Premature and accelerated aging: HIV or HAART?

Abstract

Highly active antiretroviral therapy (HAART) has significantly increased life expectancy of the human immunodeficiency virus (HIV)-positive population. Nevertheless, the average lifespan of HIV-patients remains shorter compared to uninfected individuals. Immunosenescence, a current explanation for this difference invokes heavily on viral stimulus despite HAART efficiency in viral suppression. We propose here that the premature and accelerated aging of HIV-patients can also be caused by adverse effects of antiretroviral drugs, specifically those that affect the mitochondria. The nucleoside reverse transcriptase inhibitor (NRTI) antiretroviral drug class for instance, is known to cause depletion of mitochondrial DNA via inhibition of the mitochondrial specific DNA polymerase-γ. Besides NRTIs, other antiretroviral drug classes such as protease inhibitors also cause severe mitochondrial damage by increasing oxidative stress and diminishing mitochondrial function. We also discuss important areas for future research and argue in favor of the use of Caenorhabditis elegans as a novel model system for studying these effects.

Keywords: C. elegans; HAART; HIV; NRTI; antiretroviral; immunosenescence; mitochondria; premature and accelerated aging.

FIGURE 1

The HIV-1 life cycle and the antiretroviral drug class intervention points. Entry inhibitors interfere with viral entry into the host cell and are comprised of a complex group of drugs with multiple mechanisms of action. By inhibiting several key proteins that mediate the process of virion attachment, co-receptor binding and fusion, virus spreading can be mitigated (Tilton and Doms, 2010). NRTIs imitate endogenous deoxyribonucleotides and have a high affinity for the viral reverse transcriptase, thus facilitating incorporation into the viral DNA strand during synthesis. NRTI incorporation results in transcription termination as they all lack the 3′-OH group necessary for phosphodiester bond formation in DNA strand elongation (Cihlar and Ray, 2010). NNRTIs are compounds that fit into the allosteric “pocket” site of the HIV-1 reverse transcriptase and disrupt its enzymatic activity, selectively blocking HIV-1 transcription (De Clercq, 2004). Integrase inhibitors bind cofactors of the viral integrase that are essential in host DNA interaction and therefore block insertion of proviral DNA into the host genome (Schafer and Squires, 2010). Protease inhibitors bind the viral protease active site with high affinity and therefore inhibit cleavage of viral polypeptides and subsequent maturation of the virion after budding from the host cell (Adamson, 2012). HIV-1 maturation inhibitors act much like protease inhibitors in that they inhibit the processing of the HIV-1 polypeptides. However, maturation inhibitors do not bind the protease but rather the polypeptide itself, rendering it uncleavable (Richards and McCallister, 2008). The relative size of different components has been altered for pictorial clarity.

FIGURE 2

The polymerase-γ theory. NRTIs compete with endogenous nucleotides and nucleosides for transcriptase binding. Due to the surplus and high affinity of NRTIs for polymerase-γ, NRTIs are frequently incorporated into the new DNA strand which results in chain termination as they all lack the 3′-OH group necessary for phosphodiester bond formation in DNA strand elongation. This results in a reduced number of mtDNA molecules and possibly a reduction in mtDNA encoded proteins, essential components of the mitochondrial respiratory chain (MRC) complexes. In turn, this leads to disrupted electron transport through the MRC and a concomitant reduction in proton efflux, reducing the membrane potential and ATP production by the mitochondrion. This disturbed mitochondrial function can result in augmented ROS production and morphological changes. Disturbed mitochondrial function due to polymerase-γ inhibition has been proposed as a central mechanism for NRTI-induced adverse events (Lewis and Dalakas, 1995; Lewis et al., 2006).

FIGURE 3

Schematic representation of the major effects of antiretroviral drugs that drive premature and accelerated aging. Antiretroviral drugs cause mtDNA damage and depletion, oxidative stress and altered mitochondrial morphology and function. These alterations in the mitochondria contribute, either alone or in unison, to premature and accelerated aging in HAART-treated patients.