Analysis of human immunodeficiency virus type 1 gp160 sequences from a patient with HIV dementia: evidence for monocyte trafficking into brain

Towards understanding the pathogenesis of HIV dementia, we molecularly clon ed and sequenced human immundeficiency virus type 1 (HIV-1) gp160 genes fro m uncultured post-mortem tissues collected from a patient with HIV dementia . Sequences from bone marrow, lymph node, lung, and four regions of brain - the deep white matter, head of caudate, choroid plexus and meninges were c ompared. Also included were gp160 sequences recovered from blood monocytes collected 5 months prior to death. Phylogenetic analyses showed that the se quences from deep white matter were more closely related to those from bone marrow, than to those from the other tissues, and moreover, were most clos ely related to sequences from the blood monocytes. These findings suggest t rafficking of bone marrow-derived monocytes into the deep white matter duri ng this late stage of infection. Another cluster included sequences from ch oroid plexus, meninges and lymph node, and interestingly, identical pattern s of four or nine stop codons were shared among these tissues. These mutati ons appear to be the consequence of G-->A hypermutation, and could reflect independent events, or the movement of virions or infected cells, from the choroid plexus into the cerebrospinal fluid and ultimately, into the lymph node. We propose that a critical step towards the development of HIV dement ia is an increase in monocyte trafficking into the brain, and that this pro cess is either initiated and/or accelerated during late-stage infection, wh ich could explain why dementia occurs primarily during this time.