HIV dementia associated with specific HIV genetic profile found in brain, not blood

Adam Legge
Published: 27 July 2006

Reference

Pillai SK et al. Genetic attributes of cerebrospinal fluid-derived HIV-1 env. Brain 129: 1872-1883, 2006.

HIV in the blood and central nervous system (CNS) of the same individual can differ significantly, according to US researchers writing in the August edition of the journal Brain. The investigators discovered that HIV in the brain evolved to be genetically different to HIV in the blood, and that the presence of this genetically different virus in the brain was associated with disorders such as cognitive impairment. A mutation on the viral envelope, found only in virus isolated from the brain, was particularly associated with HIV dementia. The investigators hope their findings might eventually help prevent neurological disorders in people with more advanced HIV disease.

HIV crosses the blood-brain barrier when an individual is first infected with HIV (often called primary infection) and leads to neurological complications such as dementia, encephalopathy (brain damage) or neuropathy (damage to the peripheral nerve system) in about 50% of people should HIV remain untreated.

Although blood levels of the virus can drop dramatically with potent anti-HIV therapy, the CNS can act as a so-called “sanctuary” for long-term persistence of HIV because many drugs do not pass easily from the bloodstream into the CNS. Doctors often call this process crossing the blood-brain barrier. This makes the CNS a unique environment for the replication of HIV, even in the presence of HIV therapy and researchers from California have been investigating how HIV in the brain differs from virus in the blood.

Eighteen HIV-infected individuals were enrolled in this study, which was undertaken at the HIV Neurobehavioral Research Center in San Diego. All the patients had a lumbar puncture (or spinal tap) to take a sample of cerebrospinal fluid (CSF). HIV was isolated from the CSF and compared to the virus in their circulating blood plasma. All the patients had stable or no antiviral therapy for at least two months before the study. They had both plasma and CSF HIV levels of over 500 copies/ml and had no evidence of systemic or CNS infections, although most had advanced immunodeficiency and some had cognitive impairment.

The investigators focused their analysis on the viral envelope gene, which interacts with receptors on the surface of cells. They found that HIV was "genetically compartmentalized" between the CNS and the blood and that there was very little exchange of virus between these two locations.

In further analysis, they determined that there was a consistent genetic signature in the V3 loop sub-region of the envelope gene of HIV in the CNS of all 18 individuals. A further mutation in the VS loop region of HIV in the brain was found only in patients with dementia. "There appears to be a particular HIV mutation that is associated with dementia", emphasise the investigators.

The investigators acknowledge limitations with their study, writing: “Our results may not be generalizable to individuals with less advanced disease or those who have never seen effective antiretroviral therapy.” Also they add that individuals were chosen because they had detectable HIV in their CSF and the results may not be applicable to those who do not.

However, they believe that their results could have important implications for drug treatment and patient monitoring. "The detection of particular viral genotypes may lead physicians to select for antiretroviral regimens that cross the blood-brain barrier", they write, adding that drug therapy might actually be designed to "target these genetic variants that are responsible for the neurological damamge."