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SUPPLEMENT ARTICLE

Basic science and pathogenesis of ageing with HIV

potential mechanisms and biomarkers

Lagathu, Clairea,b,c; Cossarizza, Andread,*; Béréziat, Véroniquea,b,c; Nasi, Milenae; Capeau, Jacquelinea,b,c,*; Pinti, Marcellof

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doi: 10.1097/QAD.0000000000001441
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Abstract

Introduction

At the level of whole organism, ageing is defined as a progressive loss of physiological integrity, with heterogeneous organ decline, naturally ending by death. Ageing is associated with decreased ability to face stress, increased frailty, and increased prevalence of age-related comorbidities. All these alterations are connected, and raise the possibility of developing novel multidisease preventive and therapeutic approaches [1]. Ageing rate varies among individuals, because of genetic heterogeneity and environmental factors. Tissue ageing and functional loss define the biological age, which could markedly differ from the chronological one, and is associated with healthy aging. Indeed, in addition to life span, which continues to rise in the general population, it is important to consider ‘healthspan’. Healthy ageing is defined as no major chronic diseases or major impairments in cognitive or physical function or mental health [2] and is not keeping pace with life span [1]. This is of major importance for HIV-infected patients. Even if life span is getting closer to that of the general population, these patients, and mainly the older ones, present an increased prevalence of age-related comorbidities [3], precluding healthspan, and which could result from some enhanced ageing mechanisms. Similarities and dissimilarities exist between HIV-infection and normal ageing. Therefore, an important question is whether ageing mechanisms associated with HIV-infection are similar or not to those observed in the general population [3].

At the cellular level, ageing results from time-dependent accumulation of cellular damage affecting molecules or organelles [4]. Once a certain level of damage is reached, cells undergo temporary cell cycle arrest, apoptosis, or cellular senescence [5].

Here, we present the main ageing mechanisms according to the seven pillars of ageing [1,6] and also to the mechanisms detailed by Lopez-Otin [7] (Fig. 1). We then evaluate their potential role in the ageing process observed in HIV-infected older individuals (Figs 1 and 2).

Fig. 1
Fig. 1:
General and HIV-specific mechanisms of ageing.ART, antiretroviral therapy; CMV, cytomegalovirus; HCV, hepatitis C virus; mtDNA, mitochondrial DNA; NRTIs, nucleoside analogue reverse transcriptase inhibitors; PI, protease inhibitor; SASP, secretory-associated senescence phenotype. Mechanisms enhanced in HIV-infected patients are indicated in red. Mechanisms specific to HIV-infected patients are indicated in white.
Fig. 2
Fig. 2:
Molecular and cellular mechanisms of ageing in HIV-infected patients.Ageing and age-related comorbidities result from multiple mechanisms with inflammation and innate immunity activation probably playing a leading role. These mechanisms are enhanced in response to residual HIV infection and to some ART molecules but also to personal lifestyle factors. ART, antiretroviral therapy; CMV, cytomegalovirus; HCV, hepatitis C virus; NRTIs, nucleoside analogue reverse transcriptase inhibitors; Nef, negative regulatory factor; PIs, protease inhibitors; Tat, transactivator of transcription; Vpr, viral protein r.

Genetics and epigenetics

The genetic contribution to human life span is about 25–30% [8,9], mainly after 60 years [9,10]. The two main loci [11] are APOE encoding apolipoprotein E, involved in lipoprotein metabolism, cognitive function, and immune regulation [12] and forkhead box O3A (FOXO3A) involved in apoptosis and oxidative stress [13]. In addition, genome-wide association studies (GWAS) [14–16] identified new loci as multiple inositol-polyphosphate phosphatase 1 (MINPP1) [17], otolin1 (OTOL1) [18], and calcium/calmodulin dependent protein kinase IV (CAMKIV) [16].

In HIV-infected patients over 60 years, apolipoprotein E4 (APOE4) allele is correlated with decreased cognitive performance, premature brain ageing, and atrophy. APOE4 carriers show a higher frequency of HIV-associated neurocognitive disorders, particularly dementia, suggesting that APOE4 can exacerbate age-related cognitive decline [19].

Mitochondria play a crucial role in ageing. The mitochondrial DNA (mtDNA) C150T mutation is associated with extended life span in Finnish and Japanese individuals [20,21]. Haplogroup J is overrepresented in long-living Italian [22], Irish, and Finnish people [23,24].

In HIV-infected and noninfected patients, some haplogroups were associated with age-related disorders as insulin resistance, cardiovascular diseases, abnormal fat metabolism, and/or distribution. Otherwise, haplogroups J, U5a and HV were associated with accelerated progression to AIDS and CD4+ recovery [25], African haplogroup L2 with poorer CD4+ recovery and lower activation in antiretroviral treatment (ART)-treated non-Hispanic Blacks [26,27], European haplogroup H (and clade HV) with lower likelihood of AIDS progression and improved recovery of CD4+ during ART [28,29].

Ageing is also linked to epigenetic alterations in response to exogenous and endogenous factors [30], leading to an abnormal chromatin condition, genomic instability, and accumulation of DNA mutations [31]. Recently, Horvath [32] proposed that DNA methylation age could measure the cumulative effect of an epigenetic maintenance system. This novel epigenetic clock addresses the biological age in tissues. Both chronic and recent HIV infection in ART-receiving patients led to an average ageing advance of 4.9 years, increasing expected mortality risk by 19%. Specific decreased methylation of the human leucocyte antigen (HLA) locus was predictive of lower CD4+:CD8+ ratio, linking molecular ageing, epigenetic regulation, and disease progression [33]. Adjustment on cytomegalovirus (CMV) infection, which is more prevalent in HIV-infected patients and a major driver of immunosenescence, is required.

Macromolecular damage

Damage to protein, DNA, lipids, and other macromolecular components is an important contributor to specific age-related diseases [34]. DNA modifications can occur spontaneously, or be caused by environmental factors, and accumulate when cell repair system cannot cope with damage [35].

Telomeres, repetitive nucleotide sequences at each chromosome end, protect genome. In the absence of telomerase reverse transcriptase activity, a small portion of telomere sequence is lost after each cell division. When telomere length reaches a critical size, cells undergo senescence and/or apoptosis [36]. Thus, telomere length decreases with age [37] and is associated to age-related diseases and decreased life span [38].

Decreased telomere length was reported in peripheral blood mononuclear cells (PBMC) isolated from ART-naive or ART-controlled HIV-infected patients, compared with noninfected individuals [39,40] and associated with poor immune recovery. Nucleoside analogue reverse transcriptase inhibitors can alter telomerase reverse transcriptase activity, resulting in telomere length shortening [41,42].

Adaptation to stress

Mitochondrial dysfunction and oxidative stress

Progressive mitochondrial dysfunction is a hallmark of ageing [7], and accelerates ageing in high energy-demanding tissues as heart, skeletal muscle, kidney, liver, or brain [43–47]. It mainly results from a reduced ability to cope with reactive oxygen species (ROS). ROS exert positive physiological effects within a narrow range of concentrations, and detrimental effects when excessive. mtDNA is particularly susceptible to oxidative damage because of its proximity to free radical sources and the relative lack of a protein scaffold [48]. ROS generated by respiratory chain cause mtDNA mutations or deletions, leading to impairment in mitochondrial protein synthesis, to loss of oxidative phosphorylation efficiency, and ultimately to premature senescence and ageing [49]. This particularly impacts type II muscle fibers, predominantly lost with ageing [50].

HIV can directly induce mitochondrial ROS production [51,52]. It impairs complex I activity, causing loss of mitochondrial membrane potential and apoptosis [53]. Viral infection per se reduces mtDNA level [54,55]. Some nucleoside analogue reverse transcriptase inhibitors, mainly stavudine and zidovudine, affect mitochondria, in part by inhibiting the DNA polymeraseγ [56], causing mtDNA depletion, mitochondrial dysfunction, oxidative stress, all features shared with ageing. Moreover, some protease inhibitors can increase oxidative stress, because of prelamin A accumulation (see below).

Control of cell death, autophagy

Cell propensity to apoptosis undergoes age-dependent changes, and is altered in several comorbidities [57]. Lymphocytes are continuously exposed to damage, and respond with a series of mechanisms, including apoptosis [58]. Cells from elderly are less prone to damage and ROS-induced apoptosis [59,60], whereas mainly CD4+ and also CD8+ cells are more sensitive to tumor necrosis factor-alpha, (TNFα)-induced apoptosis [61,62]. Activation-induced cell death (AICD) of immune cells is often impaired with ageing, with a progressive increased expression of CD95+, the main mediator of AICD [63].

During HIV infection, chronic immune activation is accompanied by higher expression of TNF superfamily ligands and their receptors, particularly Fas ligand or CD95L and tumor-necrosis-factor-related apoptosis inducing ligand (TRAIL), and higher AICD [64]. Regarding HIV proteins, secreted transactivator of transcription (Tat) upregulates CD95L and TRAIL in T cells or macrophages [65–67], whereas negative regulatory factor (Nef) and glycoprotein 120 (gp120) upregulate CD95L expression [68] resulting in bystander apoptosis of uninfected T cells. Viral protein r (Vpr) can also induce intrinsic T-cells apoptosis, causing a rapid decrease in mitochondrial membrane potential and the release of cytochrome c. As well, Tat downregulates B-cell lymphoma 2 (Bcl-2) [69].

Autophagy is a mechanism through which cargo is sequestered in a double-membrane vesicle, which then delivers the content to a lysosome for degradation [70]. Autophagy declines with ageing, and is a major contributor to this process [71]. Its impairment could accelerate ageing through aberrant nuclear division [72]. Accordingly, in animal models, pharmacological or genetic autophagy enhancement extends life span, whereas its inhibition shortens life span [73–75]. Downregulation of key autophagy genes, as autophagy-related 5 (ATG5) and autophagy-related 7 (ATG7), was reported in human brain ageing [76], and autophagy is altered in age-related neurodegenerative diseases, as Alzheimer and Parkinson diseases [77,78]. Mitophagy, the autophagic mitochondria degradation, is required to guarantee mitochondrial quality control and cell survival [79] and is defective during ageing, leading to the accumulation of dysfunctional mitochondria [80].

Several HIV proteins can interfere with autophagy. Tat alters neuronal autophagy by modulating autophagosome fusion to the lysosome. Its overexpression in mice increased accumulation of autophagosomes in neurons, altered microtubule-associated protein 1A/1B-light chain 3II (LC3II) levels, and induced neurodegeneration [81]. Accordingly, autophagy was downregulated in the brain of aged HIV-infected patients with encephalitis or dementia, and in aged mice overexpressing gp120, whereas activation of autophagy by beclin-1 gene transfer ameliorated the neurodegenerative phenotype [82–84]. Nef inhibits autophagy by interacting with beclin-1, and thereby induces oxidative stress and mesenchymal stem cells (MSC) senescence [85].

Proteostasis

Ageing is accompanied by a gradual increase of protein oxidative damage and an imbalance in proteostasis, because of the impairment of protein degradation by the ubiquitin-proteasome system and the low efficiency of autophagy [86]. Misfolded proteins accumulation triggers the ‘unfolded protein response’ (UPR), aimed at restoring the homeostatic equilibrium through upregulation of chaperones and proteases. Both mitochondrial and endoplasmic reticulum UPR declines with age [87,88].

Tat induces the UPR response, along with mitochondria hyperpolarization, in the central nervous system, which can contribute to the cognitive decline of HIV-infected patients [89]. Protease inhibitors activate UPR in hepatocytes and macrophages, with an increased expression of TNFα and interleukin-6 (IL-6), thus promoting the premature onset of cardiovascular diseases [90–92]. Endoplasmic reticulum stress and UPR are induced in intestinal epithelial cells by protease inhibitors, resulting in disruption of the epithelial barrier integrity [93], and in hepatocytes by efavirenz [94].

Inflammation

Human ageing is characterized by a gradually increasing state of low-grade sterile inflammation often referred to as ‘inflammageing’ [95]. The level of systemic biomarkers of inflammation, as C-reactive protein, IL-6, soluble-TNFα receptors, is related to ageing, to the long-term occurrence of morbidity, and to mortality [96]. In controlled HIV-infected patients, increased systemic inflammation and innate immune activation solubleCD14 (sCD14) have been associated with most non-AIDS-related comorbidities, frailty, and mortality [97–99].

Inflammation results from multiple causes. First, damaged macromolecules such as extracellular ATP, excess glucose, ceramides, amyloids, urate, and cholesterol crystals, all of which increase with age [100,101], can mimic bacterial products and function as endogenous ‘damage’-associated molecular patterns that activate innate immunity and the NOD-like receptor family pyrin domain containing 3 (NLRP3) inflammasome pathway, leading to IL-1β and IL-8 release. However, in PBMC from ART-controlled patients, the expression of the inflammasome components was not altered [102].

Second, inflammation can result from cell senescence, a stable cell cycle arrest characterized by a specific secretory-associated senescence phenotype, which includes inflammatory cytokines and extracellular matrix-remodeling proteins [103]. Replicative senescence results from telomere shortening, whereas stress-induced senescence is induced by oxidative stress or damage to organelles. Cell cycle checkpoint proteins are increased, stopping cell division until damage repair, or cell elimination by the immune system. The two main senescence pathways involve cyclin-dependent kinase inhibitor 2A, multiple tumor suppressor 1 (p16INK4a)/retinoblastome and cyclin-dependent kinase inhibitor 1 (p21WAF-1)/protein 53 (p53) [103], p16INK4a being now considered as the main actor controlling ageing and age-related diseases [104]. Senescence can also result from the accumulation of farnesylated prelamin-A (or its truncated form progerin), the precursor of the nuclear protein lamin-A, belonging to the lamina meshwork. This accumulation results from mutations in the gene encoding lamin-A/C, responsible for Hutchinson–Gilford progeria, or from deficiency in the activity of the metalloprotease ZMPSTE24, maturating prelamin-A to lamin-A [105]. During ageing, senescent cells accumulate in some tissues (skin, lung, spleen, endothelium, adipose tissue) [7], which is deleterious in older organisms, and results in decreased tissue function, impaired regeneration, fibrosis, and secretory-associated senescence phenotype-related inflammation [103].

PBMC of naive HIV-infected patients presented features of ageing and senescence, p16INK4a increased expression, and reduced telomere length [39]. In ART-controlled patients, these two markers were associated with lower current CD4+ levels [39]. Tat and Nef activated senescence pathways in MSCs, and induced a proinflammatory profile [85]. In cultured adipocytes and MSCs, first generation protease inhibitors inhibited ZMPSTE24 and caused farnesylated prelamin-A accumulation [106,107], which contributes to premature senescence in tissues of protease inhibitor-treated individuals [108]. As well, endothelial and vascular smooth muscle cells, treated with ritonavir-boosted protease inhibitors, presented, to different extents, features of cell senescence and inflammation [109,110].

Third, inflammation and innate immune activation can result from harmful products, as lipopolysaccharide, produced by oral or gut microbiota, leaking into the blood. The microbiota composition modification during ageing participates to low-grade inflammation [111,112]. In ART-naive and ART-controlled patients, gut microbiota presents dysbiotic features associated with inflammatory markers [113]. The pathway of kynurenine formation from tryptophan, evaluated by the kynurenine/tryptophan ratio [113], is altered. Enrichment in proinflammatory Prevotella and decreased abundance of anti-inflammatory butyrate-producing Firmicutes, are associated with colonic mucosa dendritic and systemic T-cells activation [114]. This could result from increased gut permeability, only partly restored after ART, from the profound Gut-associated lymphoid tissue (GALT) depletion or from residual HIV [115,116]. Importantly, gut epithelial dysfunction, innate immune activation, and inflammation, but not T-cell activation or senescence, can predict mortality in HIV-treated patients with a history of AIDS [117].

Finally, increased inflammation can also result from immune activation by common chronic pathogens as CMV and hepatitis C virus, from inflammatory cytokine production by expanded visceral adipose tissue [118], or from environment-related conditions as smoking.

Metabolism

Nutrient sensing is playing a major role in ageing in most species. Intracellular signaling by insulin and insulin-like growth factor-1 use the same insulin and insulin-like growth factor signaling (IIS) pathway, conserved during evolution. Its activation by nutritional signals exerts negative effects on life span. Important targets, that negatively control life span, are the FOXO family of transcription factors and the mammalian target of rapamycin complexes, involved in autophagy. By contrast, activation by caloric restriction/starvation of two nutrient sensors, AMP-activated protein kinase (AMPK) and sirtuins, favors healthy ageing and prolongs life span. However, this beneficial effect is difficult to be ascertained in humans but prolonged life span is associated with preserved insulin sensitivity. Metformin, activating AMPK and decreasing insulin resistance, increases longevity in several species and decreases overall mortality in humans [119]. In HIV-infected patients, insulin resistance remains frequent [120].

Ageing also involves changes in endocrine, neuroendocrine, and neuronal communications, with dysfunction of the hypothalamopituitary axis, leading to androgen deficiency in men, decreased growth hormone and dehydroepiandrosterone secretion, responsible for loss of muscle and bone mass. Androgen and growth hormone deficiency are commonly reported in HIV-infected patients [121,122].

Ageing and altered gut microbiota are associated with central fat redistribution, further enhancing chronic systemic inflammation. Adipose tissue represents one of our largest organs and exerts numerous roles as energy storage, adipokine and cytokine secretion, and immune functions. Thus, adipose tissue is at the nexus of pathways involved in life span, age-related diseases, inflammation, and metabolism [123,124]. During ageing, accumulation of senescent adipocyte precursors with decreased adipogenesis results in deleterious hypertrophy of existing adipocytes [125,126].

HIV-infected patients receiving first generation ART developed lipodystrophy with peripheral lipoatrophy and sometimes central fat accumulation, associated with fat inflammation and metabolic disorders [127]. Lipodystrophic features are still observed in some patients [128,129]. HIV itself could be involved in the adipose tissue proinflammatory phenotype, as adipose tissue is an HIV reservoir with latently infected cell populations, despite effective ART [130,131]. Ageing and HIV-linked lipodystrophies present similar adipose tissue dysfunction, with low-grade inflammation and extracellular-matrix remodeling, in addition to central fat redistribution, increased visceral and ectopic fat, and dysmetabolic features [127,132].

In vitro, Tat, Nef, and Vpr affect adipocyte differentiation [133–136], and Tat and Nef induced premature senescence of adipose tissue stem cells (personal results). Adipocytes treated with stavudine or zidovudine were senescent with increased p21WAF-1 and p16INK4a expression and prelamin-A accumulated in protease inhibitor-treated cells and adipose tissue from protease inhibitor-treated patients [19,106,108,110,137,138].

Stem cells

Ageing and metabolic disorders could also result from a progressive and irreversible exhaustion of adult stem cells [139,140]. Adult MSCs are specialized repairing cells, capable of differentiation toward multiple lineages (adipose, bone, muscle, endothelium, and so on), mainly present in the bone marrow (BM), but also in blood and adipose tissue.

Inflammatory signals could promote irreversible and premature MSC exhaustion [95]. Indeed, tissue inflammation but also prolonged stresses, as DNA damage, oxidative stress, and mitochondrial dysfunction, result in MSC senescence leading to loss of MSC homeostasis by endless mobilization.

Tat and Nef induce premature senescence of BM-MSC and impair their osteoblastic potential, suggesting the contribution of MSC senescence to osteoporosis [85]. Some protease inhibitors also lead to BM-MSC senescence [107] and could participate to MSC loss.

Immunosenescence

Immunosenescence involves remodeling in the organization and functionality of the immune system, that renders elderly individuals more prone to infectious diseases and less responsive to vaccination [141]. Regarding innate immunity, neutrophil and monocyte functions (including chemotaxis, intracellular bacterial killing, phagocytosis, and neutrophil extracellular traps formation) are impaired [142], as well as antigen presentation by dendritic cells and macrophages [141]. The number of natural killer cells increases with age, but their cytotoxic function is impaired [143,144].

The adaptive immune system undergoes deeper modifications and remodeling during ageing, with progressive thymic involution and reduction in the output of naive T cells [145], evidenced by the progressive reduction of T cells positive for the T-cell receptor rearrangement excision circles [146]. This decrease is mirrored by increased frequency and oligoclonality of terminally differentiated effector memory re-expressing CD45RA (TEMRA) cells [147]. Many TEMRA cells are anergic, with senescent, cytotoxic, and inflammatory features [148,149]. Regulatory T cells expansion [150] and an inverted CD4+:CD8+ ratio are frequently observed in elderly individuals [151,152], together with CD28 downregulation [153,154]. Many of the CD8+CD28 expanded clones are the result of persistent infection by viruses, especially CMV [155].

B-cell number also decreases with age [141]. Their repertoire is reduced [156], the expression of activation-induced cytidine deaminase is lower [157] and somatic hypermutation and class switch recombination are impaired [158,159].

In chronic HIV infection, persistent inflammation and systemic immune activation [160] cause premature ageing of the immune system [161]. This immune activation results from the persistent gut microbial translocation [162], sustained chronic antigenic stimulation, low-level HIV viremia [163], and coinfections by persistent pathogens, including CMV, hepatitis B and C viruses, and Mycobacterium tuberculosis[160,164–167]. Chronic HIV and CMV infections result in senescent T-cells expansion [168], cell surface markers and functions being similar to those of healthy elderly individuals [141,161,169]. However, HIV-related CD8+ senescent phenotype is quite distinct from that observed in ageing, with expansion of well differentiated CD28CD8+ and reduction of CD28CD8+ cells expressing CD57 [170]. Regarding causality, it has been proposed that chronic inflammation associated with HIV disease drives excess activation and proliferation of T cells, which in turn leads to telomere shortening and, ultimately, poor immune recovery and immunosenescence [40]. However, even if adaptive immune activation and immune senescence markers are increased in ageing HIV-infected patients, they fail to predict non-AIDS-defining morbidity and mortality in most studies evaluating these patients, by contrast to markers of innate immune activation and inflammation [97,98].

Environment-related factors

Behavioural risk factors are strongly associated with ageing. Smoking, excessive consumption of alcohol, poor diet, and low levels of physical activity are contributing to half of the burden of age-related illness in developed countries [2]. Alcohol-induced macrophage inflammation enhances hepatocyte senescence [171]. Cigarette smoke is a strong inducer of senescence in lung cells [172,173], strongly associated with chronic lung diseases [174]. Smoking is detrimentally associated with healthy ageing, quality of life, or well-being outcomes. The Mediterranean diet and physical activity are positively associated with healthy and successful ageing, whereas a Western diet (with high intakes of fried and sweet food) is associated with worse outcomes. Drug abuse is also linked to ageing. PBMC from heroin users had lower telomerase activity than healthy controls [175].

Among HIV-infected individuals, deleterious lifestyle factors are frequently observed and associated with enhanced immune activation, smoking, hazardous alcohol consumption, abusing addictive substances, past histories of drug [97,176,177], leading to early ageing and elevated rates of mortality. Most chronic chemical addictions are associated with age-related complications, as neurological and immunological defects and altered metabolic and hepatic biomarkers [178,179]. Alcohol ability to induce liver inflammation might be enhanced in HIV-infected individuals, as well as alcohol-mediated hepatocyte senescence [180]. Smoking is highly prevalent among HIV-infected individuals and associated with enhanced inflammation [181], senescence, and increased mortality [182]. Other lifestyle factors, including obesity and sedentary behavior, shorten life [183].

What biomarkers can be proposed?

To find biomarkers, whether responsible of or associated with ageing, is an important goal for HIV-infected patients. Biomarkers validated in the general population need to be assessed but we also require markers specific to HIV-infected individuals. In addition to ‘universal’ aging markers addressing the biological age, some markers can address specific ageing mechanisms and/or tissue dysfunctions. It is important also to acknowledge that, even if a number of biomarkers are altered in HIV-infected patients, this does not result, at present, in a clear interventional strategy for a given patient.

Genetic and epigenetic markers

We propose to analyze the APOE4 genotype, which was shown to be associated with neurocognitive impairment and with accelerated cognitive decline in HIV-infected patients independently of cholesterol levels [184]. Measures of the epigenetic clock and of the specific hypomethylated status of the HLA region require further validation [33].

Macromolecular damage

Telomere length and telomerase activity are related to ageing and affected by ART. Because of the different replicative potential of different leukocytes, analysis should be performed on purified subpopulations. However, telomere length, considered as a validated biomarker of ageing in the general population, is affected by a number of confounders and technical difficulties with a wide range of variation. In HIV-infected patients, telomere length has not been associated with comorbidities, except an inverse relationship to lung function in patients with chronic obstructive pulmonary disease [185], and therefore could not be recommended at the individual level.

Adaptation to stress

Accumulation of mtDNA mutations represents a useful marker, particularly when performed in highly purified T-cell subsets. Mitochondrial dysfunction could be addressed by quantifying the level of heteroplasmy and the amount of mtDNA.

Markers of oxidative stress can be analyzed both on PBMC and in plasma. Glutathione, superoxide anion, and hydrogen peroxide can be quantified simultaneously inside PBMC, but the analysis needs to be performed rapidly after cell isolation [186]. In plasma, the amount of oxidized forms of metabolites, such as oxidized low density lipoproteins (LDL), carbonylated, or nitrated proteins can represent an indirect but relatively simple measurement of oxidative stress. Importantly, serum oxidized LDL level is elevated in HIV-infected patients, associated with atherosclerosis and decreased in response to statin therapy together with reduced coronary atherosclerosis [187]. This marker appears useful.

Inflammation

It is important to determine which markers could be useful to follow ageing and age-related comorbidities in well controlled HIV-infected patients. The levels of inflammatory markers such as high sensitivity C-reactive protein (hsCRP), IL-6, and D-dimers or of innate immune activation as sCD14 are mildly to moderately increased in infected versus noninfected individuals [181], and generally found associated with comorbidities and mortality, the severity of HIV infection, and/or ART molecules. Their level is also modulated by other factors as age, race, education level, BMI, smoking, hepatitis C virus coinfection [181,188]. hsCRP or D-Dimer, available in the routine care, can be informative for HIV-infected patients’ follow-up, outside of any clinical acute condition. However, there are no clinical interventions showing that decreasing inflammation improved health in these patients. IL-6 or sCD14, evaluating low-grade inflammation and innate immune activation are not routinely performed. Results from the randomized trial to prevent vascular events in HIV REPRIEVE (ClinicalTrials.gov NCT02344290) testing whether pitavastatin could decrease atherosclerosis and inflammation are awaited. It would also be important to validate indexes using several markers.

Circulating mtDNA increases with age, and is related to proinflammatory molecules (IL-1β and TNFα), and also increases during HIV infection [189,190]. Thus, mtDNA could become a useful parameter for monitoring inflammation.

Senescence markers can be assessed in PBMC. The validated biomarker of ageing, expression of cyclin dependent kinase inhibitor 2a (CDKN2A), encoding p16INK4a, is increased with age and in HIV-infected patients but can also be affected by smoking and other factors [39,191]. The level of senescence proteins can also be evaluated such as prelamin-A, p16INK4a, p21WAF-1, p53, and activated phospho-p53.

Metabolism

Metabolomics, proteomics, and computational tools have dramatically increased the knowledge of patterns associated with different diseases, at different levels, giving an integrated support for personalized medicine [192,193]. The metabolome, the complete repertoire of small systemic molecules, is studied through metabolome-wide association studies. Metabolomics biomarkers are useful because changes in metabolism can be rapid, and reveal the host physiological status. Metabolomics studies can highlight interactions between inflammation/immune activation and/or senescence and cellular metabolism. In HIV-infected patients receiving protease inhibitor-based ART, metabolomics analysis has revealed that lipid alterations are linked to markers of inflammation, microbial translocation, and hepatic function [194]. In cerebrospinal fluid, the metabolomics profile of young HIV-infected patients presented similarities to that of aged HIV-negative controls, and was associated with worse neurocognitive test scores and plasma inflammatory biomarkers [195]. In oral wash samples, ART-naive individuals presented an increased ratio of phenylalanine/tyrosine associated with immune activation [196]. Metabolomics can also reveal microbiota modifications because some biomarkers could be the end products of microbes’ metabolism. Thus, microbiota-derived metabolites from choline, as trimethylamine and its liver-produced derivative trimethylamine-N-oxide, are markers of cardiovascular risk in HIV-infected patients [197]. In long-term ART-treated patients, HIV infection was associated with defects in metabolites recovered from proline, phenylalanine, and lysine metabolism and accumulation of products of the kynurenine pathway derived from tryptophan metabolism [198]. The serum kynurenine/tryptophan ratio was associated with non-AIDS related outcome and death [98] and with gut dysbiosis [113]. Determination of this ratio should be important for patients’ follow-up [199].

Adaptive immune activation and immune senescence markers

Some age-related markers of adaptive immunity are modified during HIV infection and could be informative in addition to the CD4+:CD8+ ratio: expansion of terminally differentiated CD28 T cells [200–204] and increased frequency of T-cell receptor rearrangement excision circle-positive T cells [146,205,206]. The number of CMV+ T cells could also be monitored, to assess the effect of latent viral infection. Regarding B cells, the analysis the expression of activation-induced cytidine deaminase could be useful to monitor their capability to respond to new antigens, and particularly to vaccines.

Global score of ageing

In the general population, the ‘Biological Age Score’ as determined by the European MARK-AGE consortium uses a set of biomarkers, including the markers resulting from age-modified protein N-glycosylation, combined in an algorithm that would measure biological age (patent method for the determination of biological age in human beings, EP 2976433 A1). In women, these markers are the cumulative level of cytosine methylation at different loci of two genes, ELOVL (elongation of very long chain fatty acids) and FHL2 (four-and-a-half-LIM-only), evaluated in blood cells, together with the serum levels of dehydroepiandrosterone-sulfate (DHAES), ferritin, α-tocopherol, and, regarding the N-glycosylation status of serum proteins, the peak 6 (NA2F) and the log ratio of NGA2F (peak1) and NA2F. In men, in addition to the methylation status of ELOVL and FHL2, and the protein glycan peak 6, plasma levels of DHEAS, α2-macroglobulin, lycopene, and prostate-specific antigen. This algorithm is currently evaluated in the European Coordination Of Biological and chemical information technology Research Activities (COBRA) project. Data presented at the CROI 2017 meeting [207] find that biological age was significantly greater than chronological age by 13.2 years in the HIV-infected group, and by 5.5 years in the non-infected group, with a significant difference between the two groups.

Prospective: what will be our priorities for future research and biomarkers?

Some, but not all, age-related comorbidities have an increased prevalence in ART-treated ageing HIV-infected patients. As well, some mechanisms of ageing are enhanced in these patients and associated with increased morbidity/mortality. This could be the consequence of factors specific to HIV infection, as the virus and some ART, in addition to enhanced classical risk factors. The role of inflammation and innate immune activation in non-AIDS-related comorbidities was well demonstrated, although adaptive immune activation and senescence markers failed to predict mortality, by contrast to the general population. Further studies are required to better understand these dissimilarities.

To evaluate gene expression and proteins in PBMC requires these cells to be separated and prospectively stored, together with serum/plasma samples. It would be important to further identify robust systemic inflammatory and/or immune activation markers or indexes, using several of these markers, to quantify the ageing process in HIV-infected patients. Up to now, these markers, widely used in clinical studies, which were consistently reported to be increased in comorbid HIV-infected patients, have not yet been proven to have clinical utility for patients’ follow-up. The search for biomarkers of ageing will benefit from large-scale approaches as metabolome-wide association studies. Results regarding biological age, analyzed with the MARK-AGE algorithm, need to be pursued in the HIV-infected population.

Owing to the complexity of the ageing process and its multifactorial components, it could be difficult to identify pertinent ‘universal’ biomarkers. We need to search also for more focused biomarkers linked to different mechanisms, tissue dysfunctions, and/or comorbidities.

Animal studies, as simian immunodeficiency virus-infected and treated macaques, or HIV-expressing mouse models, can only partly answer these questions. Such studies will mainly benefit from large cohorts of well paired ageing HIV-infected and noninfected individuals, prospectively followed.

We can expect that data issued from large-scale ‘omics’ approaches obtained in large cohorts will rapidly emerge, to better quantify biological ageing, better predict morbidity and mortality in these patients, and increase their healthspan.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

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* Andrea Cossarizza and Jacqueline Capeau contributed equally to the writing of this article.

Keywords:

antiretroviral treatment; biomarkers; damage; HIV proteins; immune activation; inflammation

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