Genetic analysis and clinical studies have revealed that the AIDS virus in the cerebrospinal fluid (CSF) of some people with AIDS-related dementia evolves independently of the virus in their blood, leading to two genetically distinct forms of the virus. The finding poses a new challenge for treatment of these patients, suggesting that drugs effective against HIV-1 in their blood may not do the job in the central nervous system, and vice versa.
The discovery, by a research team from the Gladstone Institute of Virology and Immunology at UC San Francisco, was presented at the Sixth Conference on Retroviruses and Opportunistic Infections in Chicago earlier this week (February 2).
"Our data show independent viral evolution in the cerebrospinal fluid and plasma in subjects with AIDS dementia complex (ADC)," says Natalia Inkina Marlowe, PhD, lead author on the study and a postdoctoral fellow in the laboratory of Robert Grant, MD, of the Gladstone Institute. "Those with AIDS dementia may need drugs with a high capacity to penetrate the blood-brain barrier in order to treat HIV that is evolving independently in the central nervous system."
At the very least, the findings suggest that clinical trials should evaluate the success of new HIV drug treatments in the blood and the central nervous system separately, according to the research team, and success or failure in one system does not necessarily imply the same result in another.
The independent population of HIV does not appear to evolve in the CSF of neurologically normal HIV patients, the researchers found.
While the CSF and brain are different "compartments" within the central nervous system, Marlowe explains, there are parallels in their relation to systemic infection and barriers to drug penetration. As a result, the new observations may have implications for treatment of brain infection, she says.
Why HIV evolves independently in the CSF of the demented patients is not clear, Marlowe says. It may reflect a separate viral subpopulation thriving in their central nervous systems, or maybe those with dementia have progressed further in immunodeficiency that may allow HIV-1 to become more virulent.
The scientists also found preliminary evidence that in some ADC patients, the HIV virus in the CSF compartment is more resistant to antiretroviral drugs than is HIV in the blood. This can cause rebound of virus levels in the CSF while the viral load in the blood is suppressed. Ongoing studies of resistant mutations should clarify this pattern, the researchers conclude.
The researchers detected the different HIV-1 "quasispecies" by sequencing two genes of HIV--called pol and env--in ADC and neurologically normal people. To study the appearance of drug resistance in the CSF and blood, they analyzed longitudinal samples from 20 people undergoing aggressive protease inhibitor and reverse transcriptase inhibitor therapy. Study subjects participated through the General Clinical Research Center at San Francisco General Hospital Medical Center (SFGHMC).
The principal investigator of the study is Richard W. Price, MD, UCSF professor of neurology at SFGHMC. Co-investigators are Robert M. Grant, MD, director, and Jason Barbour, MHS, and Nirmala Bandrapalli, MS, Laboratory of Clinical Virology, Gladstone Institute of Virology and Immunology; Silvija Staprans, PhD, Emory University; Tatjana Novakovic-Agopian, PhD, SFGHMC neurology department.
The Gladstone Institute of Virology and Immunology, founded in 1991, focuses its research on HIV and AIDS. The Institute is one of three that make up the J. David Gladstone Institutes, a private biomedical research institute affiliated with UCSF and named for a prominent real estate developer who died in 1971. His will created a testamentary trust that reflects his long-standing interest in medical education and research.