Analysis of human immunode®ciency virus type 1 evidence for monocyte traf®cking into brain

Towards understanding the pathogenesis of HIV dementia, we molecularly cloned and sequenced human immunde®ciency virus type 1 (HIV-1) gp160 genes from 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 compared. Also included were gp160 sequences recovered from blood monocytes collected 5 months prior to death. Phylogenetic analyses showed that the sequences from deep white matter were more closely related to those from bone marrow, than to those from the other tissues, and moreover, were most closely related to sequences from the blood monocytes. These ®ndings suggest traf®cking of bone marrow-derived monocytes into the deep white matter during this late stage of infection. Another cluster included sequences from choroid plexus, meninges and lymph node, and interestingly, identical patterns of four or nine stop codons were shared among these tissues. These mutations appear to be the consequence of G?A hypermutation, and could re ̄ect independent events, or the movement of virions or infected cells, from the choroid plexus into the cerebrospinal ̄uid and ultimately, into the lymph node. We propose that a critical step towards the development of HIV dementia is an increase in monocyte traf®cking into the brain, and that this process is either initiated and/or accelerated during late-stage infection, which could explain why dementia occurs primarily during this time. Journal of NeuroVirology (2000) 6, S70 ± S81.