Intrinsic Folding Properties of the HLA-B27 Heavy Chain Revealed by Single Chain Trimer Versions of Peptide-Loaded Class I Major Histocompatibility Complex Molecules.

Peptide-loaded Major Histocompatibility Complex (pMHC) class I molecules can be expressed in a single chain trimeric (SCT) format, composed of a specific peptide fused to the light chain beta-2 microglobulin (ß2m) and MHC class I heavy chain (HC) by flexible linker peptides. pMHC SCTs have been used as effective molecular tools to investigate cellular immunity and represent a promising vaccine platform technology, due to their intracellular folding and assembly which is apparently independent of host cell folding pathways and chaperones. However, certain MHC class I HC molecules, such as the Human Leukocyte Antigen B27 (HLA-B27) allele, present a challenge due to their tendency to form HC aggregates. We constructed a series of single chain trimeric molecules to determine the behaviour of the HLA-B27 HC in a scenario that usually allows for efficient MHC class I molecule folding. When stably expressed, a pMHC SCT incorporating HLA-B27 HC formed chaperone-bound homodimers within the endoplasmic reticulum (ER). A series of HLA-B27 SCT substitution mutations revealed that the F pocket and antigen binding groove regions of the HLA-B27 HC defined the folding and dimerisation of the single chain complex, independently of the peptide sequence. Furthermore, pMHC SCTs can demonstrate variability in their association with the intracellular antigen processing machinery.

Delivering specialised care to people ageing with HIV in the UK: experience and evolution of services from 2009 to 2019.

BACKGROUND: The introduction of antiretrovirals has resulted in a demographic shift with an increasing proportion of people living with HIV older than 50 years and a change in the spectrum of diseases affecting this population. A specialised clinical service dedicated to older people living with HIV was implemented at Chelsea and Westminster Hospital, London, UK in 2009, following training of health-care providers in HIV, ageing, comorbidity, and polypharmacy management. We report the results of a service evaluation reviewing 10 years of activity of this specialised clinic, including lessons to be applied in routine practice. METHODS: We estimated the prevalence of multimorbidity and polypharmacy and described algorithms devised for use across our HIV outpatient services following implementation of the specialised clinical pathway. The service evaluation was approved by our local clinical governance system and data relative to the period 2009-19 were collected on a secured trust database. FINDINGS: Dedicated time was created for senior and junior doctors, a nurse, and a pharmacy to create clinical appointments for older people living with HIV referred by all service care providers. The team would review different clinical scenarios, book follow-up appointments to review results, refer to different specialists or to complex multidisciplinary teams when necessary. 744 people with HIV aged 50 years and older attended our services (93% [691] male, 7·1% [53] female; mean age 56·5 years [SD 5·5]; 84·2% [622] White, 7·5% [56] Black, 0·9% [7] Asian, 7·5% [56] other race or ethnicity). The prevalence of multimorbidity was 69·3% and of polypharmacy was 46·6%. The most common comorbidities were vitamin D deficiency (428 of 690, 62%), dyslipidaemia (373, 50·1%), hypertension (157, 21·5%), depressive or anxious disorders (117, 15·8%), osteoporosis (91, 12·2%), obesity (98, 13·2%), chronic kidney disease (56, 7·5%), and diabetes (43, 5·7%). Patients with dyslipidaemia, osteoporosis, and metabolic disorders were referred to a live well pathway clinic focusing on targeted lifestyle interventions, including diet and physical exercise, under the supervision of a dietician and a physiotherapist. INTERPRETATION: We have described how our HIV over-50 clinic was organised and implemented, and we reported data showing high rates of comorbidities and polypharmacy, which led to the establishment of a specialised care pathway for all HIV care providers and to the implementation of further joint HIV and specialty clinics (cardiology, metabolic, menopause, nephrology, neurology, and geriatric). FUNDING: None.

Evaluation of a Clinic Dedicated to People Aging with HIV at Chelsea and Westminster Hospital: Results of a 10-Year Experience.

Successful management of HIV infection as a chronic condition has resulted in a demographic shift where the proportion of people living with HIV (PLWH) older than 50 years is steadily increasing. A dedicated clinic to PLWH older than 50 years was established at Chelsea and Westminster Hospital in January 2009 and then extended to HIV services across the directorate. We report the results of a service evaluation reviewing 10 years of activities of this clinic between January 2009 and 2019. We aimed to estimate the prevalence of major noninfectious comorbidities, polypharmacy (≥5 medications), and multimorbidity (≥2 non-HIV-related comorbidities) and describe algorithms devised for use in HIV outpatient clinics across the directorate. A cohort of 744 PLWH older than 50 years attending this service were analyzed (93% male; mean age of 56 ± 5.5 years; 84% white ethnicity); 97.7% were on antiretroviral treatment and 95.9% had undetectable HIV-RNA at the time of evaluation. The most common comorbidities diagnosed were dyslipidemia (50.1%), hypertension (21.5%), mental health disorders (depression and/or anxiety disorders, 15.7%), osteoporosis (12.2%), obesity (11.9%), chronic kidney disease (7.5%), and diabetes (5.8%). Low vitamin D levels were found in 62% of patients [43% with vitamin D deficiency (<40 mmol/liter) and 57% with vitamin D insufficiency (40-70 mmol/liter)]. The overall prevalence of polypharmacy and multimorbidity was 46.6% and 69.3%, respectively. This study showed significant rates of non-HIV-related comorbidities and polypharmacy in PLWH older than 50 years, leading on to the implementation of clinical care pathways and new joint HIV/specialty clinics (cardiology, nephrology, neurology, metabolic, menopause, and geriatric) to improve prevention, diagnosis, and management of major comorbidities in people aging with HIV.

Sestrins induce natural killer function in senescent-like CD8+ T cells.

Aging is associated with remodeling of the immune system to enable the maintenance of life-long immunity. In the CD8+ T cell compartment, aging results in the expansion of highly differentiated cells that exhibit characteristics of cellular senescence. Here we found that CD27-CD28-CD8+ T cells lost the signaling activity of the T cell antigen receptor (TCR) and expressed a protein complex containing the agonistic natural killer (NK) receptor NKG2D and the NK adaptor molecule DAP12, which promoted cytotoxicity against cells that expressed NKG2D ligands. Immunoprecipitation and imaging cytometry indicated that the NKG2D-DAP12 complex was associated with sestrin 2. The genetic inhibition of sestrin 2 resulted in decreased expression of NKG2D and DAP12 and restored TCR signaling in senescent-like CD27-CD28-CD8+ T cells. Therefore, during aging, sestrins induce the reprogramming of non-proliferative senescent-like CD27-CD28-CD8+ T cells to acquire a broad-spectrum, innate-like killing activity.

Polypharmacy and evaluation of anticholinergic risk in a cohort of elderly people living with HIV.

: As a consequence of ageing, the number of prescribed medications for people living with HIV is increasing. Concomitant use of different drugs and their potential interactions may increase anticholinergic exposure and escalate the risk for side effects. We conducted an analysis in our cohort of people living with HIV over 50 years of age to evaluate the overall anticholinergic risk, as it is useful to identify, prevent, and manage increased side effect risks.

Senescent cells evade immune clearance via HLA-E-mediated NK and CD8+ T cell inhibition.

Senescent cells accumulate in human tissues during ageing and contribute to age-related pathologies. The mechanisms responsible for their accumulation are unclear. Here we show that senescent dermal fibroblasts express the non-classical MHC molecule HLA-E, which interacts with the inhibitory receptor NKG2A expressed by NK and highly differentiated CD8+ T cells to inhibit immune responses against senescent cells. HLA-E expression is induced by senescence-associated secretary phenotype-related pro-inflammatory cytokines, and is regulated by p38 MAP kinase signalling in vitro. Consistently, HLA-E expression is increased on senescent cells in human skin sections from old individuals, when compared with those from young, and in human melanocytic nevi relative to normal skin. Lastly, blocking the interaction between HLA-E and NKG2A boosts immune responses against senescent cells in vitro. We thus propose that increased HLA-E expression contributes to persistence of senescent cells in tissues, thereby suggesting a new strategy for eliminating senescent cells during ageing.

Convergence of Innate and Adaptive Immunity during Human Aging.

Aging is associated with profound changes in the human immune system, a phenomenon referred to as immunosenescence. This complex immune remodeling affects the adaptive immune system and the CD8+ T cell compartment in particular, leading to the accumulation of terminally differentiated T cells, which can rapidly exert their effector functions at the expenses of a limited proliferative potential. In this review, we will discuss evidence suggesting that senescent αßCD8+ T cells acquire the hallmarks of innate-like T cells and use recently acquired NK cell receptors as an alternative mechanism to mediate rapid effector functions. These cells concomitantly lose expression of co-stimulatory receptors and exhibit decreased T cell receptor signaling, suggesting a functional shift away from antigen-specific activation. The convergence of innate and adaptive features in senescent T cells challenges the classic division between innate and adaptive immune systems. Innate-like T cells are particularly important for stress and tumor surveillance, and we propose a new role for these cells in aging, where the acquisition of innate-like functions may represent a beneficial adaptation to an increased burden of malignancy with age, although it may also pose a higher risk of autoimmune disorders.

Sowing the seeds of cancer: telomeres and age-associated tumorigenesis.

PURPOSE OF REVIEW: Advances in the health system and medical sciences are continuously pushing the barrier of life-expectancy. As a consequence, humans are being increasingly afflicted by age-associated diseases, such as cancer. The challenge now lies in understanding the mechanisms underlying ageing in order to reduce the lifetime risk for cancer. RECENT FINDINGS: In long-lived mammals, telomere length and restriction of telomerase activity are important barriers preventing the uncontrolled cell division. Absence of telomerase dictates the continuous telomere erosion with each cell division, thus restraining the proliferation of incipient tumour cells. However, recent findings have revealed the unintended consequences of telomere control of cell division. Cells with short telomeres accumulate in older individuals increasing the risk of telomere depletion. Loss of telomere protection results in tetraploidization and genomic instability characteristic of epithelial cancers. Additionally, telomere shortening blocks cell proliferation and induces cell senescence. Senescent cells secrete proinflammatory factors and reactive oxygen species that increase the likelihood of cellular transformation and create the perfect soil for cancer development. SUMMARY: Telomere shortening thus provides an example of antagonist pleiotropy, in which a beneficial characteristic that acts during the reproductive years of an organism may, later in life, contain the seed to its demise.