Evidence of brain methyltransferase inhibition and early brain involvement in HIV-positive patients

Abstract

The myelopathy associated with human immunodeficiency virus (HIV) infection closely resembles that in subacute combined degeneration, a disorder of vitamin B 12 metabolism. To investigate whether the disorders share a pathogenetic mechanism, S-adenosylmethionine (SAM) and S-adenosylhomocysteine (SAH) were measured in the cerebrospinal fluid (CSF) of 20 HIV-seropositive patients and 30 HIV-negative patients who were undergoing lumbar puncture for other medical reasons. The HIV-seropositive patients had significantly lower CSF concentrations of SAM (mean 77 [SD 25] vs 131 [35] nmol/l; p < 0·001) and significantly higher concentrations of SAH (30·5 [6·8] vs 19·0 [7·1] nmol/l; p < 0·001) than the controls. There was therefore a significant difference between the groups in the SAM/SAH (methylation) ratio (HIV 2·7 [1·0] vs control 7·6 [3·4]; p < 0·001). There were no correlations between SAM or SAH concentrations or methylation ratio and age or sex in both groups, or serum B 12 and folate concentrations, CSF folate, serum or CSF methylmalonic acid, risk factors, body mass index, specific drug treatment received, or disease stage in the HIV group. This finding suggests that HIV affects the brain from a very early stage of the infection. We suggest that, as in the pig, the CSF methylation ratio closely reflects that in the brain. In HIV-infected patients a reduced brain methylation ratio would inhibit methyltransferase enzymes, which would lead to hypomethylation in the central nervous system and ultimately to neurological lesions. In a pig model of subacute combined degeneration and in vitamin-B 12-deficient human beings, the primary cause of the low methylation ratio is impaired recycling of SAH back to SAM, a process which requires vitamin-B 12-dependent methionine synthase. The HIV patients in this study were vitamin B 12 and folate replete, which suggests a different cause for the low methylation ratio.