The Hallmarks of Ageing in Human Immunodeficiency Virus Infection and the Impact of Antiretroviral Therapy on Telomeres: A Molecular Perspective

Abstract

Ageing is a complex and unavoidable physiological process which, in simple terms, consists of a progressive deterioration in the functionality of cells, tissues and organs, culminating in an increased risk of developing chronic pathologies. Telomeres, the repetitive nucleotide structures at the end of chromosomes, ensure genomic integrity and modulate cellular senescence. The progressive shortening of telomere length with each cell division directly correlates with an increased susceptibility to developing chronic pathologies. However, this shortening, normally physiological and inevitable, can be markedly accelerated in the presence of chronic infections, such as HIV-1 infection, by sustained and continuous activation of the immune system, chronic inflammation, generation of oxidative stress, or direct alterations produced by viral proteins. Thus, in this narrative review, we discuss the 12 hallmarks of ageing in the context of HIV-1 infection, as understanding the molecular changes induced by HIV-1 through these well-established pillars could provide a holistic approach to the management of HIV-positive patients. At the same time, considering that telomeres are at the centre of all these changes, an assessment of the impact of antiretroviral therapy on telomere length is necessary to guide clinical decisions. The ultimate goal of this research is to develop personalised therapies to increase the quality of life and health outcomes of HIV patients.

Keywords: HIV-1; accelerated ageing; ageing; ageing biomarkers; molecular alterations in HIV-1; personalised therapy; pharmacotherapy on telomeres; telomere attrition in HIV-1; telomere length.

Figure 1

Age-related diseases induced or aggravated by accelerated ageing (Created with BioRender.com). Legend: CAD—coronary artery disease; GI—gastrointestinal; NAFLD—non-alcoholic fatty liver disease.

Figure 2

HIV-1-induced DNA damage (Created with BioRender.com). Legend: HIV—human immunodeficiency virus; ROS—reactive oxygen species; Vpr—viral protein R; Tat—transactivator of transcription; Vif—viral infectivity factor; gp120—glycoprotein 120; Nef—negative regulatory factor; G-rich—guanine-rich; eNOS—endothelial nitric oxide synthase; MMP—matrix metalloproteinases; NADPH oxidases—nicotinamide adenine dinucleotide phosphate oxidase; DDR—DNA damage response.

Figure 3

HIV-1-induced mitochondrial dysfunction [128,129] (Created with BioRender.com). Legend: ATP—adenosine triphosphate; Ca²⁺—calcium ion; ETC—electron transport chain; Env—envelope proteins; gp120—glycoprotein 120; gp41—glycoprotein 41; HIV—human immunodeficiency virus; Mfn2—mitofusin 2; O₂⁻—superoxide anion; ROS—reactive oxygen species; Tat—transactivator of transcription; Vpr—viral protein R; Vpu—viral protein U.

Figure 4

NF-κB, PI3K/Akt/mTORC1, and p53 signalling pathways in HIV-1 infection (Created with BioRender.com). Legend: AKT—protein kinase B; CD4—cluster of differentiation 4; Env—envelope proteins; Gag—group-specific antigen; GDP—guanosine diphosphate; GTP—guanosine triphosphate; HIV—human immunodeficiency virus; IKB—inhibitor of nuclear factor kappa-B; IKKα—IκB kinase alpha; IKKβ—IκB kinase beta; IKKγ—IκB kinase gamma; mTORC1—mechanistic target of rapamycin complex 1; MDM2—mouse double minute 2 homolog; Nef—negative factor; NF-κB—nuclear factor kappa-light-chain-enhancer of activated B cells; PDK1—3-phosphoinositide-dependent kinase 1; PI3K—phosphoinositide 3-kinase; PIP₂—phosphatidylinositol 4,5-bisphosphate; PIP₃—phosphatidylinositol (3,4,5)-trisphosphate; p53—tumor suppressor protein 53; Rheb—Ras homolog enriched in brain; TSC1/2—tuberous sclerosis complex 1/2; Tat—transactivator of transcription; Ub—ubiquitin; Vif—virion infectivity factor; Vpr—viral protein R; Vpu—viral protein U.