Creepy HIV memory forces a patient's immune system to keep him always sick

Antiretroviral therapy (ART) limits HIV infection to very low levels in the blood by using anti-HIV medicines. Still, patients living with even controlled HIV infection are found to be at risk of chronic inflammation that further leads to heart and brain disorders, but why? 

A team of researchers at George Washington University (GWU) has found the perfect answer to this question. They argue that ART is only able to suppress the infection and prevent its further transmission. What remains unnoticed is that HIV also changes the genetic behavior of immune cells such that the pro-inflammatory genes (genes that cause inflammation) in these cells continue to express themselves. 

So whether a cell contains HIV (human immunodeficiency virus) protein or is free from it after ART, if it has ever been infected with HIV, it is likely to undergo inflammation forever. Lead researcher and professor of microbiology at GWU, Michael Bukrinsky, told IE, "Inflammation is the critical component of many, if not most, diseases associated with controlled HIV infection, the major of which are cardiovascular and neurocognitive disorders"

He further added, "Our study demonstrated that immune cells acquire a pro-inflammatory memory that makes them overproduce inflammatory factors even when no viral protein is around, thus supporting persistent inflammation"

When a natural immune response starts working like HIV memory

According to the researchers, the expression of pro-inflammatory genes is the essence of inflammation. They refer to the continuous expression of such genes in HIV patients as immunologic memory. It is a natural response of the human body cells to develop an immune memory for rapid action against an infection that also affected a person in the past.

This type of memory has also been described previously for other infections, including COVID, but this is the first time it has been noticed in the case of HIV. The current study reveals that immunologic memory in HIV patients is the root cause of prolonged inflammation. In order to prove the same, they performed an interesting experiment with human immune cells.

They cultured some immune cells in the lab and then divided them into two groups. The cells in the first group were exposed to the HIV protein called Nef. They received the same dose of Nef as found in the cells of patients with controlled HIV infection (virus count is so low that it can not be detected in a viral load test). 

The researchers then subjected cells in both groups to a bacterial toxin to observe the difference in their immune response. They noticed high levels of inflammatory proteins (cytokines) and also identified activated pro-inflammatory genes in the cells of the first group. 

On the other side, the immune cells that weren't subjected to Nef didn't express any such behavior. These findings confirm immunologic memory (or trained immunity) resulting from HIV infection and its role in inflammation. "While this 'trained immunity' evolved as a beneficial immune process to protect against new infections, in certain cases, it may lead to pathological outcomes. The ultimate effect depends on the length of this memory, and extended memory may underlie long-lived inflammatory conditions as we see in HIV infection or long COVI," said Professor Bukrinsky

He further suggests that apart from being responsible for cardiovascular and neurocognitive disorders, inflammation is also the underlying contributor to many human diseases, including diabetes, cancer, and Alzheimer's.

The memory factors shouldn't be ignored  

The study also suggests that Nef is the major pathogenic factor of HIV (and Nef-deficient HIV does not cause inflammation and diseases). However, it does not exclude the possibility that other HIV proteins may also cause a similar effect. 

The authors point out that the main limitation of this research work is that it was done on human cells and mice, so the results need to be verified in real-life human infection. Nevertheless, the current study highlights an important pathogenic factor that needs to be addressed in the treatment of HIV-infected people and to cure HIV. 

It might be possible that a similar phenomenon also takes place in other viral infections such as COVID. Understanding this further might explain the long-term complications of such infections.

The study is published in the journal Cell Reports.