Oxidative Stress during HIV Infection: Mechanisms and Consequences

Abstract

It is generally acknowledged that reactive oxygen species (ROS) play crucial roles in a variety of natural processes in cells. If increased to levels which cannot be neutralized by the defense mechanisms, they damage biological molecules, alter their functions, and also act as signaling molecules thus generating a spectrum of pathologies. In this review, we summarize current data on oxidative stress markers associated with human immunodeficiency virus type-1 (HIV-1) infection, analyze mechanisms by which this virus triggers massive ROS production, and describe the status of various defense mechanisms of the infected host cell. In addition, we have scrutinized scarce data on the effect of ROS on HIV-1 replication. Finally, we present current state of knowledge on the redox alterations as crucial factors of HIV-1 pathogenicity, such as neurotoxicity and dementia, exhaustion of CD4⁺/CD8⁺ T-cells, predisposition to lung infections, and certain side effects of the antiretroviral therapy, and compare them to the pathologies associated with the nitrosative stress.

Figure 1

Cellular sources of reactive oxygen species in HIV infection. Several HIV proteins enhance ROS production by different mechanisms. These viral proteins include amongst others the envelope protein Gp120, Tat, Nef, Vpr, and RT. The envelope protein Gp120 enhances ROS production via upregulation of cytochrome P450 2E1 (CYP2E1), proline oxidase (POX), and activation of NOX2 and NOX4. Tat protein induces spermine oxidase (SMO), an enzyme involved in catabolism of biogenic polyamines, and may impact mitochondrial function. Tat also activates NADPH (but not xanthine) oxidases and in particular Nox4, which in turn may induce other peroxide-generating enzymes involved in unfolded protein response (UPR) such as ER oxidoreductin 1α (Ero1α). Vpr protein interacts with adenine nucleotide translocator (ANT, a component of mitochondrial permeability transition pore (PTP)) that is implicated in Ca²⁺ influx into mitochondria. Nef protein can directly interact with the p22phox subunit of NADPH oxidases without affecting NOX expression. Finally, RT triggers ROS production by yet undiscovered mechanism(s).

Figure 2

Mechanisms of HIV neurotoxicity. Enhanced ROS production, triggered by gp120, Tat, and Vpr proteins that circulate in the blood, results in alteration of blood-brain barrier (BBB) through matrix metalloproteinase 2/9- (MMP2/9-) mediated disruption of tight junction receptors ZO-1, laminin, claudin 5, and occludin. Gp120, Tat, and Vpr proteins activate a consequence of proapoptotic events. They include (i) oxidation of DNA and consequent genomic and mitochondrial DNA instability, (ii) increased lipid peroxidation and accumulation of ceramide that aggravates toxicity, (iii) induction of spermine oxidase (SMO) augmenting oxidative stress and producing toxic acrolein, (iv) stimulation of A-type transient outward K⁺ currents by Kv channels, and (v) induction of proinflammatory cytokines. In addition, it upregulates expression of opioid receptors that contribute to neurotoxicity in HIV-infected drug addicts.