HIV cure likely lies in targeting dormant virus reserves

HIV inserts itself directly into the DNA of our immune cells. AIDS develops when the virus hijacks cell machinery and replicates itself, gradually weakening our immunity. Anti-HIV therapy interrupts the hijacking but does not touch intact virus that remains dormant. Now, a new study shows how lurking pools of dormant HIV may hold the secret to curing the disease.

HIV belongs to a family of viruses that insert themselves directly into the DNA of their host cells.

The researchers, led by a team from Rockefeller University, New York, NY, report their findings in the journal Cell.

HIV belongs to a family of viruses that insert themselves directly into the host's genome.

In the case of HIV, it inserts itself into the DNA of a type of white blood cell called CD4 T lymphocytes. These cells are involved in triggering immune responses.

When HIV inserts itself into the DNA of CD4 T cells, one of two things can happen. 

Either it becomes active and hijacks the cell to make copies of itself that then invade and take over other cells (and this eventually kills the host cell); or it lies dormant, the only sign of its presence being a tiny fragment of foreign DNA in the cell's genome.

However, in most cases, what happens is something in-between. Some of the virus goes on to cause infection, hijack cells and proliferate, and some of it lies dormant. As the years go by, these dormant pools pose a persistent and growing potential threat to a victim with a gradually weakening immune system.

Latent reservoir of HIV unlikely to be in expanded immune cell clones

As anti-HIV drugs only target the active infection - when the virus is taking over cell machinery and making copies of itself - the dormant virus lies untouched and continues lurking in the dormant pool, ready to wake up at any time.

If a patient stops taking antiretrovirals, the infection rebounds. It is truly amazing that the virus can give rise to AIDS 20 years after the initial infection.

The researchers believe the dormant pool of HIV hides out in a type of CD4 T cell that helps the immune system remember particular pathogens. When they meet a pathogen they have come across before, they trigger production of clone T cells tuned to recognize it. Previous studies have suggested this clonal expansion is how HIV maintains its latent reservoir.

This latest study found the latent reservoir is unlikely to be in the clones:

The researchers stated that, it has recently been shown that infected white blood cells can proliferate over time, producing many clones, all containing HIV's genetic code. However, they found that these clones do not appear to harbor the latent reservoir of virus. Instead our analysis points to cells that have never divided as the source of the latent reservoir.

Tests showed HIV in expanded clones could not hijack cells and replicate

Using blood samples from 13 people infected with HIV, the team sequenced the sites in the genomes of infected cells where HIV had inserted itself.

With the help of specially designed analytical techniques, they could see if an infected cell had previously been copied in the clonal expansion part of an immune response: that is whether it was a cloned or unique CD4 T cell.

"Given the size of the human genome, it is highly unlikely the virus would insert itself in exactly the same place more than once. So, if multiple cells contained virus with identical integration sites, we classified them as clones. Meanwhile, if a cell had a unique integration site, one not shared with any other cell, then we assumed that cell was unique."

Altogether, the team tested 75 viral sequences they found in the expanded clones to see if they had the potential to go on to the hijacking stage and produce more virus. None could, so they concluded it was highly unlikely that viable dormant virus was lurking in cloned cells.

References:

1.     HIV-1 integration landscape during latent and active infection, Lillian B. Cohn, et al., Cell, doi:10.1016/j.cell.2015.01.020, published online 29 January 2015, abstract.

2.     The Rockefeller University news release, accessed 2 February 2015.