Ageing and inflammation in patients with HIV infection

Summary

Nowadays, HIV⁺ patients have an expected lifespan that is only slightly shorter than healthy individuals. For this reason, along with the fact that infection can be acquired at a relatively advanced age, the effects of ageing on HIV⁺ people have begun to be evident. Successful anti‐viral treatment is, on one hand, responsible for the development of side effects related to drug toxicity; on the other hand, it is not able to inhibit the onset of several complications caused by persistent immune activation and chronic inflammation. Therefore, patients with a relatively advanced age, i.e. aged more than 50 years, can experience pathologies that affect much older citizens. HIV⁺ individuals with non‐AIDS‐related complications can thus come to the attention of clinicians because of the presence of neurocognitive disorders, cardiovascular diseases, metabolic syndrome, bone abnormalities and non‐HIV‐associated cancers. Chronic inflammation and immune activation, observed typically in elderly people and defined as ‘inflammaging’, can be present in HIV⁺ patients who experience a type of premature ageing, which affects the quality of life significantly. This relatively new condition is extremely complex, and important factors have been identified as well as the traditional behavioural risk factors, e.g. the toxicity of anti‐retroviral treatments and the above‐mentioned chronic inflammation leading to a functional decline and a vulnerability to injury or pathologies. Here, we discuss the role of inflammation and immune activation on the most important non‐AIDS‐related complications of chronic HIV infection, and the contribution of aging per se to this scenario.

OTHER ARTICLES PUBLISHED IN THIS REVIEW SERIES

Immunosenescence: the importance of considering age in health and disease. Clinical and Experimental Immunology 2017, 187: 1–3.

The convergence of senescence and nutrient sensing during lymphocyte ageing. Clinical and Experimental Immunology 2017, 187: 4–5.

Immune senescence: significance of the stromal microenvironment. Clinical and Experimental Immunology 2017, 187: 6–15.

Innate immune responses in the ageing lung. Clinical and Experimental Immunology 2017, 187: 16–25.

Age‐related alterations in immune responses to West Nile virus infection. Clinical and Experimental Immunology 2017, 187: 26–34.

Intracellular signalling pathways: targets to reverse immunosenescence. Clinical and Experimental Immunology 2017, 187: 35–43.

Considerations for successful cancer immunotherapy in aged hosts. Clinical and Experimental Immunology 2017, 187: 53–63.

Ageing and obesity similarly impair antibody responses. Clinical and Experimental Immunology 2017, 187: 64–70.

The life cycle of a T cell after vaccination – where does immune ageing strike? Clinical and Experimental Immunology 2017, 187: 71–81.

Herpes zoster and the search for an effective vaccine. Clinical and Experimental Immunology 2017, 187: 82–92.

Adult vaccination against tetanus and diphtheria: the European perspective. Clinical and Experimental Immunology 2017, 187: 93–99.

Introduction

The introduction of highly active combined anti‐retroviral therapy (cART) in the mid‐1990s has improved the immune responses and changed the morbidity and mortality of HIV⁺ individuals significantly. At present, HIV⁺ patients have an expected life span that is only slightly shorter than HIV‐uninfected individuals 1. As a consequence of the increased life expectancy, the effects of ageing on HIV⁺ people have begun to be evident 2, 3. Several disorders that typically affect the aged population now appear in relatively young HIV⁺ patients who can come to the attention of clinicians with different pathologies, which include neurocognitive disorders, cardiovascular diseases (CVD), metabolic syndrome (MS), bone abnormalities and non‐HIV associated cancers 4. Most of these age‐associated diseases are caused, at least in part, by the chronic inflammation and activation of the immune system observed typically in elderly people 5, which has been defined as ‘inflammageing’ 6, 7 or that, in the case of the final phase of HIV infection, could be defined as ‘inflammAIDS’ 4.

It is notable that, in recent years, in Europe and United States the proportion of HIV⁺ patients aged ≥ 50 years is augmented dramatically due to either improved survival of younger infected individuals or to increasing rates of infection among older people, who often present to clinical observation with advanced infection, if not as AIDS presenters. As a result, in 2013 in the United States, people aged ≥ 50 accounted for 27% (7108) of the estimated 26 688 AIDS diagnoses 8. These considerations have led to growing concern that HIV⁺ people experience a type of premature ageing which affects life quality. This relatively new condition is clearly extremely complex, and involves organs and systems other than those responsible for immunity. Important factors have now been identified beside the traditional behavioural risk factors that are the toxicity of anti‐retroviral treatments and the above‐mentioned chronic inflammation, leading to a functional decline and a vulnerability to injury or pathologies 9. In this review, the role of inflammation and immune activation on the most important non‐AIDS‐related (NAR) complications of chronic HIV infection and the contribution of ageing to this scenario, represented schematically in Fig. 1, will be discussed.

Figure 1.

Virus, ageing and combined anti‐retroviral therapy (cART) play a role in causing several morbidities present during HIV infection.

Immunosenescence and chronic inflammation

In the last decade, the concept that the progression of HIV infection is mediated, to a significant extent, by a rapid depletion of memory CD4⁺ T cells that reside mainly in the gut has emerged. Such depletion is followed by the deterioration of the intestinal epithelium and by an increased translocation of microbial products 10. The release in the circulation of bacterial products provokes a persistent, systemic activation of the innate immune system that triggers and maintains inflammation 11, 12. The increasing amount of data supporting this concept has changed profoundly the view of HIV infection, which can be also considered, at least in part, a disease where an important role is played by inflammatory components. As a consequence, successfully treated patients can experience several NAR complications that can be considered as a direct or indirect consequence of chronic inflammation 4.

Untreated HIV infection is characterized by a strong production of proinflammatory cytokines such as interleukin (IL)−1β, IL‐6 and tumour necrosis factor (TNF)‐α and by activation of the coagulation system. The production of most of these molecules declines after treatment with anti‐retrovirals, but the level of inflammation, defined by IL‐6, C‐reactive protein, cystatin C and D‐dimers tends to remain high 13, suggesting that the therapy is not completely able to restore damages in the gut or in other organs and tissues. However, other factors are responsible, at least in part, for this persistent inflammation, including ongoing HIV production, cytomegalovirus (CMV) infection, loss of regulatory T cells and damage of the thymus and lymphoid infrastructure 14, 15.

Ageing per se may also influence HIV‐related enteropathy that enhances microbial translocation and immune activation. Mucosal barrier function is also affected by ageing, and there is evidence that immune activation is also linked to microbial translocation in elderly people 16. This gives an inflammatory phenotype, which is associated with increased morbidity and mortality in older adults 17, 18. The persistent immune activation present in HIV infection leads to a subsequent exhaustion of the T cell compartment. Thus, several abnormalities are similar to what happens during ageing 19, among which the shrinkage of the T cell repertoire 20, the accumulation of oligoclonal expansions of memory/effector cells directed toward infectious agents, the involution of the thymus 21 and the exhaustion of naive T cells 22.

Finally, it has been shown that even patients with complete recovery of the CD4⁺ T cell pool do not reconstitute normal levels and functionality of γδ T cells fully 23. Thus, it has been suggested that these cells could represent a sort of historical record of the disease, their variations being a barometer for the current state of the infection that reflects the capacity of the immune system to control opportunistic infections, tumours and immune activation as well as other conditions that can be observed during the disease 24. Taking into account that γδ T cells can also express low levels of CD4 and can be infected by HIV 25, alterations in this compartment add further fuel to the immune fire triggered by the virus. Immune deficits due to poor activity of γδ T cells can thus be involved in several comorbidities and have to be considered carefully in designing strategies to eradicate HIV using cytotoxic T lymphocytes of natural killer (NK) cells.

Metabolic disorders

In the setting of HIV infection, the introduction of cART was followed by the observation that drug‐related changes in fat distribution were associated with metabolic abnormalities 26. Fortunately, the last generation of anti‐retrovirals has greatly decreased the incidence and gravity of the devastating side effects that we observed only few years ago, but a drug devoid of toxicity still has to be synthesized. Moreover, because of socio‐economic reasons and lack of resources, if not true poverty, several countries continue to treat HIV⁺ patients with compounds that are no longer utilized in western countries because of their well‐known side effects.

Thus, several HIV⁺ patients may experience metabolic abnormalities that resemble those present during metabolic syndrome, i.e. hypertriglyceridaemia, low‐ and high‐density lipoprotein cholesterol and insulin resistance, that are important risk factors for CVD 27, 28, 29. However, unlike the general population, HIV⁺ patients are exposed to additional specific, non‐classical CVD risk factors associated with the infection and its treatment. Those risk factors are related to the effects of the combination of anti‐retroviral therapy and inflammation which follows chronic infection 30, 31. Persistent inflammation is thought to be the major determinant in the pathogenesis of metabolic disorders and atherosclerosis that are, in turn, risk factors for the development of physical impairment or frailty. The incidence of metabolic syndrome (MS) in HIV⁺ patients has been examined in western countries but different definitions and criteria were used, so that its prevalence is estimated at between 7 and 45% 32, 33.

The relationship between long‐term use of cART and disturbances of adipose tissue distribution accompanied by metabolic and endocrine disorders is referred to collectively as anti‐retroviral‐associated lipodystrophy syndrome (LD) 34. Morphological disorders include peripheral lipoatrophy (atrophy of subcutaneous fat tissue in the face, limbs and buttocks) and isolated or co‐existing lipoaccumulation (fat hypertrophy around the abdomen, trunk, nape and neck, as well as visceral fat hypertrophy). Visceral obesity is considered a risk factor for several age‐associated complications, including the above‐mentioned CVD, as well as for neurocognitive disorders. Visceral obesity is also a source of many inflammatory proteins that influence both ageing and HIV infection 35. Finally, visceral obesity is a strong predictor of insulin resistance, which is common in HIV⁺ patients and is a strong determinant of ageing 36.

Lipoatrophy should be differentiated from cachexia and malnutrition, diagnosed typically during AIDS or chronic infections that often accompany advanced HIV infection 37. A number of studies indicate the association between occurrence of MS and use of anti‐retrovirals, in particular protease inhibitors (PI) or nucleoside analogue reverse transcriptase inhibitors (NRTI) 38. With regard to PI, several studies associated the occurrence of MS with current exposure to PI 39, 40, 41, while others have not shown significant differences in the incidence of MS between treated and untreated patients 42.

At present, it is accepted widely that PI can be the cause of common side effects, including dyslipidaemia, insulin resistance and LD, as well as CVD and cerebrovascular diseases 43, 44. These drugs are able to induce the accumulation of intracellular free cholesterol and lipid by decreasing active nuclear sterol regulatory element‐binding protein 1 (SREBP‐1), an endoplasmic reticulum‐derived transcription factor that regulates the expression of genes involved in lipogenesis 45. PI can block glucose uptake in adipocytes by inhibiting the glucose transporter‐4 46, 47 and can inhibit the proteasome, causing the accumulation of unfolded proteins, endoplasmic reticulum stress and triggering of autophagy 48.

NRTI contribute to the pathogenesis of cART‐related LD by binding the mitochondrial DNA‐polymerase gamma, inhibiting enzyme activity 49, 50. As a result, respiratory chain and adenosine triphosphate (ATP) production are inhibited, mitochondrial functionality is altered and irreversible metabolic damage can occur, leading to adipocyte death 51, 52, 53, 54, 55, 56. High viraemia and very low CD4⁺ T cell count are considered risk factors for development of MS, and this underlines further that the development of MS is also related strictly to the progression of HIV infection 57.

Several studies have investigated the incidence of host genetics not only on the progression of the infection but also on MS development, finding that polymorphisms of genes involved in apoptosis and adipocyte metabolism are related significantly to cART‐associated LD 58, 59, 60, 61, 62. Furthermore, mitochondrial DNA haplogroups have been investigated to ascertain their role in the genetic predisposition to LD during cART, but results did not indicate a specific risk haplotype 63, 64.

The effects of ageing on the alterations of adipose tissue in HIV infection lead to a final consideration of the so‐called ‘obesity paradox’, defined as an inverse association between excess adiposity and mortality. This paradox is typical of complex chronic disease, and has been documented in older HIV⁺ patients 65, 66. An excessive amount of adipose tissue may contribute to sarcopenia and may be one mechanism underlying accelerated loss of muscle mass and strength 67, that in older HIV⁺ adults are important predictors of frailty 68.

Cardiovascular diseases

While mortality rates related to CVD have decreased over time among adults with HIV, increased risk of CVD in HIV⁺ population may persist despite cART and the control of risk factors for CVD. This phenomenon is more evident with the ageing of the HIV⁺ population 69. In developing countries, approximately 20% of the daily deaths due to HIV/AIDS are attributed to CVD 70. Recent studies suggest that HIV infection may also be associated with left ventricular systolic and diastolic function, interstitial myocardial fibrosis and increased cardiac fat infiltration 71, 72.

Despite the development of anti‐retrovirals with minor metabolic side effects, the effects of chronic immune activation and inflammation remain the major contributor to CVD risk development 73. Recent studies suggest that monocytes are the major source of inflammatory mediators that promote CVD, even in treated HIV⁺ patients 74. For example, plasma levels of soluble CD14 are associated with more rapid progression of carotid atherosclerosis 75, while soluble CD163 (another marker of monocyte/macrophage activation) is associated with arterial wall inflammation, suggesting that monocyte and macrophage activation may play a mechanistic role in HIV‐associated CVD 76.

Immunological abnormalities that are affected directly by HIV infection (i.e. current and nadir CD4 cell count) have been associated independently with CVD risk, similarly to markers of immune activation and senescence. Low CD4⁺ T cell count was associated with CVD 77, and an increased risk of morbidity and mortality of CVD was observed in patients who fail to restore a normal peripheral CD4⁺ cell count 78.

The precise degree to which HIV infection itself, traditional cardiovascular risk factors or cART contribute to the elevated risk of CVD in HIV⁺ patients is unknown. However, several studies suggest that drugs used during cART, such as indinavir and nevirapine, might contribute to the risk of cardiac events, while others do not exert a similar effect 79.

Neurocognitive disorders

Behavioural abnormalities, motor dysfunction, and dementia are well‐known clinical manifestations of HIV‐associated neurocognitive disorders (HAND) 80. These disorders have a different clinical severity that ranges from asymptomatic neurocognitive impairment (ANI) and mild neurocognitive disorder (MND) to the most severe HIV‐associated dementia (HAD) 81. The overall prevalence of HAND, approximately 50%, has not changed from the pre‐ to the cART era. However, probably because of successful cART, the prevalence of the most severe form, i.e. HAD, decreased from 18 to < 5%, whereas that of MND and ANI increased (from 12 to 17% and from 20 to 28%, respectively) 82.

HIV can enter the brain soon after infection, and this organ continues to be a reservoir for the virus even in patients who receive effective cART. A persistent and progressive neuronal loss can occur in people with chronic infection despite successful viral suppression 83, suggesting that neuronal injury may be caused not only by the virus itself, but also by chronic immune activation and inflammation 84. In addition, neurotoxicity can also be caused directly by viral proteins or by some drugs that are able to cross the blood–brain barrier 85.

There is common agreement that in HIV⁺ patients ageing increases the risk of cognitive impairment. Thus, the convergence of ageing and HIV infection has relevant implications for the central nervous system (CNS), raising the possibility of developing accelerated neurodegenerative syndromes 86. Indeed, the effects of HIV infection and age on cognitive impairment are synergistic, as demonstrated by the fact that older HIV⁺ subjects can exhibit a significant decline of memory shortly after infection. Middle‐aged people with HIV are cognitively more like elderly people (70–80 years) 87, with a main involvement of learning and memory 88, 89.

Bone implications

Among NAR comorbidities, bone alterations revealed by decreased bone mineral density (BMD) and the consequent osteopenia, osteoporosis and fractures are becoming increasingly important, especially in light of the increased age of HIV⁺ patients 90. Several studies reporting increased fracture rates in HIV⁺ population are emerging, with rates that are three times higher than those observed in uninfected subjects 91, 92. This impairment is a clear consequence of loss of bone mass present in elderly men and women with HIV. Interestingly, a decreased body mass index was the most important risk factor associated with decreased BMD. Changes in bone composition appear to be multi‐factorial and derive from a complex interaction among traditional osteoporosis risk factors, low vitamin D, ageing, HIV infection per se, cART and persistent inflammation 93. cART seems to exacerbate bone loss independently of the type of regimen 94. It is notable that cART‐naive subjects also have a high prevalence of osteopenia 95. This suggests that BMD can be affected by uncontrolled viraemia, probably through the effects of systemic inflammation on bone remodelling, similar to what happens during postmenopausal osteoporosis, which is the result of immune dysregulation associated with a persistent low‐grade inflammatory state 96, 97. Thus, the persistent inflammation observed in HIV infection and the consequent immune alterations might also be responsible for the bone abnormalities present in these patients 98, who display a higher prevalence of fractures in both genders and critical fracture sites. Most importantly, the difference in the prevalence of fractures between HIV⁺ and controls increases with age for both genders 91. Finally, with regard to the possible mechanism of bone damage, it has been shown that HIV proteins are able to induce osteoclastic activity and promote osteoblast apoptosis 99, 100.

Cancer

HIV⁺ individuals have an elevated risk for a number of cancers 101, and this risk is 50% higher in HIV⁺ patients than in seronegative controls 102. In elderly people, HIV infection is associated with a higher risk of developing different cancers, although some associations were weaker than expected, perhaps reflecting effects of non‐HIV pathways on cancer development 102.

In HIV‐negative individuals, the most frequently diagnosed cancers are those associated typically with ageing, i.e. lung, prostate, colorectal and breast cancers, and non‐Hodgkin lymphomas. The risk of lung cancer and non‐Hodgkin lymphoma may be influenced by both HIV and age 103, 104. Probably because of poor immunological control of oncogenic viruses, HIV infection is also associated with a higher incidence of several virus‐related cancers, such as Kaposi sarcoma (due to human herpesvirus‐8), lymphomas (Epstein–Barr virus), anal cancer (human papillomavirus) and liver cancer (hepatitis C and B viruses) 105. Conversely, and at variance with that observed in seronegative subjects, no association with HIV is present for breast and colorectal cancer, while the incidence of prostate cancer appeared lower 102.

Frailty

Frailty is a clinical syndrome characterized by an age‐related deterioration in multiple physiological systems and homeostatic mechanisms, resulting in greater vulnerability to stressors 106. Frail individuals often show non‐specific health complaints, fluctuating disability, falls and delirium, and are at higher risk for multiple adverse outcomes, including longer hospital stays, postoperative complications, poor responses to vaccination, functional decline and death 106. Frailty is now recognized as a common and important HIV‐associated non‐AIDS condition 107. In HIV⁺ patients, frailty is diagnosed according to the five Fried phenotypical criteria: weight loss, exhaustion, low physical activity, decreased grip strength and slow gait 108. Thus, frailty and untreated HIV infection share several features that include immune activation and weight loss 4, 109. Interestingly, for the other comorbidities, in the general population chronic inflammation plays an important role in the development of frailty. The prevalence of frailty is lower in the era of potent anti‐retroviral therapy and is always correlated inversely with the CD4⁺ T cell count 108, 110. As expected, the prevalence of frailty increased with age in both HIV⁻ and HIV⁺ men, but is much higher in HIV⁺ people after the age of 50 years 111.

In old frail adults, the mechanisms underlying reduced physical performance are multi‐factorial. Similarly, in HIV⁺ populations, impairment of physical performance probably results from multiple mechanisms, related to both direct and indirect effects of HIV. A study performed on a cohort of middle‐aged people provides evidence that HIV infection is associated strongly with reduced physical performance, which acts in combination with the virus to increase the risk of mortality 112.

Ageing is accompanied by a low‐level chronic systemic inflammatory state that contributes strongly to frailty. Indeed, significant associations exist between frailty and increased levels of inflammation markers, such as proinflammatory cytokines, IL‐6 production by peripheral blood mononuclear cells, up‐regulation of the chemokine CXCL‐10 in monocytes and neopterin 113. Immunological changes associated with frailty have been investigated in several studies in the general elderly population, but few studies exist on HIV⁺ patients, who are not always able to control their inflammatory status even if they receive successful treatment 114. Indeed, it has been shown that several activation markers that are associated with immunological ageing remain elevated, including IL‐6 and TNF‐α 115, indicating that people living with HIV experience premature or accelerated ageing 116.

With regard to T cell subsets, frailty is associated with an increased amount of CD8⁺ T cells with a memory proinflammatory phenotype; i.e. these are cells that do not express CD28, are characterized by a state of replicative senescence 117 and express CCR5⁺ 118. Similar changes can be present during successful anti‐retroviral therapy, and are associated with high CD8⁺ T cell activation and elevated IL‐6 levels 119. Studies from the Veterans Ageing Cohort Study (VACS) have finally correlated fragility fractures of elderly HIV⁺ patients with the ‘VACS index’, which includes age, CD4⁺ T cell count, plasma HIV RNA and several soluble markers of inflammation 120, 121.

Conclusions

A persistent, low‐grade chronic inflammation that typically characterizes immunological ageing is an essential contributor to several comorbidities in the setting of HIV infection. This inflammation is particularly evident in older adults with chronic, well‐treated HIV infection. The precise mechanism(s) of this residual immune activation are poorly understood, and the impact of ageing in treated long‐life HIV⁺ is not yet clear. Thus, in order to reduce morbidity and mortality, there is an urgent need to understand more clearly the causes of such inflammation and to develop interventions for attenuating the effects of chronic inflammation and immune activation in people living with HIV infection.

Disclosure

All authors declare that they have not received support from any company for the submitted work, have no relationships with any company that might have an interest in the submitted work and have no financial or non‐financial interests that may be relevant to the submitted work.