Soluble HIV-1 infected macrophage secretory products mediate blockade of long-term potentiation: a mechanism for cognitive dysfunction in HIV-1-associated dementia

It is generally accepted that viral and cellular products from immune compe tent mononuclear phagocytes (MP) (brain macrophages and microglia) underlie the neuropathogenesis of HIV-1-associated dementia (HAD), What remains una nswered, however, is the composition of and mechanisms for such MP-induced neurological dysfunctions. In attempts to address these issues culture flui ds from HIV-1(ADA)-infected monocyte-derived macrophages (MDMs) (depleted o r enriched with progeny virus) were placed onto the CA1 area of rat hippoca mpal brain slices (the site of mammalian learning and memory) and neuronal long-term potentiation (LTP) assayed. LTP was induced by high frequency sti mulation (HFS). Lipopolysaccharide (LPS) served as a surrogate macrophage a ctivator. Synaptic strength was assayed by the initial slope of evoked fiel d excitatory postsynaptic potentials (EPSPs). Synaptic potentiation followi ng HFS was observed in slices incubated with uninfected (control) MDM cultu re fluids. The magnitude of the LTP response was 150.2 +/- 21.10% compared to basal levels (n=6). Synaptic strength was enhanced in virus-infected (13 5.7 +/- 28.9%, n=8) and LPS-activated MDM (123.3 +/- 5.1%, n=7) but at lowe r levels than controls. The lowest levels of LTP were in brain slices incub ated with virus-infected and LPS-activated MDM fluids at (109.5 +/- 9.9% n= 12). Interestingly, bath application of progeny HIV-1 virions showed minima l LTP effects. Virus-infected, LPS-activated MDM fluids, with progeny virus , reduced synaptic strength but were not statistically different than repli cate culture fluids depleted of virus. In contrast, IL-1 beta and quinolini c acid, significantly diminished synaptic strength. These results, taken to gether, suggest that soluble HIV-1-infected MDM secretory products, but not virus per se, significantly affect LTP. This electrophysiological system, which monitors neuronal function following cell exposure to HIV-1 infected materials could provide a novel testing ground for therapeutics designed to protect brain function in HAD.