The human immunodeficiency virus (HIV) has ravaged populations for years and, until the advent of anti-retroviral drugs in the mid 1990s, it seemed like there was nothing to prevent its deadly spread. Close to 40 million people on the planet are currently infected with the virus, which infects and kills immune cells that usually fight off infections, leading people who progress to AIDS to die from other infections.
The reason behind the death of infected immune cells — CD4 T cells — has been unclear. It was only known that at the peak of viral concentration in the blood, after infection, CD4 cells start dying in droves. Since adults do not produce new CD4 cells, the immune system is permanently damaged, leaving infected individuals to walk around with far fewer CD4 cells than they had before infection.
When HIV infects a cell, it takes its own genes and permanently places them in the genome of the person's cell, a process that is called integration and that makes HIV so difficult to cure. The virus essentially has a backup copy of its genetic code in the DNA of the infected cell for as long as the cell lives. If not properly treated with anti-HIV medications, the cells can produce the virus from the backup blueprints that were placed in the person's DNA.
Now researchers at the National Institute of Allergy and Infectious Disease (NIAID) at the National Institutes of Health have found the reason why CD4 cells die in such great numbers after infection. When the HIV virus integrates its genetic code into a person's genetic code, it creates breaks in the DNA strands. Breaks in DNA are seen when people are exposed to radiation as well, and the cell senses that there is a problem that could potentially lead to cancer. In order to prevent the cell from living with damaged DNA, an enzyme called DNA-dependent protein kinase (DNA-PK) gets activated and tries to repair the damage.
The NIAID scientists found that when HIV integrates its DNA into the infected cell's DNA, DNA-PK gets activated as well and then causes the cell to commit suicide in a process called apoptosis. As a result, the cells that are supposed to react to the infection are infected themselves and ultimately kill themselves, leaving the individual with a deficient immune system. When the researchers used a pharmaceutical drug that blocks the integration step, but not the infection step, they saw that the CD4 cells survived infection.
The researchers suggested that the data indicates HIV treatment should be administered as soon as possible to prevent the collateral damage the virus causes by killing immune cells. The scientists also suggested that their findings may help researchers better understand reservoirs of cells that have been infected with but not killed by HIV, hopefully leading to better treatments or eventual elimination of these reservoirs.
Source: Cooper A, Garcia M, Petrovas C, Yamamoto T, Koup R, Nabel G. HIV-1 causes CD4 cell death through DNA-dependent protein kinase during viral integration. Nature. 2013.