Work

HIV and Aging in the Era of ART and COVID-19: Symposium Overview

Year: 2022

Type: article

Abstract: Antiretroviral therapy (ART) has altered the clinical environment of HIV, shifting the traditional focus on AIDS-induced opportunistic infections and cancers to one in which the most common morbidities and causes of death differ little from those seen in noninfected adults. The primary distinction is that these conditions, which include cardiovascular diseases, declining physical function, neurocognitive and neuropsychiatric disorders, and alterations in body composition, first manifest in people living with HIV (PLWH) approximately 5–10 years earlier than HIV-uninfected individuals.1–3 The accelerated aging in HIV has now been further complicated by the emergence of SARS-CoV-2 infection and postacute COVID syndrome (PACS). Exploring the linkages—and points of difference—between these 2 viral conditions, while promoting multidisciplinary collaboration among researchers to identify new perspectives on HIV and aging, was the aim of “HIV and Aging in the Era of ART and COVID-19 inter-CFAR symposium.” The symposium started with a keynote address by Dr. Steven Deeks entitled, "The impact of viral infections on long-term health." In his keynote presentation, Dr. Deeks maintained that persistent viral-mediated tissue damage along with alterations in inflammation and immune function are common observations in PLWH, and these findings, which led to the introduction of ART, suggest that viral persistence, even in the absence of replication, is deleterious and contributes to various comorbidities, including a hypercoagulable state and coronary artery disease.4,5 Studies of HIV persistence may be particularly applicable to SARS-CoV-2 infection because SARS-CoV-2 RNA is detectable in autopsy tissues weeks after acute infection and can be identified in gut tissue for at least 6 months.6 In this study, too, the evidence indicates that inhibiting viral persistence is associated with a lower risk of disease, and ongoing research is exploring the extent to which antiviral therapy during acute COVID-19 prevents long-term disease, especially because immune dysregulation and inflammation have been shown to produce serious adverse outcomes, such as longer hospitalization and death.7,8 Although current vaccines seem to reduce viral burden and, therefore, the severity of infection, their effectiveness in preventing long-term complications of COVID-19 remains to be established. Thus, the mechanistic overlaps between the 2 conditions, which include viral persistence, the etiology of virus-associated comorbidities, immune dysfunction, and inflammation, are informing SARS-CoV-2 pathogenesis studies and disease management for patients. The identification of PACS, the subset of people with acute SARS-CoV-2 infection who develop long-term morbidities, is of particular resonance regarding HIV. At present, the data on the mechanistic features and treatment of PACS are limited, and as a result, the condition remains poorly defined.9 Nevertheless, it seems reasonable to expect the manifestations of PACS to be similar to those seen in patients recovering from other acute viral infections. Furthermore, although HIV and SARS-CoV-2 are fundamentally different infections—the former is chronic and latent, whereas the latter is acute and resolved—and their long-term complications are distinct, the mechanisms are related and, as a consequence, the most efficacious therapies for HIV infection may have utility in COVID-19 (eg, antiviral drugs to treat persistent infection and immunomodulators and anticoagulants for more severe disease).10 Well-designed and carefully performed proof-of-concept interventional studies, drawn partly from previous HIV research, are determining the precise mechanisms involved in SARS-CoV-2 pathogenesis and the appropriate management strategies to address them. SESSION 1: THE BASIC SCIENCE OF INFLAMMATION, METABOLISM, AND EPIGENETICS IN AGING: DEFINING THE EFFECTS OF HIV ON AGING Metabolic Control of T-Cell Aging T-cell aging is a degenerative process involved in many immune-mediated diseases. Reviewing the landmark findings of her group in models of rheumatoid arthritis (RA), Cornelia M. Weyand reported that in successful T-cell aging, the number of naïve cells, repertoire diversity, and activation thresholds are maintained. By contrast, in diseases such as RA, which are characterized by maladaptive T-cell development, protective immune responses decline, whereas proinflammatory pathways are triggered. As a consequence, the host is rendered susceptible to chronic tissue damage. In fact, when naïve T cells from patients with RA were compared with those from healthy controls, the former had telomere lengths similar to those from healthy individuals who were more than 20 years older.11 In RA and most autoimmune illnesses, the breakdown of self-tolerance and production of autoimmune antibodies precedes disease onset, which suggests that the chronic rewiring of the immune system occurs over time. T cells, which are primary players in inflammatory lesions and supporters of B-cell autoantibody production, have high metabolic requirements and depend on bioenergetics and biosynthetic plasticity to support their functioning. It is now clear that T cells from healthy people and patients with RA use different metabolic pathways. For instance, because of misplaced energy-sensing enzymes, such as activated protein kinase, T cells from patients with RA are unable to balance catabolic and anabolic processes, thereby shunting glucose away from glycolysis and Adenosine triphosphate (ATP) production toward the pentose phosphate pathway. In so doing, lipogenesis is upregulated, inducing increased motility and tissue invasiveness.12 Another major contributor to the bioenergetic failure of T cells in autoimmune diseases such as RA, Weyand contended, is the DNA repair nuclease MRE11A, which accumulates around the site of telomeres. This protein is reduced in T cells from patients with RA, and this deficiency reduces mitochondrial oxygen consumption and ATP production. The ensuing loss of function leads to the leakage of mitochondrial DNA into the cytosol, triggering inflammasome assembly, the activation of caspace-1, pyroptotic cell death, loss of tissue homeostasis, and profound tissue inflammation. Notably, restoration of MRE11A expression restores mitochondrial fitness and protects tissue from the effects of local inflammation.13 A review article on the metabolic complication of B cells in aging and HIV contributed by Dr. Frasca has been included in this supplement. HIV, Aging, Clinical Cohorts, and Comorbidities Research Although the introduction of ART has reduced mortality, PLWH experience high rates of comorbidities, multimorbidity (>1 major chronic illness), and steeper functional decline (10–15 years earlier) compared with uninfected controls. As Heidi Crane observed, this conflation of poor outcomes increases rates of hospitalization and death and the prevalence of geriatric syndromes such as frailty and falls.14 For these reasons, future research should emphasize the health span of PLWH, rather than just mortality, the aim of which should be to better understand how to prevent comorbidities and determine the best approaches to assess and manage the increasingly complex needs of these patients. Tracing the history of clinical cohort development, which has evolved with advances in information technology, Crane charted the path from early HIV collaborations of Center for AIDS Research (CFAR) in the mid-1990's to contemporary multicohort HIV research partnerships, which broaden the geographic distribution and increase the sample size, both of which, among other benefits, permit the detection of rare events. For example, the CFAR Network of Integrated Clinical Systems has 8 sites with approximately 35,000 PLWH older than 18 years in HIV care, whereas the North American AIDS Cohort Collaboration on Research and Design partners with 200 sites in the United States and Canada and draws on a patient pool of more than 200,000 from 20 different cohorts. The knowledge gleaned from these—and other—international cohort collaborations has yielded 3 core lessons: the need for careful adjudication of measurements to accurately identify discrete comorbidities in aging PLWH populations; a cautious use of composite outcomes, as evidenced by the differences in cardiovascular disease (CVD) events stemming from the presence of distinct biomarkers; and the importance of using contemporary data when evaluating research findings, including such changes as have emerged in ART and nucleoside reverse transcriptase inhibitor classes over time.15 Doing so allows the possibility of charting the life-course trajectory of PLWH when interpreting research findings. In this supplement, Dr. Crane has contributed an article detailing her talk related to this topic. Why do Older Folks With COVID-19 Have Worse Outcomes? Although it is now uncertain why the elderly persons fare worse with the disease, Michael Saag explored the biological factors driving the pathogenic trajectory of COVID-19, the immune considerations necessary to interpret disease severity, and future treatment options. What is clear is that death rates vary by age and sex, so that older individuals, especially men and those older than 80 years, have an elevated risk of mortality.16 Predisposing conditions, such as cardiovascular disease, diabetes, and obesity, along with race and ethnicity, also increase the likelihood of death. But most important, aging is associated with immunosenescence, the aged-related impairment of the immune response. Because SARS-CoV-2 protective immunity requires a rapid innate immune response, including, primarily, interferons (IFNs) and, secondarily, specific antiviral adaptive immune cells, older individuals are placed at higher risk because of their impaired upregulation of IFN-stimulating genes and suboptimal adaptive B-cell–mediated and T-cell–mediated responses.17 These considerations are critical when considering viral load at the time of infection: those with a lower load tend to produce an early and robust IFN response, rapid viral clearance, and, as a consequence, mild disease. By contrast, individuals with a high viral load, including older hosts, experience a delayed IFN response and associated lymphopenia and immunosuppression, extended viral persistence, destructive tissue inflammation, and severe disease, including multiorgan failure, disseminated intravascular coagulation, and death.18,19 Understanding the trajectory of disease has clarified patient management and treatment choice, Dr. Saag added. SESSION 2: GEROSCIENCE AND SENOLYTICS: POTENTIAL FOR CLINICAL TRIALS IN AGING PLWH NAD Metabolism and Aging Sirtuins are a family of nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase (SIRT1-7) implicated in aging dynamics.20 Recent research, Eric Verdin pointed out, demonstrates that SIRT1 and SIRT3 activities decrease during senescence due to downregulation of these factors, causing a host of deleterious health and life span effects, including increased stress responses, chronic inflammation, impaired lipid metabolism, and diminished DNA repair. Furthermore, decreased levels of SIRT1 and SIRT3 are now known to be a byproduct of reduced NAD+ in vital tissue. The focus of much current study, including that conducted by Verdin's group, is on identifying the mechanism of NAD+ decrease and the means to correct it. Shaping our understanding of NAD+ metabolism and the biological mechanisms of aging has been the identification of several key pathways that contribute to the reduced release of NAD+ during the aging process. In addition to the sirtuins, the poly (ADP-ribose) polymerases, which are vital to the process of DNA repair, and the immune molecules CD38 and CD157, which contribute to cell adhesion, signal transduction, and calcium signaling, serve to regulate NAD+ levels in tissue. Competition between these enzymes diminishes NAD+: increased polymerase activity and CD38 activation, which occurs during the aging process, siphon off NAD+, thereby preventing the sirtuins from exerting their seroprotective effects.21 In this regard, Dr. Verdin reviewed a body of ongoing research examining the role of CD38 in NAD+ metabolism. These studies were prompted by the recognition that, in mouse models, levels of the ectoenzyme increase, whereas concentrations of NAD+ decrease, in resident macrophages of adipose tissue during aging.22 Of particular interest was the finding that in CD38-knockout mice, NAD+ levels persisted as the animals grew older. Contributing to the robust expression of CD38 in these macrophages is the presence of the senescence-associated secretory phenotype (SASP), which is characterized by the release of high levels of inflammatory cytokines, immune modulators, growth and hemostatic factors, reactive metabolites, and proteases. In sum, Verdin argued, the emerging evidence suggests a model of aging, in which senescence leads to inflammation, increased CD38, and reduced NAD+ expression, and, most importantly, contributes to both metabolic inefficiency and sirtuin dysfunction. The linkage of these pathways also provides the first evidence of why chronic inflammation is deleterious to the aging host. Dr. Montano has contributed a research article linking NAD levels in skeletal muscle and physiologic frailty and coinfection in PLWH. Developing Drugs That Target Fundamental Aging Processes The aging of the global population, in which nearly 70%–80% of individuals aged 65 years and older have at least 2 chronic diseases, requires a new approach to medical care. Can we treat aging itself, Laura Niedernhofer asked, thereby preventing, delaying, or ameliorating multiple debilitating, chronic, and degenerative diseases, while avoiding polypharmacy and reducing escalating health care costs? She identified multiple and interconnected pillars of aging, among them macromolecular damage, epigenetics, inflammation, metabolism, adaptation to stress, proteostasis, stem cell dysfunction, and cellular senescence.23 Therapeutic interventions targeting any of these pillars will improve the status of them all. In particular, cellular senescence is now considered a causal agent of aging, not merely a consequence of getting older. Evidence from models demonstrates that cells mortality, thereby health The complex in which cells are overlaps with cellular alterations of autoimmune diseases, chronic infection, and of including and stress, along with DNA damage and mitochondrial dysfunction, also these and other of specific of cellular senescence have as been Research in has led to the of a of drugs that can be as those that do not cell and both and cell pathways also are in cells, and this led to the identification of the first and which are and such as which are more These which also include and have been by various and these increase the of cells, and, in models, improve physical function and in Dr. Niedernhofer that have the to and reverse disease, loss of tissue homeostasis, stem cell dysfunction, and The of and HIV At the of HIV and geriatric and the emerging of a of with for the of future clinical and patient care. These observed, be considered the Why that should the during life with HIV should this approach be What approaches be the most will the studies be and who will and of the in linking the medical from a between the of disease pathogenesis in geriatric and HIV and the in which more accurately the of common chronic diseases and geriatric In this new a risk a risk which causes a decline in function and the emergence of clinical disease. This etiology is further by considerations such as and and of which the to function and Although these risk factors contribute to the of comorbidities in older a number of them are For example, individuals with lower are much more to have and both can a of geriatric including and functional targeting these risk factors can improve functional and prevent the of multiple geriatric Thus, in clinical studies targeting HIV a should with the those with in HIV geriatric and functional determine the of comorbidities over time between PLWH and those that the agent is to be by the in the evidence to support use in targeting functional outcomes that are both to patients and and the treatment has the to improve and time to disease. Although many of these to be the emergence of for a approach that has the of outcomes, reducing chronic and comorbidities that to frailty and and promoting the of to disease article by Niedernhofer and is included in this supplement. Aging With for PLWH of the biological features of aging is gut a by in the the presence of such as and HIV, host factors, and of which can contribute to the in the his research into the role of the a for and gut which is elevated in HIV and with can increase inflammation and the immune activation of and cells, and B cells, thereby to disease further gut damage, inflammation, and ART can levels of that the a to prevent Another of growth a by cells and known to Notably, is of and use seems to reduce body of In that study, the also was a of increased mitochondrial stress and a which can be by the of a characterized by a a and an In this to long-term utility as an of and associated effects on mitochondrial The article by Dr. on this is included in this supplement. SESSION COVID-19 IN AGING HIV AGING HIV for this be to treat In his review of emerging COVID-19 explored how for HIV and aging be for use in the the SARS-CoV-2 As the has the presentation, we a and other antiviral drugs not a in patients in 2 signal other mechanistic of infection may antiviral approaches include using such as were considered in older patients and those with of antibodies for example, a of and reduced the viral load in COVID-19 patients to were reported for in with patients also a response, and for a of and Of are to be more new SARS-CoV-2 and in the of will produce better Systems to of SARS-CoV-2 A contributes and the pathogenesis and of severe As the by and especially those who are tend to have lower a inflammatory response, and, therefore, worse This is by an response, in which in the and with innate immune cells, thereby immune that inflammation. the of infection, the of immune activities in by antibodies (eg, and allows them to serve as the innate immune system a of to Systems is a means to these the immune thereby to identify the of activity that protective from responses and which do better or The findings, especially those to are Although SARS-CoV-2 infection is in is evidence of serious disease. In fact, the response of and with mild disease are By contrast, with severe disease have a different of response because produce levels of at the of infection, along with elevated concentrations of such antibodies as and are also the key between the 2 seems to be the higher release of and in older patients and those with serious disease, which contributes to and the production of and the critical of the early proinflammatory and, as a consequence, severe tissue damage and also is associated with a distinct functional response, one that in older is toward immune activities and higher of and In responses with disease severity in driving a robust inflammatory response that contributes to the of and in PLWH the COVID Era For people living in the the COVID has been an one that effects in the including PLWH. to assess argued, is to the in that the risk of outcomes, with the to to physical or life A the between the 2 health in PLWH to identify the different that of life and the composite of physical and individuals can on during their a of physical and including the frailty and the the that, of the PLWH who in the and the was to this were HIV and was identified for biological cell or the presence of different emerged in this and the COVID-19 the first yielded the outcomes because the for from health events was the to during of the findings that frailty and should be in PLWH to identify individuals and the appropriate health of the conducted by Dr. is in the article contributed by to this supplement. and of the impact of COVID-19 on aging people were by a that included including and and was by Dr. Michael Saag and Dr. in this were by the specific has living with HIV and any other comorbidities during the current What do for in a for HIV who are aging experience such as cardiovascular disease, and these tend to PLWH at an earlier What has been experience with these of aging and to care are a CFAR do that the can more of a in these do with new treatment are to their that COVID-19 has including the of PLWH. The and identified several that COVID-19 has the of PLWH. that PLWH are the of COVID-19, a disease, to their reduced immune due to HIV. related that just when their health was for HIV and other for their chronic conditions, serious and that are for the of effects on PLWH. The new also are an and PLWH do not from The identified increased use of which has better to both physical and health care, as a of the were and over 3 The CFAR conducted a on the for the to on the path to and In this the their trajectory of as a model and the the and were who the The symposium of and high for the and The had more than over the 2 more than from the the of other the of and this symposium in their understanding of the and in their

Source: JAIDS Journal of Acquired Immune Deficiency Syndromes

DOI: 10.1097/qai.0000000000002837