A genetic analysis of HIV taken from the brain of a patient who died with severe HIV-associated dementia has shown that dementia may be caused by rapid evolution of HIV in certain brain regions, leading to a cycle of infection of macrophages and inflammation. The findings were presented in the September edition of the Journal of Virology.
Although less common since the advent of effective antiretroviral therapy, dementia still occurs in some patients with CD4 cell counts below around 50 cells/mm3. However, HIV is known to enter the brain soon after infection and to spread through the brain by infecting macrophages, a type of white blood cell. Since it can take many years for CD4 cell counts to fall to low levels, experts are uncertain as to the reasons for the long delay in the development of HIV-associated dementia.
To gain a better understanding of how HIV behaves in the brain, investigators extracted virus from various regions of the brain of a patient who had died with severe HIV-associated dementia. By comparing the genetic sequences in the virus particles in the different areas of the brain, they found evidence that HIV moved around the brain in distinct paths, and that it evolved at different rates depending on where it was in the brain.
The investigators found that migration of HIV occurred most commonly from the meninges - the membrane surrounding the brain - to the temporal lobes, as well as to other areas of the brain and spinal cord.
They also found evidence that HIV in the meninges and temporal lobes evolved more rapidly than elsewhere. In the meninges, the patient’s HIV had evolved 30 times more rapidly than other areas, while HIV in the temporal lobes had evolved 100 times more quickly. While the meninges are probably the site of initial brain infection with HIV, the temporal lobes are one area where damage to brain cells causes the symptoms of dementia.
“Considering that damage to the temporal lobe is associated with symptoms typically reported in HIV-associated dementia, such as cognitive / motor disorders, information retrieval difficulties, and behavioural changes, the HIV-1 evolutionary dynamics observed in the current study could be related to the evolution of dementia,” the investigators write.
The researchers found evidence that the regions of the virus’s genetic material that enabled it to infect macrophages were expanded in the brain. They argue that these new HIV variants would normally be cleared by the immune system.
However, once HIV has damaged the immune system, the new HIV variants are no longer removed from the brain and they can go on to infect and activate macrophages. These then activate further macrophages, as well as release HIV particles, resulting in a large increase in the number of activated macrophages in the brain. These activated cells are responsible for the inflammation and brain cell damage that is thought to underlie dementia.
“The higher evolutionary rate in the meninges and temporal lobe could be due to an enhanced infection / expansion rate of macrophages as a result of the immune system failure,” they write. “After immune failure newly produced viral variants, which would be rapidly cleared under normal conditions, begin to infect macrophages in a ‘self-amplifying’ cycle of infection / inflammatory response that could be at the origin of HIV-associated dementia.”
As this study only analysed HIV from one patient, these findings must be interpreted cautiously. However, they seem to confirm previous theories on how HIV-associated dementia develops and form a model that can be tested in future investigations.