called a capsid) that tricks the cell into reverse transcribing the virus RNA into DNA. That DNA can then sometimes insert itself into the genome of the host cell. Subsequently when that "gene" is expressed the resulting RNA is another copy of the virus.
One other piece of the story: there are two kinds of retroviruses: exogenous and endogenous. An exogenous virus is one that infects an organism from the outside, e.g. when a virus is passed from one person to another via transmission. But remember that successful retroviruses become incorporated in the genome of the host. Therefore, if the retrovirus infects a germ cell (sperm or egg) and becomes incorporated in that cell's DNA, the virus is then passed to offspring produced by the germ cell via normal DNA replication. Now it is a potentially permanent part of the genome of that family tree. Whether it becomes permanent, of "fixed", depends on whether and how it affects the selection outcome for the infected organism: for example if it kills the host before reproduction it cannot become fixed in the population. Once it becomes fixed in the genome it is an endogenous retrovirus. It is estimated that 8% of the human genome consists of (inactive) endogenous viruses. Compare that to the 1.2% of the human genome that comprises our genes.
Once can look for endogenous viruses in various species' genomes. It turns out that many primates, including our closest relative the chimpanzee, have multiple copies of an endogenous virus called PtERV, which appears to have become extinct as an exogenous virus approximately 4 million years ago. Humans do not carry PtERV, which may mean that early humans had resistance to the virus.
Cells have various defenses against viruses. One form is an antiviral protein that binds to the virus capsid and affects the virus in some adverse way. For example, it may disassemble the virus. Only two antiviral proteins have been discovered in humans so far, both were discovered coincidentally as part of HIV-related research. Kaiser's work focused on an antiviral protein named Trim5α. She was curious whether Trim5α may have protected early humans from PtERV. Trim5α is one of the set of genes that undergo the most dynamic mutation, presumably because it is responding to rapidly evolving viruses.
How do you test restriction of a virus that has apparently been extinct for 4 million years? You resurrect it. Remember, we have many copies of the DNA template for the virus sitting in all those primate genomes. So Kaiser identified the pertinent portions of the virus genome and used genetic engineering to make cat kidney cells produce them. She did this in three pieces so as not to actually recreate the whole virus - she really only needed the capsid for her work.
It turns out that the human Trim5α protein is quite good at restricting the resurrected PtERV virus. A whole bunch more work with Trim5α from various primate species essentially showed that Trim5α can either be good at restricting PtERV or it can be good at restricting HIV-1 but generally not both. Rhesus macaque monkeys, for example, are essentially immune to HIV-1 because their form of Trim5α is good at restricting the HIV-1 virus.
So her hypothesis after all of this: humans suck at fighting off HIV-1 because we were good at fighting off PtERV 4 million years ago.
Along the way, she made a lot of discoveries that could be helpful in fighting HIV-1. For example, could we enhance human resistance to HIV-1 by modifying the human Trim5α gene? Time will tell.
