Table 1.

Summary and key findings from studies investigating Vpr-induced neuroinflammation from myeloid and microvascular endothelial cells

Vpr status	Model	Markers Investigated	Assay	Key findings for marker levels	Other key findings	References
Viral protein R (Vpr)+	Microglia	Chemokine (C-C motif) ligand CCL5/RANTES, Interferon gamma-induced protein 10 (IP-10) and CCL2	Enzyme-linked immunosorbent assay (ELISA)	↑CCL5	1. Vpr was required for efficient viral replication and chemokine expression in microglia.	[37]
Vpr+	Monocyte-derived macrophages (MDMs)	Interleukin (IL)-1β, IL-8 and Tumour necrosis factor (TNF)-α	ELISA	↑IL-1β, IL-8 and TNF-α	1. Vpr presence activated the p38 and stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK) more than HIV-1 (Vpr deleted mutant)-infected MDMs. 2. The increased expression of IL-1β, IL-8 and TNF-α increased the neurotoxicity of primary neurons	[36]
Vpr+	Macrophages/microglia	IL-1β	Immunofluorescence	↑IL-1β	1. Pseudotyped viruses containing Vpr led to a significant reduction in cell viability in differentiated THP-1 cells and microglia. 2. Increased NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), caspase-1, and IL-1β expression was evident in HIV-1 Vpr transgenic mice compared to wild-type littermates, following systemic immune stimulation 3. Treatment with the caspase-1 inhibitor, VX-765, suppressed NLRP3 expression with reduced IL-1β expression and associated neuroinflammation which results in an improvement in neurobehavioral deficits in Vpr transgenic animals.	[32]
Vpr+	Myeloid	TNF-α and IFN-α	Polymerase chain reaction (PCR)	↑IFN-α and TNF-α	1. Vpr was found in human brain tissue and peripheral blood mononuclear cells (PBMCs) 2. Vpr transcripts were found in the human brain and were significantly higher among HIV-associated dementia (HAD) patients (59%) compared with non-demented (ND) patients (31%). 3. Vpr amino acid signature 77Q was largely present in HAD and 77R was present in ND participants 4. Myeloid transfected cells with Vpr 77R induced TNF-α and IFN-α significantly more than Vpr 77Q and Vpr (-). 5. Supernatants derived from Vpr + transfected cells and added to human fetal neurons led to significant reductions in neuronal viability compared with supernatants from the Vpr(-) transfected cells.	[39]
					6. Interestingly, Vpr R77 showed the greatest neurotoxicity, in line with the neuroimmune response. 7. Human fetal microglia were exposed to Vpr peptides revealing that Vpr77R peptide activated greater IFN-α compared to Vpr 77Q or mock exposed glia cell. 8. A reduced number of neurons were found in animals implanted with the full-length Vpr and Vpr 77R. 9. Both full-length Vpr and Vpr77R caused significantly increased rotary behaviour compared with Phosphate-buffered saline (PBS)-implanted animals 10. Findings show that in that Vpr containing 77R was more neurovirulent compared with the 77Q peptide or controls.
Vpr+	Microvascular endothelial cells (MVECs)	TNF-α	ELISA	↑TNF-α	1. Vpr induced increased apoptosis in MVECs	[23]
Vpr+	Monocytes	IL-6	PCR	↓IL-6	1. Lower IL-6 transcript levels were found in the basal ganglia (BG), cortex, and hindbrain of Vpr Transgenic animals compared with wild-type controls	[22]

The table is presented according to the findings presented in Sect. 3.3

Abbreviations: Basal ganglia (BG), Chemokine (C-C motif) ligand, Enzyme-linked immunosorbent assay (ELISA), HIV-associated dementia (HAD), Interferon gamma-induced protein 10 (IP-10), Interleukin (IL), Microvascular endothelial cells (MVECs), Monocyte-derived macrophages (MDMs), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3), Non-demented (ND), Peripheral blood mononuclear cells (PBMCs), Phosphate-buffered saline (PBS), Polymerase chain reaction (PCR), Stress-activated protein kinase (SAPK)/c-Jun N-terminal kinase (JNK), Tumour necrosis factor (TNF)-α, Viral protein R (Vpr)+