A study led by researchers at the San Francisco VA Medical Center has revealed a possible answer to a longstanding AIDS mystery: why only some people infected with HIV go on to
develop 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 - for example, the detection of particular viral genotypes may lead physicians to select for antiretroviral regimens that cross the blood-brain barrier into the CNS most efficiently.” Or, he speculates, “we might actually try to design a drug to target these genetic variants that are responsible for the neurological damage.”
Pillai notes that the issue of HIV dementia is particularly important in regions outside North America and Europe where state-of-the-art antiretroviral medications are not widely available and HIV infection frequently leads to dementia.
SFVAMC staff physician Joseph K. Wong, MD, associate professor of medicine at UCSF and senior author of the study, adds, “In addition to the implications of this new knowledge for the 40 million people infected with HIV, this study may also contribute to our general understanding of viral encephalitis,” or brain inflammation caused by other viruses. “These results suggest that specific features of viral components themselves, and not just the immune response to viral infection, may be responsible for direct damage to the nervous system.”
Pillai says that even though the study included almost 500 gene sequences, it is still exploratory: “We are now in the process of expanding this to a survey of 100 to 150 individuals.”
The study’s co-authors were Sergei L. Kosakovsky Pond, PhD, of UC San Diego; Yang Liu, PhD, of Monogram Biosciences, South San Francisco; Benjamin M. Good, MS, of UCSD and VA San Diego Healthcare System; Matthew C. Strain, MD, PhD, of UCSD; Ronald J. Ellis, MD, PhD, and Scott Letendre, MD, of UCSD and the HIV Neurobiological Research Center, San Diego; Davey M. Smith, MD, of UCSD and VASDHS; Huldrych F. Gunthard, MD, of University Hospital Zurich, Switzerland; Igor Grant, MD, Thomas D. Marcotte, PhD, and J. Allen McCutchan, MD, of UCSD and HNRSC; and Douglas D. Richman, MD, of UCSD and VASDHS.
The study was supported by funds from the National Institutes of Health that were administered in part by the Northern California Institute for Research and Education and by the Department of Veterans Affairs.
NCIRE is the largest research institute associated with a VA medical center. Its mission is to improve the health and well-being of veterans and the general public by supporting a world-class biomedical research program conducted by the UCSF faculty at SFVAMC.
SFVAMC has the largest medical research program in the national VA system, with more than 200 research scientists, all of whom are faculty members at UCSF.