HIV and the Brain
By Jeffrey Laurence, M.D.
September 6, 2006—amfAR fellow Dr. Jayanta Bhattacharya wants to understand how HIV spreads among immune cells in the body and, more importantly, how this spread can be halted. In a recent article I highlighted research in which Dr. Bhattacharya described part of the mechanism by which HIV exits a cell, enabling it to infect other cells. In the July issue of the Journal of Virology, this prolific research fellow, with his mentor Dr. Paul Clapham and several colleagues, presents additional amfAR-funded research aimed at defining the means by which different varieties of HIV (known as isolates) preferentially infect specific tissues, particularly the brain. These investigations have the potential to illuminate ways of preventing such infections and their devastating consequences.
Before anti-HIV drug "cocktails" became available, up to one in every three people with AIDS had evidence of HIV-related cognitive impairment, all too often manifest as dementia. Combination antiretroviral therapy has reduced the number of new cases of AIDS dementia, but it is now occurring in people with higher CD4+ T cell counts. And other ways in which HIV affects brain function, leading to less dramatic cognitive and neurobehavioral problems, are actually on the rise.
Concurrent with these clinical findings, autopsy reports suggest that HIV continues to affect the brain despite antiretroviral use. Some of this may be attributable to the poor penetration of certain anti-HIV drugs into the CSF—the fluid bathing the brain and spinal cord. But it may also relate to the peculiar characteristics of different HIV isolates. Drs. Bhattacharya, Clapham and associates focused on the latter.
Brain tissue is an "immune privileged site." It is protected from many environmental assaults by the so-called blood-brain barrier, which also restricts entry of antibodies and immune cells into the brain. The potential role of this barrier in the selection and harboring of specific types of HIV—away from the effects of anti-HIV antibodies and T cells prevalent elsewhere in the body—was studied and the results were compared to another site of “immune privilege,” the testes, which has its own blood-testis barrier. Other investigators had attempted such work, but they mainly relied on test tube models. What made the studies of the Clapham group unique was their collection of HIV directly from the brains or CSF of patients with neurologic disorders, along with virus captured from blood and semen.
Everyone thought they understood how certain AIDS viruses are limited to infecting certain cells, with so-called R5 virus isolates predominantly targeting CCR5-bearing macrophages, another type of immune cell. Dr. Bhattacharya and colleagues found, in striking contrast to accepted dogma, that R5 viruses in blood, semen and lymph node were very poor infectors of macrophages. Only R5 viruses from the brain had a special affinity from the macrophage. They also identified a potential mechanism for these associations.
The authors concluded that, "The remarkable variation in R5 tropism shown here is likely to have a profound impact on pathogenesis ... and on the efficiency of transmission." Given the heightened importance of HIV’s effects on the nervous system as people with AIDS live longer and more productive lives, we will follow the work of these investigators with great interest.
Dr. Laurence is amfAR’s senior scientific consultant.