Natural defenses our cells have against HIV

Human cells have some natural defenses called “restriction factors” that protect cells against infection by viruses.

Three main ones talked about in the HIV field are:

     

  • TRIM5-alpha
  • Tetherin
  • APOBEC-3G
  •  

Don’t let the acronyms intimidate you. These proteins are present in all of our cells and have very specific functions against viruses like HIV.

Keeping HIV boxed in

TRIM5-alpha is a protein in human cells that unfortunately doesn’t actually work against HIV.

However, it does protect human cells against other viruses. Furthermore, in certain monkeys, it seems to be the reason that they can’t get infected with HIV.

When it works, TRIM5-alpha interferes with a process called “uncoating” in a retrovirus (such as HIV). Essentially, uncoating occurs when the viral capsid (basically the box where it keeps its genome) dissolves to release the genome into a cell.

In certain monkeys, TRIM5-alpha seems to be able to prevent this essential step in the life cycle of HIV from occurring, meaning the genome is stuck in the capsid and that these monkeys can’t get infected by HIV.

Lassoing HIV to the cell

Tetherin is a molecular “lasso” that “tethers” new baby viruses to a cell as they try to escape.

In this figure, taken from Stuart and colleagues in the journal Nature, we see a bunch of HIV virus particles (the little black circles) all clumped around a cell.

This doesn’t normally happen with HIV. Usually new baby viruses bud out of cells and move along to infect new ones.

What’s causing this clumping?

Tetherin! It latches onto these new viruses and keeps them on the cell surface, which prevents them from moving on to infect new cells.

But this doesn’t usually occur in HIV infection. Most new viruses are able to escape the effect of tetherin. In real life, tetherin activity is so bad from HIV’s point of view, that HIV actually has a protein called Vpu that it uses to block tetherin.

The figure from the Stuart paper shows what happened when the experimenters deleted the Vpu gene from HIV and allowed the virus to replicate itself in cells. What happened is that without the action of HIV’s Vpu protein, all the new baby viruses got stuck to the cells and clumped together because of tetherin. Blocking Vpu might even make an attractive target for an antiretroviral drug by allowing tetherin to do its job.

What got me writing this post this week was a new paper that came out about how HIV targets another restriction factor called APOBEC3G, and how it might use that to its advantage.

Mutant-maker

APOBEC3G is another restriction factor that we have in our cells. APOBEC3G (pronounced “ape oh Beck 3G”) has a weird way of messing with HIV.</span<

It introduces mutations in the HIV genome by essentially changing the DNA base guanosine (G) into adenosine (A).

It’s actually a bit more complicated than that but the end-result is the same: APOBEC3G changes Gs in HIVs genome to As. Now introducing all these mutations into its genome is bad for HIV because the mutations can mean that its proteins won’t work as well. So yet again, HIV has a protein that counteracts this restriction factor. That protein is called Vif.

APOBEC Advantage

Last year, Fourati and colleagues published a nice paper where they looked at whether antiretroviral therapy could result in changes in Vif, the anti-APOBEC3G protein. Their idea was that HIV might be able to use the mutagenic (mutation introducing) activity of APOBEC3G to its advantage.

We know that mutations in HIV can cause drug resistance, which allows the virus to replicate even in the presence of antiretrovirals. For instance, a single mutation in HIV’s reverse transcriptase gene (a mutation to the amino acid valine at position 184) can allow the virus to replicate in the presence of the antiretroviral drugs lamivudine (3TC) and emtricitabine (FTC).

Fourati and colleagues had the idea that a mutation Vif might slightly reduce its ability to block APOBEC3G. Vif blocks APOBEC3G mostly by targeting it to be degraded by the cell, which reduces the levels of APOBEC3G within the cell.

So, a mutation in Vif could potentially allow a little bit more APOBEC3G to stick around in cells, which could make the build-up of mutations a bit faster, without allowing APOBEC to go crazy and introduce too many mutations. If this actually did happen, you’d expect to find Vif mutations in HIV from patients who are failing therapy due to drug resistance. This is exactly what the Fourati group found.

Specifically, there was a mutation in Vif called K22H (a change at position 22 from the amino acid lysine to a histidine) that was almost 10 times more common in patients who were failing therapy. They then performed experiments where they took HIV with the K22H mutation and grew it in cells. If the mutation decreases Vif’s action against APOBEC, you would expect more of those G to A mutations in the resulting viruses.


Indeed, when they looked, 72% of viruses with the K22H mutation had at least 2 known drug resistance mutations that get made from changing a G to an A. The frequency of these various drug resistance mutations is shown with black bars in the figure from the Fourati paper above. The grey bars indicate viruses where the Vif protein wasn’t mutated. These were less likely than the mutant viruses to have the drug resistance mutations, perhaps because APOBEC3G wasn’t being blocked as well by the K22H Vif mutant protein.

The Vif mutation is more common in certain HIV strains

Finally, there was a recent letter in the Journal of Antimicrobial Chemotherapy from Yebra and Holguín. They looked at whether this K22H mutation was more common in certain “clades” of HIV.

HIV can be divided into several different clades, usually named with letters. Each clade has a slightly different sequence for its genome, which gives it slightly different properties compared to other clades. In North America, most people have clade B HIV. However, worldwide, clade C is most common, and almost all the different clades of HIV are present and quite common in Africa.

Yebra and Holguín scanned through the big database for HIV sequences at Los Alamos and looked at whether the K22H mutation in Vif is more common in some clades than others. For clade B, only 3% of the documented viruses have H at that position. However, for clade A1, a full 18% of the documented sequences had the 22H mutation. The prevalence of the 22H mutation was also higher in “recombinant” clades that contain parts of genomes from more than one clade.

Interestingly, this higher prevalence of H in certain clades also appeared to be associated with higher prevalence of two drug resistance mutations: M36I and M46I, both of which increase resistance of HIV to the protease inhibitor class of antiretrovirals.

In conclusion

To sum up, human cells have specialized proteins that can restrict the replication of viruses like HIV. But being the nasty virus it is, HIV often finds ways to bypass these restriction factors, or possibly even use them to its advantage.

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Comments
2 Responses to “Natural defenses our cells have against HIV”
  1. lynn says:

    Very interestin…thank you!!

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