A cure for AIDS may not be far away by turning a provirus into a friend

41 years after the discovery of AIDS, antiretroviral therapy has become the standard treatment for people living with HIV
.

Thanks to the continuous improvement of this program, the life expectancy of HIV-infected people is no different from that of the general population
.

But HIV cannot be cured so far, and the side effects of long-term medication have greatly reduced the quality of life of many patients
.

Both the public and the medical community are eagerly awaiting the advent of an effective HIV vaccine, or the birth of a curative drug
.

It is worth noting that a small number of groups in the population are naturally resistant to HIV.
Even if they are infected with HIV, the virus replication rate in their bodies is far lower than that of most people, and they do not even need drug control
.

The study of these people, known as the "elite group," may help us finally defeat HIV
.

researchers found that the biggest difference between elite groups and ordinary infected people is that they have a stronger anti-HIV immune response, which is likely to be closely related to the latent site of HIV provirus in their body
.

As the name suggests, HIV provirus is the state before the birth of the full HIV virus
.

After HIV invades the human body, it first binds to the CD4 molecule of the cell, and then releases the viral RNA into the cell
.

With the help of reverse transcriptase, RNA is converted into double-stranded DNA
.

This double-stranded DNA will further enter the nucleus and integrate into the genome of the cell.
At this time, the HIV information exists in the cell in the form of DNA.
This state is the provirus
.

Knowing that the provirus produces RNA along with the transcription of cells, and then translates various proteins, which assemble with the viral RNA into complete viral particles, namely HIV virus
.

The virus particles are then released into the bloodstream and infect other healthy cells, a life cycle of HIV
.

But not all proviruses carry the complete HIV genetic information
.

There are also a large number of defective proviruses in infected people.
These proviruses can be regarded as "disabled versions" of HIV.
They can express part of HIV proteins or nucleic acids, but cannot assemble into complete virus particles.
Therefore, it is often considered that is harmless
.

In recent years, research has gradually realized that defective proviruses have the role of helping HIV evade immune attack
.

These defective proviruses produce parts of HIV that are activated by the human immune system to attack the protein or nucleic acid
.

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com However, the complete HIV provirus is the real enemy of the immune system, but the immune system is lured by the defective provirus and cannot concentrate its firepower on the intact virus particle
.

The strategy of adjusting the complete and defective proviruses to help HIV escape the human immune system smoothly, and can replicate and spread rapidly
.

Although intact and defective proviruses also exist in elite groups, their integration sites into the host genome are distinct, giving the immune system a turnaround for normal antiviral function
.

The researchers found that in the elite group, HIV has lower immune escape mutations to humoral and cellular immunity than the general population, which means that the immune system can play a stronger anti-HIV role
.

But why HIV's immune escape mutations are limited in these populations remains a mystery
.

doi: 10.
1126/scitranslmed.
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Further research found that the intact proviruses in these groups tend to integrate into a special chromatin region of the host, and the replication activity of this part of the region is very low.
As a result, the replication level of the provirus is also corresponding lower
.

This could explain the low levels of virus in elite groups
.

The researchers believe this characteristic is caused by immune stress
.

The immune system of an elite population can recognize highly active proviruses and then attack and eliminate these active proviruses
.

Proviruses that integrate into regions that are not easily replicated have survived because they are less active and not easily detected by the immune system
.

After the general population is infected with HIV, the body's immune response is at a moderate level.
This level cannot really eliminate the provirus, but instead promotes the occurrence of various mutations that are beneficial to HIV
.

The immune response of the elite group is high, it can eliminate the provirus before it has mutated, and only the provirus that is latent in the low activity area can survive
.

doi: 10.
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abl4097.
The paradox is that these latent intact proviruses, due to their special location in chromatin, can only weakly secrete viral antigens, which are not sufficient to stimulate a sufficiently strong immune response
.

Further research found that this high level of immune response in the elite population cannot be separated from the help of a defective provirus
.

These defective proviruses are like a training ground, constantly producing part of the antigenic material of the virus, stimulating the immune system to be on high alert
.

It can be seen that the defective provirus that helps HIV evade immune pursuit in ordinary infected people has become a comrade-in-arms of the immune system in the elite group
.

The next study is to find out why the elite group has a higher level of immune response than the general infected
.

doi: 10.
1126/scitranslmed.
abl4097.
Defective proviruses play a role in elite populations just like vaccines, providing a new direction for HIV vaccine development
.

If the vaccine can also be integrated into the host chromatin and stably express antigenic substances to stimulate the body to produce a highly active antiviral immune response, it may be able to play a good role in resisting infection
.

Over the past 40 years, HIV infection has gradually changed from an incurable disease to a preventable and controllable chronic disease
.

Looking forward to the future, we look forward to more breakthroughs in HIV prevention and treatment in the next 40 years
.

References Lian XD, et al.
Signatures of immune selection in intact and defective proviruses distinguish HIV-1 elite controllers.
Sci Transl Med, 2021, 13(624): eabl4097.
doi: 10.
1126/scitranslmed.
abl4097.
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