title: HIV-1 clade B and C isolates exhibit differential replication: relevance to macrophage-mediated neurotoxicity.
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.
authors.affiliation: Laboratory of Neuroimmunology and Regenerative Therapy, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, 985930 Nebraska Medical Center, Omaha, NE 68198-5930, USA.
authors.forename: Agnes A
authors.initials: AA
authors.lastname: Constantino
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Huang
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Charles
authors.initials: C
authors.lastname: Wood
authors.forename: Jialin C
authors.initials: JC
authors.lastname: Zheng
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000633:toxicity; D004622:Embryo, Mammalian; D004797:Enzyme-Linked Immunosorbent Assay / Q000379:methods; D015497:HIV-1 / Q000145:classification* / Q000235:genetics* / Q000302:isolation & purification; D006801:Humans; D020287:In Situ Nick-End Labeling / Q000379:methods; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000821:virology*; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000821:virology*; D051381:Rats; D013997:Time Factors; D014779:Virus Replication
chemical_list: D017077:Culture Media, Conditioned; C489788:MAP2 protein, human; D008869:Microtubule-Associated Proteins