Table 1.
Summary of HIV-induced mechanisms contributing to neurodegeneration/AD-like pathology.
| HIV Components | Mechanism | Consequences/Conclusion | References |
|---|---|---|---|
| Neuro-Inflammation | |||
| HIV-infected microglia, macrophages, astrocytes | HIV infection of CNS cells provides an inflammatory stimulus and promotes secretion of viral proteins, e.g., Tat, gp-120 | Cycle of excessive cytokine/chemokine production, Aβ production, ROS production | [48,97] |
| HIV Proteins | |||
| Tat | Forms highly neurotoxic complexes with Aβ; inhibits neprilysin; inhibits microglial phagocytosis of Aβ; stimulates Aβ 1–42 release and promotes plaque accumulation; enhances cleavage of Aβ precursors; alters BBB permeability (see BBB damage) | More Aβ is produced in the CNS while less is cleared; alteration of Aβ degradation/metabolism; BBB damage | [27,53,54,55,57,59,60] |
| Gp-120 | Like Tat, alters Aβ trafficking/accumulation and enhances cleavage of Aβ precursors; alters BBB permeability (see BBB damage) | More Aβ is produced in the CNS while less is cleared | [62,63] |
| Gag | Aβ precursor, APP, binds and sequesters Gag in lipid rafts within macrophages to prevent viral spreading. In defense, Gag enhances APP cleavage | Increased Aβ production | [65] |
| Excitotoxicity and oxidative stress | |||
| HIV-infected microglia, macrophages, astrocytes | Infected CNS cells release pro-inflammatory chemicals that activate NMDARs | Excessive activation of NMDARs promotes excitotoxicity and free radical production | [69,70,71,76] |
| Tat, gp-120, Nef, Vpr | Viral proteins injure neuronal cells directly and disrupt calcium homeostasis, activate caspases, promote ROS accumulation; alter BBB permeability via oxidative stress pathways (see BBB damage) | Excitotoxicity/Induction of oxidative stress; BBB damage | [73,74,75,77] |
| BBB Damage | |||
| HIV virus | Affect HBMECs by releasing HIV gene products, inflammatory cytokines, and adhesion molecules on brain endothelium | Induction of oxidative stress | [84] |
| Tat, gp120, Nef | Alteration of the levels of tight junction proteins, nitric oxide, pro-inflammatory and interferon-inducible genes, leukocyte adhesion, trans-endothelial electrical resistance, and matrix metalloproteinases | Increased permeability of HBMEC | [58,85,87,88,89,90] |
| Aging | β-amyloid generation | Higher Aβ | [98] |
| ART Medication | |||
| ART | Increased oxidative stress; IRIS promotes vasculitis, hyperlipidemia, diabetes, coronary artery disease; Nelfinavir inhibits Aβ degradation enzyme | Contributes to AD risk factors and Aβ accumulation | [94,95,96] |