Background:  HIV-associated dementia (HAD) is a disease mediated by chronically infected macrophages through unknown mechanisms. The goal of this study was to apply phylodynamic  analysis, a process that combines various statistical procedures to correlate the epidemiological and evolutionary behavior of HIV DNA within a HAD brain macrophage reservoir.

Methods:  Tissues were obtained from the ACSR. Multiple HIV-1 gp120 envelope DNA sequences (V1, V2, and V3 region) were isolated from different brain compartments (meninges, frontal lobe subcortex, occipital and temporal lobe, spinal cord) of a T-cell-depleted patient diagnosed with severe HAD at the time of death.

Results:  All sequences appeared to be macrophage tropic by V3 loop charge analysis. In agreement with previous reports, phylogenetic analysis showed distinct virodemes, but also revealed a significant amount of viral gene flow among different brain compartments. Three types of flows were observed: main outflow from the meninges and the occipital lobe cortex, main inflow into the temporal lobe, and equal exchange of viruses between the frontal subcortex and the spinal cord. Local molecular clock analysis showed that HIV-1 meninges and temporal lobe subpopulations evolved about 30 and 100 times faster, respectively, than the other viral populations in the brain. However, maximum likelihood codon-based substitution models did not detect any site under significant positive selective pressure, and the main cause of HIV-1 genetic variation appeared to be random genetic drift. Therefore, the faster evolutionary rate in meninges and temporal lobe could be due to an enhanced infection or expansion rate within macrophages as a consequence of the immune system failure. In addition, signature pattern analysis did not reveal any significant neurotropic viral variant. However, a close inspection of the amino acid alignment showed a loss of known T-cell epitopes and glycosylation sites usually present in the V3 region.

Conclusions:  In this case study, viral infection in the brain progressed with a non-specific genetic evolution, recurrent migration events, and an expansion of macrophage tropic sequences. The data suggest that after immune failure newly produced viral variants, which would be rapidly cleared in normal conditions, begin to productively infect macrophages in a self-amplifying cycle of infection and inflammatory response that could contribute to HIV-associated dementia pathogenesis.

Keywords: HIV; macrophage; AIDS dementia