Viral Genetic Differences Are Possible Key To HIV Dementia
The study of 18 HIV-positive subjects shows that HIV in the brain and central nervous system is genetically different from HIV that lives in the blood and peripheral tissues.
Moreover, serious cognitive impairment among the study subjects was correlated with the presence of a particular mutation in the HIV envelope gene.
The study appears in the July 2006 issue of Brain. It was led by Satish K. Pillai, PhD, a staff research associate at SFVAMC and a postdoctoral fellow at the University of California, San Francisco.
Pillai and his associates 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," Pillai says.
According to Pillai, an analysis of the sequence data suggests that HIV is "genetically compartmentalized" between the central nervous system (CNS) 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 CNS-specific viruses in all 18 individuals, recounts Pillai. They found such a pattern, consisting of four amino acids, within a subregion of the viral envelope gene known as the V3 loop. "The identification of these signature mutations presents convincing evidence that HIV adapts to the local environment within the central nervous system and, moreover, that commonalities in this environment exist across individuals," he asserts.
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 deficit. "In other words," says Pillai, "there appears to be a particular HIV mutation that is associated with dementia." He cautions that this result is "suggestive, not conclusive," because of the study's small sample size.
This information "may be clinically relevant in terms of treatment," Pillai explains. "If we identify the quintessential neurotoxic variant of HIV, could we use that as a predictor of HIV dementia?" He says that such knowledge could also help care providers make "guided therapeutic decisions