Drug cocktails have transformed HIV infection from a deadly to a chronic disease, giving HIV carriers a new lease on life. But new long-term consequences of harboring the virus and of taking powerful drugs indefinitely keep cropping up, and the prospect of an Alzheimer’s-like dementia is the latest one. At the 34th meeting of the Society for Neuroscience here in San Diego, Cristian Achim of the University of Pittsburgh Medical School, and Lynn Pulliam of UCSF, yesterday and today presented early data suggesting that middle-aged people with HIV who are on highly active antiretroviral therapy (HAART) develop Aβ deposition, both inside neurons and as extracellular plaques. The two labs are working independently of each other.
It’s long been known that HIV infection will affect the brain at some point, but this is different, the scientists report. The brain can become a reservoir for the virus even while it is undetectable in blood and the HAART-treated patient shows no outward signs of disease. Accompanying HIV-associated risk factors for dementia include damage to the blood-brain barrier, infiltration of monocytes/macrophages (which most likely carry in the virus), and high levels of inflammatory cytokines. On top of that, a more specific risk for Alzheimer’s pathology may arise from two related processes, the scientists proposed. For one, these patients tend to develop high levels of insulin and insulin resistance, and this may have to do with interactions between the HIV drugs and the Aβ-degrading enzyme IDE, Achim’s work suggests. For another, an HIV protein called stat inhibits neprilysin, another enzyme that keeps Aβ levels down, reported Pulliam.
Achim described early data of an ongoing study in which he assessed amyloid deposition in postmortem tissue of 162 cases aged 25 to 70, with an average of 40, from the University of California Los Angeles and San Diego. These people had not had HIV encephalitis. Sixty percent of them had intraneuronal Aβ deposition confirmed by immunoelectron microscopy, and half of those also had extracellular deposits, mostly diffuse plaques, but no tangles. Achim hopes to follow a group of patients on long-term HAART forward with the PET amyloid imaging agent PIB to test how amyloid deposition correlates with cognitive performance over time.
Pulliam took a different tack by studying the effect of tat, an HIV protein secreted from infected macrophages and microglia, on neprilysin. Tat inhibited neprilysin in membrane preparations from human brain cultures and led to an increase in Aβ when added to cultures directly. Then she looked for Aβ in autopsy brain sections and, like Achim, found that middle-aged people with HIV had more plaques, large diffuse ones, than did controls. Plaque number correlated with how many years the person had been infected, but not with age. Whether this AD pathology leads to clinical Alzheimer disease is unclear, as is the question of how ApoE genotype influences the outcome. Even so, independent scientists at the conference agreed that long-term HAART-treated HIV survivors might constitute a new natural model of a form of Alzheimer’s.
This study will encourage researchers who propose that bacterial or viral pathogens cause some cases of sporadic Alzheimer’s see (Alzforum Discussion). This view is not widely held in the field, but it gained support from a presentation from Pat McGeer’s lab at University of British Columbia in Vancouver, Canada, reporting the cultivation of Borrelia burgdorferi spirochetes (the bacteria that cause Lyme disease) from Alzheimer brains.—Gabrielle Strobel.