Both men were infected by the human immunodeficiency virus (HIV), one of them 30 years ago, but never developed AIDS symptoms.
The AIDS-causing virus remained in their immune cells but was inactivated because its genetic code had been altered, the scientists said.
The change appeared to be linked to increased activity of a common enzyme named APOBEC, they theorized.The "apparent spontaneous cure" throws up an intriguing avenue for drug engineers, the team said in a statement.
"The work opens up therapeutic avenues for a cure, using or stimulating this enzyme, and avenues for identifying individuals among newly-infected patients who have a chance of a spontaneous cure."
The work, published in the journal Clinical Microbiology and Infection, was carried out by scientists at France's Institute of Health and Medical Research (Inserm).
HIV replicates by invading human CD4 immune cells, which it reprogrammes to become virus factories.
A rare group of people — fewer than one per cent of those infected — are naturally able to rein in viral replication and keep the virus at clinically undetectable levels.
They are known as "elite controllers", but the mechanism by which they keep the virus at bay remains a mystery.
The French group looked at two such individuals, a 57-year-old man diagnosed HIV-positive in 1985, and a 23-year-old diagnosed in 2011, and sequenced their virus genomes.
Though they remained infected, standard tests could not detect the virus in their blood.
The team found that in both cases, the virus was unable to replicate in immune cells due to mutations in its genetic code.
The researchers suggested spontaneous evolution between humans and the virus, a process called "endogenisation" that is believed to have neutralized other viruses in humans in the past.
A similar process has been witnessed in a population of koalas that has integrated an AIDS-like virus into their genes, neutralized it, and were passing resistance on to their offspring.
"We propose that HIV cure may occur through HIV endogenisation in humans," the team wrote.
"These findings suggest that without therapeutic and prophylactic strategies, after several decades of HIV/host integrations and millions of deaths, it is likely that a few individuals might have endogenised and neutralized the virus and transmitted it to their progeny," they added.
"We believe that the persistence of HIV DNA can lead to cure, and protection, from HIV."
The approach hitherto has been the opposite: to try and clear all traces of HIV from human cells and from cell reservoirs where they hide.
"We suggest that persistence of integrated HIV DNA is not a barrier, but on the contrary, may be a prerequisite to HIV cure," said the study authors.
"We propose a new vision of HIV cure through integration, inactivation and potential endogenisation of a viral genome into the human genome."
The team said they did not believe the two patients were unique or that the phenomenon was new.
And they called for "massive sequencing" of human DNA, particularly from Africans who had been exposed to HIV for longest, to find further proof.
Only one person is thought to have ever been cured of HIV: Timothy Ray Brown who had bone marrow transplants as a treatment for leukaemia, from a donor with resistance to HIV.
A baby given anti-AIDS drugs immediately after birth for 18 months, was at first also thought to have been cured, but the virus later came back.
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