April 28, 2014 |
Scientists at the University of Pittsburgh have identified why some HIV-infected people experience much slower disease progression, even without medication, and it has to do with cholesterol levels in specific immune cells. They report their findings in mBio®, the online open-access journal of the American Society for Microbiology.
“A fascinating aspect of the AIDS epidemic is that a small percentage of HIV-1-infected persons, termed nonprogressors or controllers, maintain a relatively normal number of CD4 T cells (Th cells) and low viral load for many years without receiving antiviral therapy,” says lead author Giovanna Rappocciolo. “Knowing how these individuals naturally control their HIV-1 infection and prevent the virus from progressively destroying their Th cells could be critically important to developing effective therapeutic and prevention strategies for HIV-1/AIDS.”
When HIV enters the body, it is typically picked up by immune system cells, called antigen-presenting cells (APCs), including dendritic cells and B lymphocytes. Those cells then transport the virus to lymph nodes where the APCs pass it to other immune system cells, including Th cells, via a process known as trans infection. HIV then uses Th cells as its main site of replication. It is through replication in the Th cells that levels of HIV increase and overwhelm the immune system.
Even without antiretroviral drugs, approximately one in 20 people infected with HIV do not have the persistent increase in levels of HIV after initial infection and can sometimes go many years, even more than a decade, without the virus seriously compromising the immune system or leading to AIDS.
In the study Rappocciolo and her colleagues compared the ability of APCs from nonprogessors, progressors and uninfected control subjects to trans infect T cells. They found that while the cells from progressors and control subjects were highly effective at mediating trans infection, those from nonprogressors lacked the ability.
The researchers took a closer look and discovered that the APCs from nonprogressors had low levels of cholesterol, even though the patients had regular levels of cholesterol in their blood. Moreover, they found that trans infection could be restored by reconstituting cholesterol levels in the APCs of nonprogressors and could also be inhibited by reducing the cholesterol levels in the APCs of progressors.
Additionally, analysis of APCs from two nonprogressors obtained one to four years before primary HIV infection shows similar results, suggesting this is a genetically acquired trait.
“This defect in cholesterol metabolism is not a direct consequence of virus infection, but rather is likely present as an inherited trait in a low percentage of individuals. Understanding how this works could be an important clue in developing new approaches to prevent progression of HIV infection,” says Rappocciolo.