In a small number of people infected with HIV, the virus is naturally suppressed without medical treatment – and we might be closer to understanding why. They may carry high quantities of a protein that disrupts viral replication in cells.
Called APOBEC3G, or "A3" for short, the protein sabotages reverse transcription, the process HIV relies on for its replication. This process involves the virus transcribing its singe-stranded RNA genome into double-stranded DNA that is incorporated into the cell's genome. A3 usually stops dormant viruses in the human genome, called endogenous retroviruses, from reawakening and causing infections.
Richard D'Aquila at Northwestern University Feinberg School of Medicine in Chicago and his colleagues at Vanderbilt University in Nashville, Tennessee, took blood samples from seven "controllers" – the name given to people with HIV who have kept their infections in check without drugs. They compared the samples with blood from 11 "non-controllers" who must use antiretroviral therapy to suppress the virus.
The cytoplasm in blood cells from the controllers, who account for just 1 per cent of all people infected with HIV, contained up to twice as much A3 as normal, suggesting this is a key factor in keeping the virus in check.
D'Aquila says that the protective effect of A3 makes sense because, in non-controllers, HIV goes to great lengths to eradicate the protein. "The virus's first move is to get rid of its natural enemy, A3," he says.
If a treatment could preserve levels of the saboteur protein, this would enable many more people than at present to control the virus without medication.
Beginning antiretroviral therapy at an earlier stage after infection may be one way to do this. If the therapy keeps levels of the virus low enough to prevent it totally depleting a person's A3, then the protein may retain the upper hand over the virus as the infection continues.
This could help to explain how a baby and at least 14 adults infected with HIV were shown earlier this year to have "functional cures" thanks to very early treatment.
Boosted levels of A3 may be beneficial for another reason: the protein can kill drug-resistant mutants of HIV, because it sabotages all reverse-transcribed viral material, irrespective of what mutations it carries. D'Aquila says because A3 can recognise dormant endogenous retroviruses, it can recognise and block other viruses too.
"[A3] can't be evaded by viral mutation, because it simply recognises reverse-transcribed DNA," says D'Aquila.
In the next stage of the research, D'Aquila and his colleagues will test whether early therapy does indeed preserve levels of A3. They will also hunt for drugs that boost natural levels of the protein.
"We already know that A3 disrupts HIV," says Asier Sáez Cirión of the Pasteur Institute in Paris, France, and an authority on mechanisms of resistance to HIV. "Although this study shows a correlation between A3 levels and suppression of HIV, further work is needed to explore just how important it is for controllers," he says.
The mechanism by which controllers keep HIV in check is different from that of an even tinier number of people called "elite controllers". This group keep their viral counts consistently as low as 50 viral copies per millilitre compared with 2000 in "controllers".
Many elite controllers may rely on defects in CCR5, a protein on the surface of blood cells that acts as a kind of doorknob for HIV. If the protein is defective, HIV cannot get into cells to infect them, so people remain immune to the virus.
Journal reference: PLoS One, DOI: 10.1371/journal.pone.0076002
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