Pathogenesis of Aging and Age-related Comorbidities in People with HIV: Highlights from the HIV ACTION Workshop

Published June 17, 2020
Read in PDF format


Dana Gabuzda1, Beth D. Jamieson2, Ronald G. Collman 3, Michael M. Lederman4, Tricia H. Burdo5, Steven G. Deeks6, Dirk P. Dittmer7, Howard S. Fox8, Nicholas T. Funderburg9, Savita G. Pahwa 10, Ivona Pandrea11, Cara C. Wilson12, Peter W. Hunt6

Affiliated Institutions

1 Department of Cancer Immunology and Virology; Dana-Farber Cancer Institute; Boston, Massachusetts; Department of Neurology; Harvard Medical School; Boston, Massachusetts
2 Department of Medicine; David Geffen School of Medicine; University of California; Los Angeles, California
3 Department of Medicine; University of Pennsylvania School of Medicine; Philadelphia, Pennsylvania
4 Department of Medicine; Case Western Reserve University School of Medicine; Cleveland, Ohio
5 Department of Neuroscience; Lewis Katz School of Medicine; Temple University; Philadelphia, Pennsylvania
6 Department of Medicine; University of California; San Francisco, California
7 Department of Microbiology and Immunology; University of North Carolina School of Medicine; Chapel Hill, North Carolina
8 Department of Pharmacology and Experimental Neuroscience; University of Nebraska Medical Center; Omaha, Nebraska
9 Division of Medical Laboratory Science; School of Health and Rehabilitation Sciences; Ohio State University College of Medicine; Columbus, Ohio
10 Department of Microbiology and Immunology; University of Miami Miller School of Medicine; Miami, Florida
11 Department of Microbiology and Molecular Genetics; School of Medicine; University of Pittsburgh; Pittsburgh, Pennsylvania
12 Department of Medicine; Division of Infectious Diseases; University of Colorado Anschutz Medical Campus; Aurora, Colorado

Corresponding Author

Peter W. Hunt
Department of Medicine
Division of Experimental Medicine
1001 Potrero Ave, Rm 605B
UCSF Box 1234
San Francisco, CA 94110
[email protected]


People with HIV (PWH) experience accentuated biological aging, as defined by markers of inflammation, immune dysfunction, and the epigenetic clock. They also have an elevated risk of multiple age-associated comorbidities. To discuss current knowledge, research gaps, and priorities in aging and age-related comorbidities in treated HIV infection, the NIH program staff organized a workshop held in Bethesda, Maryland in September 2019. This review article describes highlights of discussions led by the Pathogenesis/Basic Science Research working group that focused on three high priority topics: immunopathogenesis; the microbiome/virome; and aging and senescence. We summarize knowledge in these fields and describe key questions for research on the pathogenesis of aging and age-related comorbidities in PWH. Understanding the drivers and mechanisms underlying accentuated biological aging is a high priority that will help identify potential therapeutic targets to improve healthspan in older PWH.

Keywords: HIV; aging; inflammaging; cellular senescence; microbiome


Despite the success of combination antiretroviral therapy (ART) in achieving durable virologic suppression, people with HIV (PWH) are at increased risk for multiple comorbidities associated with aging in the general population, including cardiovascular disease (CVD), lung disease, liver disease, kidney disease, diabetes, neurocognitive disorders, decreased bone mineral density, malignancies, and other diseases ( 1]. Evidence suggests that treated HIV infection is associated with accentuated aging phenotypes, and these age-related comorbidities can occur at younger ages (2, 3]. The pathophysiologic mechanisms that drive biological aging and age-related comorbidities are not well understood, and the impact of HIV and ART on the biology of aging remains poorly defined. To discuss current knowledge, research gaps, and priorities in HIV-associated comorbidities, a pan-NIH workshop on HIV-associated Comorbidities, Coinfections, and Complications (HIV ACTION) was held in Bethesda, Maryland on September 19-20, 2019. Six working groups were convened and met over the course of a year to prepare for the workshop. This article describes highlights from the planning summaries, talks, and discussions led by the Pathogenesis/Basic Science Research working group, which focused on the following three high priority topics selected by working group members: 1) Immunopathogenesis; 2) Microbiome/Virome; and 3) Aging and Senescence (Figure 1). Here, we summarize the background, rationale, and key questions for research on the pathogenesis of aging and age-related comorbidities in PWH, and how basic research on these questions might lead to the discovery of new targets for prevention and therapeutic intervention.

Figure 1. Venn diagram of three high priority topics for research on aging and age-related comorbidities in people with HIV on ART. These three topics were selected by the basic science working group of the HIV ACTION Workshop for presentations and discussion at the workshop. Five cross-cutting themes are shown outside the Venn diagram. Artwork courtesy of Dr. Leia Novak.

Immunopathogenesis and HIV-associated comorbidities

Immune activation and inflammation

Levels of immune activation and inflammation remain elevated in PWH on ART, even when viral suppression has been maintained for several years, and may contribute to morbidity and mortality [4, 5]. Key questions for basic research on immune activation/inflammation and immunopathogenesis related to development of HIV-associated comorbidities are shown in Table 1. Persistent inflammation likely contributes to multiple end-organ diseases in PWH, including CVD, liver, and kidney diseases, neurocognitive disorders, malignancies, and other diseases. While specific mechanisms that underlie each of these comorbidities may involve both shared and unique pathways, biomarkers of immune activation and inflammation (ie, IL-6, sCD14, sCD163, D-dimer, soluble TNF receptors 1 and 2) are broadly associated with development and progression of these comorbidities in PWH [4, 5]. Inflammatory mediators are also linked to development of these comorbidities with aging in uninfected populations. Although definitive evidence establishing a causal role of inflammation in driving disease risk in treated HIV infection is lacking, several lines of evidence support this possibility. A recent clinical trial of the IL-1β inhibitor canakinumab in HIV-uninfected individuals with heart disease showed that reducing inflammation decreases cardiovascular events and mortality from cancer [6]. Furthermore, comparative studies between progressive and non-progressive SIV infections suggest that SIV-induced inflammation contributes to development of CVD and other comorbidities [7]. Persistent inflammation and “inflammaging” (increased inflammation with advancing age) have also been identified as likely contributors to frailty [8, 9], a geriatric phenotype related to physical aging. Whether inflammatory profiles associated with increased risk of age-related comorbidities differ between PWH and uninfected populations, and whether their potential mediators and pathways are similar or different, is still unclear.

Table 1. Key Questions for Basic Research on Immunopathogenesis in HIV-associated Comorbidities

Key Questions

What are the drivers of chronic innate and adaptive immune activation in PWH?

Is residual immune activation/inflammation similar in women and men and, if not, what are the pathways that differ?

Do HIV and ART induce defects in hematopoiesis and tissue sites that ultimately drive chronic immune dysfunction in PWH? For example:

Can we develop or use tools to predict or identify specific disease pathology? Can we develop therapeutics to reduce immune activation/inflammation and what should be the main targets for such interventions?
Several potential drivers of chronic inflammation in PWH have been identified, including low-level residual HIV expression during suppressive ART, microbial dysbiosis and translocation, coinfections (eg, cytomegalovirus [CMV], Epstein Barr Virus [EBV], human herpesvirus virus 8 [HHV-8], Hepatitis C virus [HCV]), altered lipid profiles (eg, elevated cholesterol and/or triglycerides, inflammatory oxidized lipids), and lifestyle factors. Each of these potential drivers has been linked to comorbidities in PWH [4, 10). Lifestyle factors such as tobacco smoking, recreational drug use, poor diet, and lack of physical activity along with genetics and coinfections (particularly CMV) have all been linked to low-grade inflammation and development of age-related diseases in the general population (ie, CVD, diabetes, liver disease, age-related cognitive decline). Importantly, many of these lifestyle factors are enriched among PWH [11-14]. Residual immune activation and inflammation, and some other key drivers, may differ between men and women [15], racial/ethnic groups [16], and geographic regions [17] and are likely to be influenced by genetic and environmental factors as well. The list of candidate drivers described here is likely incomplete and requires further study in PWH and uninfected populations to identify root drivers and their relative importance in different settings. To address these questions, animal models are excellent biological systems in which strictly controlled studies can be performed to dissect relative contributions of different factors that are difficult to study in humans. A related question is understanding the distinct patterns of chronic inflammation (ie, “flavors of inflammation”) that underlie different organ system comorbidities in different settings. However, not all age-related morbidities are increased by HIV infection (eg, prostate, colon, and breast cancer). Additionally, PWH who start HIV treatment at high CD4 counts may be protected from some morbidities (eg, cardiovascular disease, neurocognitive dysfunction), but remain at abnormally high risk for infections and infection-related malignancies [18]. Understanding the inflammatory pathways responsible for infectious vs non-infectious complications, and the degree to which they persist in individuals who start ART early vs late in the disease course, will be important to identify the most appropriate interventional targets for different settings.

Immune cell populations and trafficking

A key issue in immunopathogenesis studies is understanding the effects of HIV and ART on immune cell subsets and their relation to residual immune activation, inflammation, and age-related comorbidities in treated HIV infection. Dysregulation of the immune system due to HIV itself, coinfections, or bystander mediators of inflammation may drive inappropriate activation and retention of immune cells within tissue sites such as blood vessels, liver, adipose tissues, and the central nervous system (CNS). Circulating immune cell populations that include activated monocytes expressing pro-coagulants (eg, tissue factor), as well as increased numbers of mature activated CD8+ T cells that can home to endothelial surfaces via expression of homing receptors including the fractalkine receptor (CX3CR1), lymphocyte function-associated antigen 1 (LFA-1), macrophage-1 antigen (Mac-1) [19, 20), C-C chemokine receptor type 2 (CCR2), and type 5 (CCR5) [21], are detected in PWH, and may be linked to development of CVD and other comorbidities [22-26]. Altered migration of activated immune cells to, and retention within, these tissues may also influence development of other end-organ diseases. Additionally, T cell subsets may be inappropriately retained within lymph nodes of PWH [27], potentially contributing to increased lymph node inflammation, fibrosis, and failure of immune cell reconstitution [28, 29]. Some ART drugs may have effects on innate and adaptive defense mechanisms, as well as on hematopoiesis, gut, and other organ dysfunction, which could also influence development of comorbidities. Chemokine receptor antagonists, in particular, may modulate migration of immune cells to the liver [30], CNS [31], and gut-associated lymphoid tissues (GALT) [32], potentially modulating immune activation and end-organ disease. It is important to determine whether HIV and ART induce defects in hematopoiesis that have downstream effects on immune activation, inflammation, and immune dysfunction [33]. Additionally, it will be important to identify the tissue sites/reservoirs (lymph node, gut, brain, etc) responsible for residual virus production that could drive immune activation/inflammation under ART [34]. For such studies, animal models are useful because they allow access to a variety of tissues and use of tagged virus strains that enable detailed characterization of the tissue sites harboring residual virus. Studies involving more limited tissue sampling of PWH will also be important, as the degree of viral suppression in most animal models may not fully reflect the degree of viral suppression in tissues among PWH on long-term ART [35]. Identification of unique biomarker signatures and immune cell populations that predict comorbid conditions will provide insights into mechanisms that drive specific end-organ diseases, and may identify populations that could benefit from personalized prevention and therapeutic strategies.

Targeting upstream drivers of immune activation/inflammation

Whether disease-associated inflammatory profiles differ in aging PWH and uninfected populations is an important question for development of targeted therapeutic interventions. Although ART prolongs the lifespan of PWH, the quality of life is dampened by side effects of ART including metabolic diseases, decreased bone mineral density, and alterations in lipid profiles and mitochondrial function [36, 37]. Therefore, understanding the effects of ART on the host is important for the optimal design of new strategies to prevent morbidity. It is unclear whether targeting common elements shared by multiple immunopathogenic pathways in treated HIV infection, targeting upstream drivers of activation/inflammation, or direct targeting of the viral reservoir itself will be most effective. It is also unknown whether comorbidities associated with treated HIV infection are driven by overlapping or distinct immunological mechanisms. Studies in uninfected individuals initiating ART as pre-exposure prophylaxis (PrEP) and in uninfected nonhuman primate (NHP) models will be important to untangle the metabolic, neurological, bone, and inflammatory consequences of some ART drugs. Clinical intervention trials offer unique opportunities to concurrently test a mechanistic hypothesis and explore potential clinical utility of the intervention, novel readouts, and disease models. Animal models also provide great opportunities to probe interventional strategies, particularly those that have safety concerns or require extensive tissue sampling. For these interventional approaches, it is important to evaluate not just the pathway being targeted, but also parallel inflammatory pathways and/or root drivers that might be affected in either a positive or negative way (ie, the “whack-a-mole” problem) [38]. Addressing these questions will help to define determinants of end-organ disease risk in PWH, targets for intervention, and whether morbid complications of aging in the general population share common pathways with these same outcomes in PWH.

Microbiome/virome in HIV-associated comorbidities

HIV-associated changes in the microbiome

The microbiome consists of the entirety of bacteria, fungi, and viruses that live in concert with the human body, including the gut, respiratory tract, female and male genital tract, oral cavity, skin, and other sites. Among these, the gut microbiome has received the greatest attention. Given the link between inflammation and comorbidities, two observations underlie high interest in the microbiome in HIV infection: (a) the gut microbiome plays a key role in both systemic and local mucosal immunological development and regulation [39-41]; and (b) profound injury to the gut immunological barrier occurs very early in HIV infection, is incompletely repaired with ART, and enables systemic translocation of microbial products that contribute to inflammation [42-45]. Research outside the field of HIV is revealing deep connections between the microbiome, host immunity [ 46], and function of multiple organ systems, in which dysbiosis is linked to CVD [47), liver disease [ 48], neurological conditions [49], cancer [50, 51], and other diseases. Metabolome alterations in plasma and other sites may reflect not only microbial products, but also secondary effects of the microbiome on host-derived metabolites mediated through its effects on bile acids, host enzymes, and local mucosal inflammation [52, 53]. Key questions for research on the microbiome that are relevant for the development of HIV-associated comorbidities are shown in Table 2.

Table 2. Key Questions for Basic Research on the Microbiome/Virome in HIV-associated Comorbidities Key Questions Does the microbiome (bacterial, viral, fungal) play a contributory role in HIV comorbidities? How do other cofactors interact with HIV infection to affect the microbiome and comorbidities?