Unlike people, certain monkey species, such as rhesus or night monkeys, are resistant to HIV thanks to TRIM5, a cellular protein: In the case of an HIV infection, the protein intercepts the virus as soon as it enters the cell and prevents it from multiplying. We have known about TRIM5 for over six years. However, the mechanism TRIM5 uses to prevent the HI virus from multiplying was still largely unknown.
The majority of the key aspects of TRIM5's defense mechanism against HIV was discovered by the Swiss research teams of Prof. Jeremy Luban, University of Geneva, and Prof. Markus Grütter, University of Zurich, in collaboration with teams from the USA and France. They demonstrated that TRIM5 immediately triggers an immune response if infected with HIV. Consequently, TRIM5 is an HIV sensor in the innate immune system. Unlike the adaptive immune system, which only develops when confronted with a pathogen, the innate immune system is already able to eliminate pathogens as soon as it comes into contact with them.
The HI virus, which penetrates the cell during an infection, has a shell, the components of which are arranged in a lattice, similar to the pattern on a soccer ball. TRIM5 recognizes this lattice structure and specifically attaches itself to it. This stimulates the protein to produce signal molecules known as polyubiquitin chains in the cell. These chains immediately trigger an anti-viral reaction. The "alerted" cell can then start eliminating cells infected with HIV by releasing messenger substances (cytokines).
Humans also have a TRIM5 protein, but it is less effective in fending off HIV. However, the findings in resistant monkeys have opened up new possibilities and ways of fighting HIV in humans. 33 million people are currently infected with HIV worldwide; two million die of AIDS each year. And with 2.7 million people becoming infected every year, HIV remains a major problem.
Markus Grütter
gruetter@bioc.uzh.ch
41-446-355-580
ENDS
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.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.
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