HIV-related
dementia may be tied to viral genetic variations

Researchers at the San Francisco V.A. Medical Center have discovered a possible answer to a long-standing AIDS mystery--why only some HIV-positive people go on to develop HIV-related dementia. Their study of 18 HIV-positive subjects shows that HIV in the brain and central nervous system is genetically different from HIV in the blood and peripheral tissues. Serious cognitive impairment among the study subjects was correlated with the presence of a particular mutation in the HIV envelope gene in virus detected in the brain and nervous system.

The scientists generated 456 nucleotide sequences of HIV from the blood and cerebrospinal fluid of the study participants. They chose to focus on the viral envelope gene, which interacts with receptors on the surfaces of host cells. "That's the gene that's most likely to vary between tissues, because it evolves rapidly and allows the virus to dock with different cell types," said lead researcher Satish K. Pillai in a press statement.

According to Pillai, an analysis of the sequence data suggests that HIV is "genetically compartmentalized" between the central nervous system and the blood, "which means that the virus is replicating in relative isolation in these tissues, with very little exchange of genetic information between the two populations."

The researchers also analyzed the sequences in search of a "genetic signature" common to the central nervous system-specific viruses in all 18 individuals. They found such a pattern, consisting of four amino acids, within a subregion of the viral envelope gene known as the V3 loop. Another mutation in the V3 loop appeared consistently in virus from study subjects who demonstrated the most severe cognitive impairment. This mutation was absent in sequences from subjects with little or no cognitive problems.

"In other words," said Pillai in the press statement, "there appears to be a particular HIV mutation that is associated with dementia." Identifying the genetic variant in HIV patients could help predict whether they are at risk for developing HIV-related dementia, added Pillai. This could help doctors prescribe antiretroviral drugs with a better ability to cross the blood-brain barrier to inhibit viral replication in the brain and central nervous system, Pillai said.

The study appears in the July 2006 issue of the journal Brain. (The Advocate)