Background:  HIV-1 clade C is now responsible for >50% of new infections and is becoming the most commonly transmitted subtype worldwide. The incidence of HIV-1-associated dementia (HAD) in regions where clade C infection is prevalent is unclear, but appears to be lower than in the clade B-infected regions. Potential differences in clade B and C neurovirulence and macrophage mediated pathogenesis have yet to be investigated. Differential regulation of proinflammatory factors and neurotoxins such as glutamate, produced by macrophage during infection by different clades or strains may differentially induce neuronal injury and dysfunction, consequently altering neuropathogenesis.

Methods:  Human monocyte-derived macrophage (MDM) were infected for 7, 14, 21, and 28 days starting with similar lTCID₅₀ by 3 HIV-1 laboratory clade B strains (ADA, DJV, M-tropic; 89.6, dual tropic), 4 primary clade B strains (G0048; A00-275; A00-086; D02-2562; M-tropic) derived from HIV-1-infected brain, choroid plexus or spleen, and 2 pairs of clade C isolates from HIV-1-infected mothers and infants (2669M/I and 1157M/I). Viral infection was monitored by reverse transcriptase activity and characterized by macrophage inhibitory protein (MIP) -1β and tumor necrosis factor (TNF) –α expression as determined by ELISA. The concentration of extracellular glutamate was measured in MDM supernatants by reverse phase high performance liquid chromatography (RP-HPLC). Primary rat cortical neurons treated with conditioned media from different viral strain infected MDM were used to assess macrophage-mediated neurotoxicity. 

Results:  Laboratory strains (clade B) and 2 primary clade B strains (A-00-086 and D02-2562) reached the highest levels of viral infection 7 to 14 days after infection, while clade C reached highest levels of viral infection at 21 days post-infection. MIP-1β production was associated with HIV-1 infection as determined by reverse transcriptase. The highest glutamate production and neurotoxicity induced by different viral strains in infected MDM ranked as:  laboratory strains > primary clade B strains > primary clade C strains. Correlation analysis with all strains tested suggests a correlation between reverse transcriptase, glutamate production, and neurotoxicity induced by HIV-1-infected MDM.

Conclusions:  These results demonstrate a potential correlation between productive infection; glutamate production and HIV-1-infected MDM-mediated neurotoxicity.  Future studies with additional primary clade B and C strains will be needed to identify  differences between clade B- and C-mediated neurovirulence.