An October 2011 study revealed a novel characteristic of HIV—it can replicate, or make new copies of itself in macrophages, cells in the immune system. This revelation is shedding light on why some patients develop a type of dementia linked to HIV despite receiving antiretroviral therapy.
The study, published in the online journal PLoS Pathogens, was conducted by researchers at the University of North Carolina at Chapel Hill School of Medicine. Collaborators from the University of California, San Francisco (UCSF) supplied samples of blood and cerebrospinal fluid (CSF) from eight HIV patients with HIV-1-associated dementia (HAD) or other neurological complications. The investigators discovered the existence of two variants of HIV in the CSF of HAD patients, which were not detectable in HIV circulating in the blood. One variant reproduced in CD4+ T cells (commonly called CD4 cells), lymphocytes in the immune system that bind HIV, allowing it a point of entry into the body. The other variant replicated in macrophages, white blood cells in the immune system that engulf and digest microorganisms. “This is the first time that anyone has demonstrated active replication of HIV in a cell type other than [CD4] cells,” said co-author Ronald Swanstrom, PhD, professor of biochemistry and biophysics and director of the UNC Center for AIDS Research, in a press release.
This finding might help explain why patients on highly active antiretroviral therapy (HAART), a combination of three or more drugs that suppress viral replication, develop neurological disorders, including HAD. Whereas HAART causes the HIV in CD4 cells, which have short half-lives, to decay by half every day or two, the HIV in CSF tended to decay much slower, up to several weeks or a month. This indicated to the researchers that the HIV was being produced by cells with longer half-lives, such as macrophages. Further, they found that one variant of HIV was attracted to macrophages and could infect them. In a few cases, the HIV-infected macrophages were present two years before patients were eventually diagnosed with dementia. Because CSF circulates in the spinal cord and brain, it could easily transport HIV from macrophages directly to the brain, causing neurocognitive disorders. However, these are preliminary data from a very small study, so they are not conclusive.
HAD commonly occurs in later stages of AIDS. Its presence signals that the immune system is severely compromised. As the amount of HIV in the blood, or viral load, increases, the number of CD4 cells decreases, typically below 200 cells per microliter. When HIV infects the brain, it damages the central nervous system and sometimes the peripheral nerves. Cases can be mild to severe, and tend to progress rapidly. Patients with HAD display a variety of cognitive, motor and behavioral symptoms, ranging from confusion to loss of muscular coordination, personality changes and psychosis.
Now that people with HIV are living longer, it is anticipated that the number of patients who develop HAD will increase. A test to determine which patients have the HIV variant that replicates in macrophages could be predictive and, for asymptomatic patients, persuasive. “If these individuals knew there was an AIDS virus replicating independently in their CNS [central nervous system], it might affect their decision when to start treatment with HAART,” Swanstrom said in a press release.
In the next phase of research, the UNC and UCSF teams will study HIV patients who have not developed dementia and are beginning HAART. They will try to identify CSF biomarkers, indicators of the HIV variant that can lead to dementia. This research is being funded by a $3 million, five-year grant from the National Institute of Mental Health at NIH.