Investigators find genetics help explain HIV dementia

Finding is a clue, but not entire answer

A definite marker that explains HIV dementia remains elusive, but investigators recently found a possible explanation within viral genetic differences.

"We're trying to establish the marker, but we're not there yet," says Satish K. Pillai, PhD, a post-doctoral fellow at the University of California, San Francisco, and a staff research associate at the San Francisco Veterans Administration Medical Center.

"The intriguing thing underlying this whole research effort is if you look at 100 untreated HIV people, between 30 and 50 percent will develop dementia," Pillai says. "So why do some develop dementia and others do not?"

There are no obvious correlates: "It's not just a matter of high viral loads in the central nervous system," Pillai says. "It's not that simple."

Other possibilities include the following, Pillai says:

  • There are certain genetic strains of the virus that are more virulent than others;
  • It may be a host's genetics which cause certain individuals to tend to be more susceptible to central nervous system disorders;
  • It is related to environmental differences, including the use of methamphetamines.

"The point is that the reason why you can see variations in dementia across individuals has some due to differences in the virus, some due to the host's genetics, and some due to environmental differences," Pillai says.

For example, methamphetamine use is very common in certain HIV communities, and so it might be interplay between the virus and meth use, he adds.

Investigators wanted to see if there were certain genetic factors contributing to the problem, and they looked for consistent differences when comparing the brain and the blood of chronically-infected individuals, he explains.

"Do we see the same genetic mutations over and over again?" Pillai says. "Are there certain strains of HIV that are more adapted to making a living in the central nervous system or are there certain strains more damaging to the central nervous system than other strains?"

To learn more about this, researchers generated a number of HIV sequences from the plasma and cerebral spinal fluid, Pillai says.

"We used cerebral spinal fluid as an indicator of what's colonizing the brain," he explains. "We looked at 18 chronically-infected individuals and took paired samples of cerebral spinal fluid and blood plasma, extracted the virus and generated clonal sequences of HIV RNA."

Investigators focused on an envelop gene of HIV because there were earlier reports that this gene might be responsible for neurotoxicity, Pillai notes.

"Our colleagues at the HIV Neurobehavioral Research Center in San Diego subjected all 18 individuals to a comprehensive neuropsychiatric exam," Pillai says.

A Global Deficit Score was determined for each person, and this is widely-recognized as measuring how cognitively impaired a person is, he adds.

Using all of this data, investigators found a difference in the envelop gene called the V3loop, Pillai says.

"It's the part of the envelop gene that dictates which receptor the virus uses to enter the cell," he says. "There's one mutation in there where a certain amino acid was only observed in individuals who had severe cognitive impairment, and it was totally absent in individuals who were not impaired."

As promising as the findings were, they only represent an exploratory cohort of 18 people, Pillai notes.

For the next step, investigators have a cohort of 100 people, and they are generating clonal sequences from blood plasma in all of those patients, he says.

"The mutation we observed in the initial exploratory cohort had an association that was highly statistically significant, but there is a possibility it was a sampling artifact," Pillai says. "So we want to see if this one amino acid is only present in strains of virus associated with demented individuals."

The project's main questions are:

  • Are there viral characteristics associated with dementia?
  • Are there viral characteristics associated with the virus in the CNS versus blood plasma?

"The idea there is that those mutations probably confer a higher fitness for the virus in the CNS," Pillai says. "Making a living in CNS is probably pretty different for a virus than making a living in peripheral tissue."

Whereas HIV typically affects CD4 cells, in the brain, HIV infects microglia cells, which are the principle target cells for the virus in the CNS, he says.

Another issue related to dementia is that a lot of antiretroviral drugs manage HIV infection but do not effectively cross the blood-brain barrier, Pillai says.

"So the lack of immune surveillance and reduced pressure from antiretroviral therapy allows the virus to grow in CNS," he says. "It seems the virus makes its way to CNS immediately, within the first week or two, but the rate at which the virus replicates and grows out of CNS is totally different from one individual to the next."

The clinical goal of this research is to identify a viral genetic marker of either dementia or something that predicts a person is likely to develop dementia, Pillai says.

If such a marker is found, then HIV clinicians could test for this marker and prescribe specific drugs that are better at crossing the blood-brain barrier to patients who have the marker, Pillai explains.

"But what I would say, because I'm a little bit pessimistic, is in the best case scenario, we'll find one or two mutations that are correlated with dementia, but it will never be the complete answer," Pillai adds. "There has to be a host genetic element and a drug element."