In a small number of people infected with HIV, the virus is naturally suppressed without medical treatment 鈥� 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 鈥淎3鈥� 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鈥檚 genome. A3 usually stops dormant viruses in the human genome, called endogenous retroviruses, from reawakening and causing infections.
at Northwestern University Feinberg School of Medicine in Chicago and his colleagues at Vanderbilt University in Nashville, Tennessee, took blood samples from seven 鈥渃ontrollers鈥� 鈥� the name given to people with HIV who have kept their infections in check without drugs. They compared the samples with blood from 11 鈥渘on-controllers鈥� who must use antiretroviral therapy to suppress the virus.
Advertisement
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.
Natural enemies
D鈥橝quila says that the protective effect of A3 makes sense because, in non-controllers, HIV goes to great lengths to eradicate the protein. 鈥淭he virus鈥檚 first move is to get rid of its natural enemy, A3,鈥� 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鈥檚 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 鈥渇unctional cures鈥� 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鈥橝quila says because A3 can recognise dormant endogenous retroviruses, it can recognise and block other viruses too.
Elite controllers
鈥淸A3] can鈥檛 be evaded by viral mutation, because it simply recognises reverse-transcribed DNA,鈥� says D鈥橝quila.
In the next stage of the research, D鈥橝quila 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.
鈥淲e already know that A3 disrupts HIV,鈥� says of the Pasteur Institute in Paris, France, and an authority on mechanisms of resistance to HIV. 鈥淎lthough 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,鈥� he says.
The mechanism by which controllers keep HIV in check is different from that of an even tinier number of people called 鈥渆lite controllers鈥�. This group keep their viral counts consistently as low as 50 viral copies per millilitre compared with 2000 in 鈥渃ontrollers鈥�.
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:
