Aging HIV patients may be at risk for dementia, study shows

Aging HIV patients whose infection has not evolved into full-blown AIDS may be at risk for developing a chronic dementia similar to Alzheimer’s disease, according to researchers at the San Francisco Veterans Affairs Medical Center and UCSF.

The findings were presented Tuesday, July 20, at the 9th International Conference on Alzheimer’s Disease in Philadelphia.

In normal aging, a protein called amyloid beta, thought to be essential to the development of Alzheimer’s disease, is produced in the brain. But in normal brains an enzyme called neprilysin (NEP) breaks down amyloid beta, preventing it from damaging brain cells.

In HIV patients, however, an HIV-associated protein (called Tat) blocks NEP, allowing amyloid beta to accumulate.

“The brain is a reservoir for HIV. Thus, even though the virus is not detected in the blood, it remains in the brain where amyloid beta accumulates with age,” said lead researcher Lynn Pulliam, PhD, UCSF professor of laboratory medicine and associate chief of staff for research at the SFVAMC.

Researchers hypothesized that the long-term accumulation of amyloid beta in the brains of HIV-infected persons (as a result of Tat’s blockage of the enzyme NEP) may increase the risk for dementia similar to Alzheimer’s disease, especially as the patient ages.

In the laboratory, researchers applied synthetic Tat to normal human brain cells that contain full-functioning NEP. They found a 125-percent increase in amyloid beta in the brain cells treated with synthetic Tat, compared to normal untreated brain cells.

To establish the relevance of this finding, the researchers stained brain sections from autopsies of 14 HIV-infected individuals (ages 31-58) with amyloid beta antibodies. They found an increase in amyloid beta in individuals with HIV-infection compared to HIV negative age-matched controls. They also found a correlation between the number of years of infection and the amount of amyloid beta found.

“This finding was consistent with other research, clearly showing that Tat blocks NEP activity,” Pulliam said.

While excessive amounts of amyloid beta alone may not cause dementia, the presence of the protein in combination with other factors may be sufficient, researchers suggested. These factors include a gene called apoE4, considered a risk factor for dementia, and age.

“These results have significant implications for individuals aging with HIV infection. Good clinical control of plasma HIV with highly active anti-viral therapy may not be sufficient to prevent HIV-related pathologies,” Pulliam said. The researchers advocate further studies on ways to eradicate HIV in the brain.

Co-author of the study is Hans C. Rempel, PhD, research biologist at the SFVAMC. In addition to her UCSF and SFVAMC appointments, Pulliam is an investigator with the UCSF AIDS Research Institute, which houses hundreds of scientists and dozens of programs throughout UCSF and affiliated labs and institutions—making it one of the largest AIDS research entities in the world.

The research was supported by a UC Universitywide AIDS Research Program grant and the National Institutes of Health.