Oxidative Stress in HIV-Associated Neurodegeneration: Mechanisms of Pathogenesis and Therapeutic Targets

Abstract

Treatment for HIV infection has become more manageable due to advances in combination antiretroviral therapy (cART). However, HIV still significantly affects the central nervous system (CNS) in infected individuals, even with effective plasma viral suppression, due to persistent viral reservoirs and chronic neuroinflammation. This ongoing inflammation contributes to the development of HIV-associated neurocognitive disorders (HANDs), including dementia and Alzheimer's disease-like pathology. These complications are particularly prevalent among the aging population with HIV. This review aims to provide a comprehensive overview of HAND, with a focus on the contribution of oxidative stress induced by HIV-mediated reactive oxygen species (ROS) production through viral proteins such as gp120, Tat, Nef, Vpr, and reverse transcriptase. In addition, we discuss current and emerging therapeutic interventions targeting HAND, including antioxidant strategies and poly (ADP-ribose) polymerase (PARP) inhibitors. These are potential adjunctive approaches to mitigate neuroinflammation and oxidative damage in the CNS.

Keywords: Alzheimer’s Disease (AD); HIV-associated neurocognitive disorders (HAND); central nervous system (CNS); human immunodeficiency virus type 1 (HIV-1); reactive oxygen species (ROS).

Figure 1

Basic mechanisms of HIV-related neurodegeneration. HIV-associated neurodegeneration begins with viral entry into the central nervous system (CNS) across the blood–brain barrier (BBB). [I] Secreted viral proteins increase BBB permeability, allowing HIV-infected monocytes and T cells to infiltrate the CNS, a mechanism often referred to as the “Trojan horse” model. [II] Once inside, the infiltrating virus, viral proteins, and infected cells induce oxidative stress in glial cells, leading to the production of proinflammatory cytokines such as interleukin-1β (IL-1β). [III] These inflammatory signals disrupt calcium homeostasis in neurons, ultimately contributing to neuronal injury and death.

Figure 2

CNS disruption by Tat protein and amyloid-β interaction. Within the CNS, HIV-1 Tat protein binds to amyloid-β (Aβ), disrupting its clearance and promoting its accumulation. Tat also induces hyperphosphorylation of tau proteins, accelerating the formation of neurofibrillary tangles. Together, these effects enhance the development of both intracellular tangles and extracellular Aβ plaques, ultimately leading to synaptic loss and neuronal dysfunction in the CNS.

Figure 3

HIV-induced production of reactive oxygen species (ROS). (A) Schematic representation of the HIV-1 genome, highlighting viral proteins implicated in ROS generation: gp120, Tat, Nef, Vpr, and reverse transcriptase (RT). (B) The envelope glycoprotein gp120 induces intracellular oxidative stress in the glial cells. Elevated ROS in glial cells promotes the release of the proinflammatory cytokine IL-1β, which disrupts calcium homeostasis in adjacent neurons, leading to neuronal injury and death. (C-I) The HIV accessory protein Nef interacts with the NADPH oxidase complex via the p22-phox subunit, increasing superoxide anion production and priming the complex for a respiratory burst. Nef also activates the Vav/Rac1/p21-activated kinase (PAK) signaling pathway, further enhancing NADPH oxidase activity. (C-II) Nef modulates ROS production in a biphasic manner, ultimately suppressing oxidase activity via IL-10 secretion. (C-III) The oxidative environment driven by Nef contributes to inflammasome activation, leading to pyroptosis of uninfected bystander CD4⁺ T cells. (C-IV) Elevated superoxide production increases ROS levels, promoting chronic inflammation through cytokines such as IL-1β and IL-18. (D) The HIV accessory protein Vpr localizes to the mitochondrial inner membrane, reaching the adenine nucleotide translocator (ANT) through the voltage-dependent anion channel (VDAC). This interaction induces mitochondrial membrane depolarization and permeabilization, resulting in elevated ROS production. The increased ROS promotes the release of pro-apoptotic factors such as cytochrome c and apoptosis-inducing factor (AIF), ultimately leading to apoptosis. Vpr-induced ROS also activates redox-sensitive transcription factors, including NF-κB and AP-1, which enhance HIV gene expression. NF-κB further drives the production of proinflammatory cytokines, contributing to chronic immune activation in PLWH. (E) HIV reverse transcriptase (RT), which converts viral RNA into DNA, also contributes to oxidative stress. Its expression in host cells induces ROS production, which is associated with upregulation of the epithelial–mesenchymal transition (EMT) marker Twist. This may promote tumorigenic processes, increased cell motility, and lipid peroxidation. In response to oxidative stress, RT-induced ROS also triggers a cellular antioxidant defense mechanism, including upregulation of heme oxygenase-1 (HO-1), a key detoxification enzyme.

Figure 4

ROS-mediated chronic HIV-associated neurodegeneration. In neurons, ROS triggers increased levels of 4-hydroxynonenal (4-HNE), a marker of lipid peroxidation. ROS also activates acid sphingomyelinase (aSMase) and neutral sphingomyelinase (nSMase), catalyzing the breakdown of sphingomyelin into ceramide. Elevated 4-HNE and ceramide levels promote apoptosis.

Figure 5

Antioxidants and PARP inhibitors suppress neuroinflammation. Antioxidants and PARP inhibitors mitigate oxidative stress by reducing the production of reactive oxygen species (ROS) in microglia and other CNS cells. This ROS suppression helps alleviate neuroinflammation and prevents subsequent neuronal death. PARP inhibitors also enhance the efficacy of HDAC inhibitor–mediated latency reversal and promote immune activation, particularly of natural killer (NK) cells, to eliminate reactivated HIV-infected cells. Combination antiretroviral therapy (cART) prevents further rounds of viral replication from reactivated cells. However, certain cART components, such as azidothymidine (AZT) and indinavir (IDV), have been shown to induce oxidative stress and mitochondrial dysfunction, underscoring the need for adjunctive strategies to protect CNS integrity.