Abstract
HIV-associated neurocognitive disorders (HAND) continue to be a consequence of HIV-1 infection among clade B-infected individuals. In contrast, the incidence of severe neurological impairment is lower among clade C-infected patients in regions of Sub-Saharan Africa and India. Biological aspects such as replication, cytopathicity, inflammatory response, and neurotoxicity unique to each clade influence neuropathogenicity and ultimately affect the clinical outcome of the disease. We hypothesize that productive infection by clade C isolates leads to macrophage-mediated neurotoxicity, although to a lesser extent than clade B isolates. Using a panel of primary isolates of clades B and C we demonstrated that clade B has higher replication efficiency in monocyte-derived macrophages (MDM) through reverse transcriptase activity assay and HIV-1 p24 antigen ELISA. To test the neurotoxicity of clades B and C, we used an in vitro neurotoxicity model. Conditioned medium from clade B-infected MDM was neurotoxic to rat and human neuron cultures. In contrast, clade C isolates mediated neurotoxicity when a higher initial viral titer was used for MDM infection. Furthermore, neurotoxicity mediated by isolates of both clades correlated with virus replication in MDM. Together, these results suggest that in comparison to clade B, primary isolates of clade C have slower replication kinetics in primary MDM, leading to lower levels of macrophage-mediated neurotoxicity. Elucidating the differences in replication and macrophage-mediated neurotoxicity between isolates of HIV-1 clades B and C will provide important insights needed to clarify the disparity seen in HAND incidence.
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Acknowledgments
We thank Dr. Nicholas P. Whitney for assistance with immunocytochemistry, microscopy, and revision of the manuscript; Dr. Hui Peng, Dr. Changhai Tian, and Dr. Min Cui for helpful discussions regarding experiments and the manuscript. Myhanh Che, Na Ly, and Emilie Scoggins provided exceptional administrative support. This work was supported in part by research grants by the National Institutes of Health, Grant numbers: R01NS41858, R01NS61642, R21MH83525, P20RR15635, and P01NS43985; National Natural Science Foundation of China, Grant number: 81028007 to Jialin C. Zheng; CA75903 and NCRR COBRE grant RR15635 to Charles Wood; and University of Nebraska Medical Center graduate student fellowship to Agnes A. Constantino.
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Constantino, A.A., Huang, Y., Zhang, H. et al. HIV-1 Clade B and C Isolates Exhibit Differential Replication: Relevance to Macrophage-Mediated Neurotoxicity. Neurotox Res 20, 277–288 (2011). https://doi.org/10.1007/s12640-011-9241-3
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DOI: https://doi.org/10.1007/s12640-011-9241-3