Many roads lead to Rome-- HIV-1 Vif vs HIV-2 Vif

"HIV mutates a lot".

People 'get' that. Why is HIV hard to stop? Why is HIV hard to treat? "HIV mutates a lot".

But HIV does not mutate willy-nilly. It mutates at an evolutionarily defined rate.

The reverse transcriptase enzyme makes mistakes during replication that are beneficial to HIV-- creating a diverse population, a quasispecies, that can 'answer' the multitude of evolutionary 'problems' the population faces. A homogeneous population would be wiped out by a particularly efficient antibody, or a targeting drug, but a diverse population means that somewhere in a population of billions, there is at least one variant that can survive the selective onslaught.

That being said, the 'goal' is not to mutate as much as possible. Too many mutations leads to the accumulation of deleterious mistakes. Too many mistakes, and the population dies out. How much variation a populations genomes can tolerate is called an 'error threshold'.

Our immune system has capitalized on this. We have a collection of proteins called the APOBEC family. When this family acts on HIV, during reverse transcription, Cs turn into Us, making Gs in the final HIV proviral DNA As. APOBEC proteins hypermutate HIV, and pushes the HIV population into error catastrophe.

YAY! Eliminate HIV by making it mutate too much! Evolution is *clever*!

... So why is HIV still around? Why didnt it 'mutate into extinction'? Well, Evolution *is* clever.

The HIV protein Vif evolved the ability to counter human APOBEC.

Interestingly, HIV-1 Vif and HIV-2 Vif 'figured out' different ways of doing this:

HIV-1 and HIV-2 Vif Interact with Human APOBEC3 Proteins Using Completely Different Determinants

HIV-1 crossed into humans from chimpanzees. HIV-2 crossed into humans from sooty mangabeys. Contrary to what Michael Behe has ignorantly suggested, SIVCPZ is not SIVSMM is not HIV-1 is not HIV-2.

Though scientists have already demonstrated that with the Vpu and Vpr proteins, that point is reemphasized once again here with Vif.

Because the evolutionary histories of HIV-1 and HIV-2 are different, there are distinct differences between the viral genomes, including the presence or absence of certain accessory proteins. These differences may be attributed in some cases to viral adaptations to new hosts during cross-species transmission events (such as the presence of Vpx in some SIVs, but not in SIVcpz or HIV-1) (23) . In addition, functionally conserved proteins have little homology between their sequences, as is the case with the accessory protein Vif.

Both HIV-1 and HIV-2 have a Vif ascessory protein that performs the same function: degradation of APOBEC proteins. BUT... Vif-1 and Vif-2 dont look a thing alike, genomically.

How can two proteins that are so different preform the same function?

Because while both proteins perform the same function, they do so in totally different ways.

When these researchers focused in on how HIV-2 Vif interacts with the APOBEC family, specifically the A3 group, they found that not only are the portions of the Vif protein that interact with the APOBEC A3 proteins different between Vif-1 and Vif-2, but also the portion of the APOBEC A3 proteins that the Vif-1 and Vif-2 interact with are different.

Why is this important?

Well, obviously it is fun from an evolutionary perspective. There is more than one 'right answer' to a the same selective pressure (human APOBEC A3). Many roads lead to Rome.

But... Many roads lead to Rome.

Scientists have developed numerous antiretroviral drugs that work by interfering with different steps in the HIV life-cycle. Some have had the fantastic idea of trying to inhibit Vif, thereby reestablishing the function of APOBEC, thus 'killing' HIV in patients by letting our immune system mutate the hell out of it.

Now we can be absolutely certain that, like other anti-HIV drugs, one drug will not allow this approach to work 'forever'. If Vif-1 and Vif-2 can figure out two entirely different ways of inhibiting APOBEC A3, then if we apply an anti-Vif drug, Vif (or another HIV protein) will likely evolve an alternative means of inactivating APOBEC. Its happened. It will happen again.

Understanding evolution means we understand how to treat patients.

 

More like this

More HIV news! HIVs ancestor, SIV (simian immunodeficiency virus), has been around a LOT longer than we previously thought. As I have mentioned before, we always assumed retroviruses like HIV, lentiviruses, are evolutionarily 'young'. They are relatively complex, so probably 'newish' in retrovirus-…
MUUUGH. Someone tell Behe to shut up about viruses. SOMEONE. From Lous notes on a recent presentation: New Dude: HIV, someone in the family died this week. Evolutionary Biology, according to evolutionary biology says that HIV comes from some predecessor. That provided a research program. Let's…
Two things I didnt intend on writing about on ERV more than a few times, but turned into repeat guests: XMRV and Vpu. Theyve finally come together. Susceptibility of xenotropic murine leukemia virus-related virus (XMRV) to retroviral restriction factors Know how I was talking about intrinsic…
This is a repost from the old ERV. A retrotransposed ERV :P I dont trust them staying up at Blogger, and the SEED overlords are letting me have 4 reposts a week, so Im gonna take advantage of that! I am going to try to add more comments to these posts for the old readers-- Think of these as '…

Yay! A vif post! I'm impressed you managed to explain this without reference to ubiquitin!

By c0nc0rdance (not verified) on 02 Aug 2014 #permalink