Is HIV a model of accelerated or accentuated aging? Pathai, Sophia; Bajillan, Hendren; Landay, Alan L ...
The journals of gerontology. Series A, Biological sciences and medical sciences,
07/2014, Letnik:
69, Številka:
7
Journal Article
Recenzirano
Odprti dostop
Antiretroviral therapy has reduced the incidence of adverse events and early mortality in HIV-infected persons. Despite these benefits, important comorbidities that increase with age (eg, diabetes, ...cardiovascular disease, cancer, liver disease, and neurocognitive impairment) are more prevalent in HIV-infected persons than in HIV-uninfected persons at every age, and geriatric syndromes such as falls and frailty occur earlier in HIV-infected persons. This raises a critical research question: Does HIV accelerate aging through pathways and mechanisms common to the aging process or is HIV simply an additional risk factor for a wide number of chronic conditions, thus accentuating aging?
Extensive literature review.
The purpose of this review is to briefly outline the evidence that age-related clinical syndromes are exacerbated by HIV, examine the ways in which HIV is similar, and dissimilar from natural aging, and assess the validity of HIV as a model of premature aging. Specific biomarkers of aging are limited in HIV-infected hosts and impacted by antiretroviral therapy, and a high rate of modifiable life style confounders (eg, smoking, substance abuse, alcohol) and coinfections (eg, hepatitis) in HIV-infected participants.
There is a need for validated biomarkers of aging in the context of HIV. Despite these differences, welldesigned studies of HIV-infected participants are likely to provide new opportunities to better understand the mechanisms that lead to aging and age-related diseases.
Colonization of the female lower genital tract with Lactobacillus provides protection against STIs and adverse pregnancy outcomes. Growth of genital Lactobacillus is postulated to depend on ...epithelial cell-produced glycogen. However, the amount of cell-free glycogen in genital fluid available for utilization by Lactobacillus is not known.
Eighty-five genital fluid samples from 7 pre-menopausal women taken over 4-6 weeks were obtained using the Instead SoftCup® (EvoFem, Inc., San Diego, CA, USA) by consented donors. Cell-free glycogen and glucose in genital fluids and estrogen and progesterone in blood were quantified.
Glycogen ranged from 0.1-32 μg/μl. There were significant differences between women in glycogen over the observation period. There was a strong negative correlation between glycogen and vaginal pH (r = -0.542, p<0.0001). In multivariable analysis, free glycogen levels were significantly negatively associated with both vaginal pH and progesterone (p < 0.001 and p = 0.004, respectively). Estrogen, glucose, age, sexual intercourse 24 hours prior to visit, and days after the initial visit were not significantly associated with free glycogen levels.
Cell-free glycogen concentrations can be very high, up to 3% of genital fluid, and are strongly associated with acidic vaginal pH. However, the fluctuations in glycogen levels in individuals and differences between individuals do not appear to be associated with estrogen.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Background
Development of human immunodeficiency virus (HIV) remission strategies requires precise information on time to HIV rebound after treatment interruption, but there is uncertainty ...regarding whether modern antiretroviral therapy (ART) regimens and timing of ART initiation may affect this outcome.
Methods
AIDS Clinical Trials Group (ACTG) A5345 enrolled individuals who initiated ART during chronic or early HIV infection and on suppressive ART for ≥2 years. Participants underwent carefully monitored antiretroviral interruption. ART was restarted upon 2 successive viral loads ≥1000 copies/mL. We compared participants of A5345 with participants of 6 historic ACTG treatment interruption studies.
Results
Thirty-three chronic-treated and 12 early-treated participants interrupted ART with evaluable time to viral rebound. Median time to viral rebound ≥1000 HIV RNA copies/mL was 22 days. Acute retroviral rebound syndrome was diagnosed in 9% of the chronic-treated and none of the early-treated individuals. All participants of the historic studies were on older protease inhibitor-based regimens, whereas 97% of A5345 participants were on integrase inhibitor-based ART. There were no differences in the timing of viral rebound comparing A5345 versus historic studies. In a combined analysis, a higher percentage of early-treated participants remained off ART at posttreatment interruption week 12 (chronic vs early: 2% vs 9%, P = .0496). One chronic-treated and one early-treated A5345 participant remained off ART for >24 weeks. All participants resuppressed after ART reinitiation.
Conclusions
Early ART initiation, using either older or newer ART regimens, was associated with a significant delay in the time to HIV rebound after ART interruption, lowering the barrier for HIV remission.
In A5345, we detected no differences in the timing of viral rebound with modern versus historic ART. Early ART was associated with a significant delay in the time to HIV rebound after ART interruption, lowering the barrier for HIV remission.
The intestinal mucosa is constantly facing a high load of antigens including bacterial antigens derived from the microbiota and food. Despite this, the immune cells present in the gastrointestinal ...tract do not initiate a pro-inflammatory immune response. Toll-like receptors (TLRs) are pattern recognition receptors expressed by various cells in the gastrointestinal tract, including intestinal epithelial cells (IEC) and resident immune cells in the lamina propria. Many diseases, including chronic intestinal inflammation (e.g., inflammatory bowel disease), irritable bowel syndrome (IBS), allergic gastroenteritis (e.g., eosinophilic gastroenteritis and allergic IBS), and infections are nowadays associated with a deregulated microbiota. The microbiota may directly interact with TLR. In addition, differences in intestinal TLR expression in health and disease may suggest that TLRs play an essential role in disease pathogenesis and may be novel targets for therapy. TLR signaling in the gut is involved in either maintaining intestinal homeostasis or the induction of an inflammatory response. This mini review provides an overview of the current knowledge regarding the contribution of intestinal epithelial TLR signaling in both tolerance induction or promoting intestinal inflammation, with a focus on food allergy. We will also highlight a potential role of the microbiota in regulating gut immune responses, especially through TLR activation.
Knowledge of aging biology needs to be expanded due to the continuously growing number of elderly people worldwide. Aging induces changes that affect all systems of the body. The risk of ...cardiovascular disease and cancer increases with age. In particular, the age-induced adaptation of the immune system causes a greater susceptibility to infections and contributes to the inability to control pathogen growth and immune-mediated tissue damage. Since the impact of aging on immune function, is still to be fully elucidated, this review addresses some of the recent understanding of age-related changes affecting key components of immunity. The emphasis is on immunosenescence and inflammaging that are impacted by common infectious diseases that are characterized by a high mortality, and includes COVID-19, HIV and tuberculosis.
The components of the human gut microbiome have been found to influence a broad array of pathologic conditions ranging from heart disease to diabetes and even to cancer. HIV infection upsets the ...delicate balance in the normal host-microbe interaction both through alterations in the taxonomic composition of gut microbial communities as well as through disruption of the normal host response mechanisms. In this article we review the current methods of gut microbiome analysis and the resulting data regarding how HIV infection might change the balance of commensal bacteria in the gut. Additionally, we cover the various effects gut microbes have on host immune homeostasis and the preliminary but intriguing data on how HIV disrupts those mechanisms. Finally, we briefly describe some of the important biomolecules produced by gut microbiota and the role that they may play in maintaining host immune homeostasis with and without HIV infection.
Over the last two decades, it has become increasingly apparent that Wnt signaling plays a critical role in development and adult tissue homeostasis in multiple organs and in the pathogenesis of many ...diseases. In particular, a crucial role for Wnt signaling in bone development and bone tissue homeostasis has been well recognized. Numerous genome‐wide association studies confirmed the importance of Wnt signaling in controlling bone mass. Moreover, ample evidence suggests that Wnt signaling is essential for kidney, intestine, and adipose tissue development and homeostasis. Recent emerging evidence demonstrates that Wnt signaling may play a fundamental role in the aging process of those organs. New discoveries show that bone is not only the major reservoir for calcium and phosphate storage, but also the largest organ with multiple functions, including mineral and energy metabolism. The interactions among bone, kidney, intestine, and adipose tissue are controlled and regulated by several endocrine signals, including FGF23, klotho, sclerostin, osteocalcin, vitamin D, and leptin. Since the aging process is characterized by structural and functional decline in almost all tissues and organs, understanding the Wnt signaling–related interactions among bone, kidney, intestine, and adipose tissue in aging may shed light on the pathogenesis of age‐related diseases.
Wnt signaling plays a crucial role in the development and homeostasis of bone tissue, as well as kidney, intestine, and adipose tissue, and it may play a fundamental role in the aging process of those organs. This review discusses recent progress in understanding the role of Wnt signaling in aging bone and other organs and tissues, with an emphasis on the interaction between inter‐organ regulation and aging bone.
Background. Defining the association of non-AIDS-defining events with inflammation and immune activation among human immunodeficiency virus (HIV)-infected persons with antiretroviral therapy ...(ART)-associated virological suppression is critical to identifying interventions to decrease the occurrence of these events. Methods. We conducted a case-control study of HIV-infected subjects who had achieved virological suppression within 1 year after ART initiation. Cases were patients who experienced non-AIDS-defining events, defined as myocardial infarction, stroke, non-AIDS-defining cancer, non-AIDS-defining serious bacterial infection, or death. Controls were matched to cases on the basis of age, sex, pre-ART CD4⁺ T-cell count, and ART regimen. Peripheral blood mononuclear cells and plasma specimens obtained at the visit before ART initiation (hereafter, baseline), the visit approximately 1 year after ART initiation (hereafter, year 1), and the visit immediately preceding the non-AIDSdefining event (hereafter, pre-event) were analyzed for activated CD4⁺ and CD8⁺ T cells, plasma interleukin 6 (IL-6) level, soluble tumor necrosis factor receptor I (sTNFR-I) level, sTNFR-II level, soluble CD14 level, kynurenine-totryptophan (KT) ratio, and D-dimer level. Conditional logistic regression analysis was used to study the association between biomarkers and outcomes, with adjustment for potential confounders. Results. Higher IL-6 level, sTNFR-I level, sTNFR-II level, KT ratio, and D-dimer level at year 1 were associated with the occurrence of a non-AIDS-defining event. Significant associations were also seen between non-AIDS-defining events and values of these biomarkers in specimens obtained at baseline and the pre-event time points. Effects remained significant after control for confounders. T-cell activation was not significantly related to outcomes. Conclusions. Interventional trials to decrease the incidence of non-AIDS-defining events among HIV-infected persons with virological suppression should consider targeting the pathways represented by these soluble markers.
The purpose of this article is to review alterations in microbiota composition, diversity, and functional features in the context of chronic inflammation and comorbidities associated with HIV ...infection.
The gut microbiome is an important mediator of host immunity, and disruption of gut homeostasis can contribute to both systemic inflammation and immune activation. Ageing and HIV share features of intestinal damage, microbial translocation and alterations in bacterial composition that contribute to a proinflammatory state and development of age-related comorbidities. One such inflammatory pathway reviewed is the nicotinamide adenine dinucleotide (NAD+) producing kynurenine pathway (KP). Kynurenine metabolites regulate many biological processes including host-microbiome communication, immunity and oxidative stress and the KP in turn is influenced by the microbiome environment. Age-associated decline in NAD+ is implicated as a driving factor in many age-associated diseases, including those seen in people with HIV (PWH). Recent studies have shown that KP can influence metabolic changes in PWH, including increased abdominal adiposity and cardiovascular disease. Furthermore, KP activity increases with age in the general population, but it is elevated in PWH at all ages compared to age-matched controls. Host or microbiome-mediated targeting of this pathway has merits to increase healthy longevity and has potential therapeutic applications in PWH.
As a growing proportion of PWH age, many face increased risks of developing age-related comorbidities. Chronic inflammation, a pillar of geroscience, the science of ageing and of age-related disease, is influenced by the gut microbiome and its metabolites. Combined, these contribute to a systemic inflammatory signature. Advances in geroscience-based approaches and therapeutics offer a novel paradigm for addressing age-related diseases and chronic inflammation in HIV infection. Whether targeted inhibition of KP activity alleviates pathological conditions or promotes successful ageing in PWH remains to be determined.
Persistent inflammation contributes to the development of cardiovascular disease (CVD) as an HIV-associated comorbidity. Innate immune cells such as monocytes are major drivers of inflammation in men ...and women with HIV. The study objectives are to examine the contribution of circulating non-classical monocytes (NCM, CD14dimCD16+) and intermediate monocytes (IM, CD14+CD16+) to the host response to long-term HIV infection and HIV-associated CVD. Women with and without chronic HIV infection (H) were studied. Subclinical CVD (C) was detected as plaques imaged by B-mode carotid artery ultrasound. The study included H-C-, H+C-, H-C+, and H+C+ participants (23 of each, matched on race/ethnicity, age and smoking status), selected from among enrollees in the Women's Interagency HIV Study. We assessed transcriptomic features associated with HIV or CVD alone or comorbid HIV/CVD comparing to healthy (H-C-) participants in IM and NCM isolated from peripheral blood mononuclear cells. IM gene expression was little affected by HIV alone or CVD alone. In IM, coexisting HIV and CVD produced a measurable gene transcription signature, which was abolished by lipid-lowering treatment. In NCM, versus non-HIV controls, women with HIV had altered gene expression, irrespective of whether or not they had comorbid CVD. The largest set of differentially expressed genes was found in NCM among women with both HIV and CVD. Genes upregulated in association with HIV included several potential targets of drug therapies, including LAG3 (CD223). In conclusion, circulating monocytes from patients with well controlled HIV infection demonstrate an extensive gene expression signature which may be consistent with the ability of these cells to serve as potential viral reservoirs. Gene transcriptional changes in HIV patients were further magnified in the presence of subclinical CVD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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