Driver of HIV-Associated Dementia Discovered

Researchers have recently uncovered the molecular process that can result in neurodegeneration in HIV-positive patients, according to a study published by Nature Communications.

Previous studies indicate that patients with HIV have increased levels of beta-amyloid protein accumulation, which can cause HIV-associated neurocognitive disorders (HAND). Despite intervention with antiretroviral therapy, up to 50% of patients develop HAND.

Aggregation of beta-amyloid is thought to accelerate neurodegeneration in numerous conditions; however, it had been largely unknown how and why beta-amyloid accumulates in patients with HIV and its affects on HAND, according to the authors.

“The HIV virus cannot infect neurons because they don’t have the right receptors,” said Mojgan Naghavi, PhD. “We’ve known about elevated beta-amyloid levels for a long time, but nobody knew how or why the protein was overproduced in response to infection.”

The authors started by analyzing interactions between various proteins and Gag, an HIV protein. They found that many proteins bind with Gag, but the interaction with membrane-associated amyloid precursor protein (APP) was notable because it can produce beta-amyloid, according to the study.

“We put 2 and 2 together: We knew APP is a precursor to beta-amyloid, so we looked for APP and found increased processing of this protein into beta-amyloid in infected macrophages and microglia,” Dr Naghavi said.

Both macrophages and microglia are types of brain cells that often act as reservoirs of HIV. The authors found that APP interferes with HIV infections and causes the virus to bypass the barrier, according to the study.

During microglia or macrophage infection, the Gag protein promotes APP processing. This action results in resistance to cell takeover and subsequently produces beta-amyloid, according to the study.

“By binding to APP, somehow Gag drags it into cell membrane regions called lipid rafts, where there are enzymes that promote processing of APP into beta-amyloid,” Dr Naghavi said. “This is the first time we’ve showed HIV is trying to overcome a block that is induced by APP in microglia and macrophages.”

To reduce amyloid-beta accumulation, the researchers targeted gamma secretase, an enzyme that cleaves APP. The APP inhibitor was observed to block infection and reduce amyloid-beta production, according to the study. These mechanisms resulted in reduced neurodegeneration and allowed APP to continue blocking infection, the authors noted.

“We’ve opened the door for how these drugs might be used to block both HIV replication and treat HIV-associated dementia,” Dr Naghavi said. “It would also be interesting to investigate whether APP affects replication of other neurotropic viruses, for example Zika or Cytomegalovirus.”

The authors caution that translating these findings to humans are still far off as these compounds could have toxic side effects.

As the HIV-positive population ages, there is an important and growing need to address chronic disease in these patients, according to the study.

“HIV patients on combination antiretroviral therapy have close to a normal life, but they are still suffering from diseases like HAND,” Dr Naghavi said. “This is just the beginning.”

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