Document Type
Article
Publication Date
2004
Abstract
Retroviruses utilize cellular dNTPs to perform proviral DNA synthesis in infected host cells. Unlike oncoretroviruses, which replicate in dividing cells, lentiviruses, such as human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus, are capable of efficiently replicating in non-dividing cells (terminally differentiated macrophages) as well as dividing cells (i.e. activated CD4+ T cells). In general, non-dividing cells are likely to have low cellular dNTP content compared with dividing cells. Here, by employing a novel assay for cellular dNTP content, we determined the dNTP concentrations in two HIV-1 target cells, macrophages and activated CD4+ T cells. We found that human macrophages contained 130-250-fold lower dNTP concentrations than activated human CD4+ T cells. Biochemical analysis revealed that, unlike oncoretroviral reverse transcriptases (RTs), lentiviral RTs efficiently synthesize DNA even in the presence of the low dNTP concentrations equivalent to those found in macrophages. In keeping with this observation, HIV-1 vectors containing mutant HIV-1 RTs, which kinetically mimic oncoretroviral RTs, failed to transduce human macrophages despite retaining normal infectivity for activated CD4+ T cells and other dividing cells. These results suggest that the ability of HIV-1 to infect macrophages, which is essential to establishing the early pathogenesis of HIV-1 infection, depends, at least in part, on enzymatic adaptation of HIV-1 RT to efficiently catalyze DNA synthesis in limited cellular dNTP substrate environments.
Recommended Citation
Diamond T.L., Roshal M., Jamburuthugoda V.K., Reynolds H.M., Merriam A.R., Lee K.Y., Balakrishnan M., Bambara R.A., Planelles V., Dewhurst S., Kim B. (2004) Macrophage tropism of HIV-1 depends on efficient cellular dNTP utilization by reverse transcriptase. Journal of Biological Chemistry 279: 51545-51553. doi: 10.1074/jbc.M408573200
Comments
This research was originally published in the Journal of Biological Chemistry. © the American Society for Biochemistry and Molecular Biology