By Vivienne Baillie Gerritsen
Face-to-face combat is not only reserved to the world of animal conflict. It also exists at the molecular level. Over time, animals have developed means to fight off foreign bodies. So far, this is nothing new. We have all heard of the immune system and the clever tactics it uses to overcome various diseases. Recently however, it was discovered that the defensive effects of one particular protein (APOBEC3G) - found mainly in human T lymphocytes - were literally wiped out by the actions of a second viral protein (VIF) which actually manages to neutralize it. The net result is viral infection of human T lymphocytes. Yes, VIF belongs to Type 1 Human Immunodeficiency Virus (HIV-1) and seems to be crucial for the development of viral infection; whilst APOBEC3G, without the counter-effects of VIF, can actually ward off HIV-1 infection on its own. The great interest is that novel therapies developed around APOBEC3G and VIF should be of tremendous help in the endless struggle to design drugs which will fight off HIV-1 infection effectively.
APOBEC3G is found in human T lymphocytes and predominantly a cytoplasmic protein - although a few individuals can be found in the cell’s nucleus. APOBEC3G is otherwise known as a cytidine deaminase nucleic acid-editing enzyme. Quite a mouthful. What it does is cause hypermutations in single-stranded DNA by deaminating cytidines. Consequently, while editing should be the source of text corrections, APOBEC3G quite happily creates errors - or mutations. It is far from the only one of its kind but what it does have is the ability to attack viral DNA. Or, more to the point: HIV-1 DNA.
When HIV-1 invades a T lymphocyte, it uses the host cell and part of its machinery to reproduce virions. Mature virions are then released - and in so doing kill the host T lymphocyte - and their sole aim in life is to invade and infect other T lymphocytes to continue the deathly cycle. However, some lymphocytes do not give HIV-1 infection a chance. Thanks to APOBEC3G. HIV-1 is a retrovirus. Its viral RNA has first to be transcripted into viral DNA. The viral DNA then inserts itself into the host DNA and the host quite innocently synthesizes copies of the viral proteins. The new viral proteins and novel copies of viral RNA are then used to make new virions. What APOBEC3G does is slip slyly into the nascent virions and hitches a ride. Each new virion is then released from the host cell. Hence, the new virions are themselves ‘infected’ by APOBEC3G.
Fig. 1 Scanning electron micrograph of HIV-1 budding from cultured lymphocyte.*
When these virions infect a T lymphocyte, APOBEC3G comes onto the scene. During the process of viral reverse transcription, APOBEC3G spots runs of cytosine (C) nucleic acids in the newly synthesized minus viral DNA (at least two cytosines in a row) and heads straight for them. It lodges itself on the nucleic acid and subsequently inserts an error by swapping cytosine for uracil (U) in the nascent transcript. Thus causing a guanine (G) to adenine (A) mutation in the viral DNA plus strand. Such action could have a number of consequences. The mutations could serve to disrupt a specific viral protein and as a result the new virions would either be non-viable or non-infectious. Or they could create such havoc on the viral DNA that all novel production of virions would just be impossible. It turns out that this is precisely what happens. G to A mutations are inserted all along the viral DNA and literally break up the viral code. The resulting virions are helpless. And infection grinds to a halt.
The wicked part for humans infected by HIV-1 is that the virus itself is armed against the doings of APOBEC3G. The HIV-1 genome is, understandably, one of the most studied genomes to date. Which, in a way, is not so difficult since it sports only nine genes which code for proteins. One of these genes, VIF or virion infectivity factor, can actually neutralize the action of APOBEC3G in two ways. First, it interferes with the translation of APOBEC3G thereby stunting its synthesis and secondly it actually clings onto APOBEC3G and triggers off its breakdown via a proteolytic pathway involving a ubiquitin-dependent proteasome. There is not much APOBEC3G can do against this and the end result is that it is given no chance to insert mutations in the virions’ DNA, which therefore continue their devious plot to infect the host’s immune system.
So APOBEC3G would have the power to invalidate HIV-1 infection were it not for the existence of VIF. The discovery is paramount. More must be done to understand in full the molecular processes underlying the action of APOBEC3G and that of VIF. However, already today, it is not an extravagant prospect to imagine the design of drugs which could interfere either with the binding of VIF to APOBEC3G, or with APOBEC3G degradation by VIF so that APOBEC3G continues to be a threat to HIV-1, causing irreparable damage to its DNA and thereby stunting the formation of new virions and the spreading of HIV. Better still, hope of such drugs lies not only in the fight against HIV-1. Indeed, APOBEC3G is non-specific enough in its action to impede the folly of other retroviruses such as Hepatitis B or indeed certain forms of leukemia also caused by retroviruses. For the time being, VIF is the craftier of the two; the trick is to push it into the back seat.
*Source: ‘Silencing Genes in HIV One of nature’s oldest tricks thwarts the AIDS virus in cell cultures’ E.R.Winstead. http://www.genomenewsnetwork.org/
Cross-references to Swiss-Prot
Q9HC16: Homo sapiens (human) APOBEC3G
References
1. Mangeat B., Turelli P., Caron G., Friedli M., Perrin L., Trono D.Broad antiretroviral defence by human APOBEC3G through lethal editing of nascent reverse transcriptsNature 424:99-103(2003)PMID: 12808466.
2. Stopak K., de Noronha C., Yonemoto W., Greene W.C.HIV-1 Vif blocks the antiviral activity of APOBEC3G by impairing both its translation and intracellular stabilityMol. Cell 12:591-601(2003)PMID: 14527406.
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