Accelerated disease progression and robust innate host response in aged SIVmac239-infected Chinese rhesus macaques is associated with enhanced immunosenescence
Hong‐Yi ZhengMingxu ZhangMin ChenJin JiangJiahao SongXiaodong LianRen‐Rong TianXiaoliang ZhangLin‐Tao ZhangWei PangGao‐Hong ZhangYong‐Tang Zheng
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Abstract The elderly population infected with HIV-1 is often characterized by the rapid AIDS progression and poor treatment outcome, possibly because of immunosenescence resulting from both HIV infection and aging. However, this hypothesis remains to be fully tested. Here, we studied 6 young and 12 old Chinese rhesus macaques (ChRM) over the course of three months after simian immunodeficiency virus (SIV) SIVmac239 infection. Old ChRM showed a higher risk of accelerated AIDS development than did young macaques, owing to rapidly elevated plasma viral loads and decreased levels of CD4 + T cells. The low frequency of naïve CD4 + T cells before infection was strongly predictive of an increased disease progression, whereas the severe depletion of CD4 + T cells and the rapid proliferation of naïve lymphocytes accelerated the exhaustion of naïve lymphocytes in old ChRM. Moreover, in old ChRM, a robust innate host response with defective regulation was associated with a compensation for naïve T cell depletion and a high level of immune activation. Therefore, we suggest that immunosenescence plays an important role in the accelerated AIDS progression in elderly individuals and that SIV-infected old ChRM may be a favorable model for studying AIDS pathogenesis and researching therapies for elderly AIDS patients.Keywords:
Immunosenescence
Simian immunodeficiency virus
Aging is accompanied by a progressive decline in the integrity of the immune system, a process known as immunosenescence. Pathological features typical of immune dysfunction in older adults, encompassing dysregulation of innate and adaptive immune responses, characterize rheumatoid arthritis (RA), an autoimmune disease whose incidence increases with age. Recent evidence suggests that certain features of immunosenescence, such as the decrease in T-cell generation and diversity, may contribute to the development of RA. Thus, physiological immunosenescence may render older adults susceptible to RA, and premature immunosenescence may contribute to the development of RA in young adults. In addition, other features of immunosenescence may result from the chronic immune stimulation that occurs in RA and lead to worsening of the disease. This article reviews the immunopathological features common to aging and RA and discusses the mechanisms by which immunosenescence may contribute to the development or progression of RA.
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Abstract Immunosenescence is an age-dependent decline in immune functions and hallmark of aging in diverse species, ranging from invertebrates to mammals. However, identifying the factors responsible for immunosenescence is challenging because of the complexity of immune systems and aging in mammals. The roundworm Caenorhabditis elegans is suitable for understanding immunosenescence because of its simple immune system and rapid aging process. In this review, we discuss the advances in our understanding of immunosenescence in C. elegans . PMK-1/p38 mitogen-activated protein kinase (MAPK), SKN-1/NRF, and ZIP-10/bZIP transcription factor regulate immunosenescence through p38 MAPK and insulin/IGF-1 signaling pathways. Because these factors and pathways are evolutionarily conserved, the findings discussed in this review may help understand the mechanisms underlying immunosenescence and develop new treatment therapy for immunosenescence in humans.
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Premature immunosenescence has been reported in different HIV scenarios. However, how premature is the HIV-related immunosenescent phenotype is still unknown. Thus, the aim of this study was to analyze the immunosenescent status of young viraemic naive HIV-infected individuals, with less than four years from infection. To this end, replicative senescence, activation and proliferation T-cell levels were analyzed in chronically HIV-infected young individuals and both, elderly and young healthy controls. We show that young HIV-infected viraemic patients, with less than four years from infection, have early immune exhaustion leading to a premature immunosenescence comparable to healthy people 40 years elder. In addition, memory T-cell subsets showed greater alterations than elder healthy controls and, in patients with high viral loads, CD57 expression at the memory T-cell subsets was correlated with lower viral increases but higher CD4 T-cell lost during follow up. Keywords: HIV, immunosenescence, CD57, premature immunosenescence, HAART onset, Exhaustion, HIV-infected individuals, CD57-expressing, CD4, expressing memory T-cell subsets
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The simian immunodeficiency viruses (SIVs) are a diverse group of viruses that naturally infect a wide range of African primates, including African green monkeys (AGMs) and sooty mangabey monkeys (SMs). Although natural infection is widespread in feral populations of AGMs and SMs, this infection generally does not result in immunodeficiency. However, experimental inoculation of Asian macaques results in an immunodeficiency syndrome remarkably similar to human AIDS. Thus, natural nonprogressive SIV infections appear to represent an evolutionary adaptation between these animals and their primate lentiviruses. Curiously, these animals maintain robust virus replication but have evolved strategies to avoid disease progression. Adaptations observed in these primates include phenotypic changes to CD4(+) T cells, limited chronic immune activation, and altered mucosal immunity. It is probable that these animals have achieved a unique balance between T-cell renewal and proliferation and loss through activation-induced apoptosis, and virus-induced cell death. A clearer understanding of the mechanisms underlying the lack of disease progression in natural hosts for SIV infection should therefore yield insights into the pathogenesis of AIDS and may inform vaccine design.
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Abstract Risk factors for the development of severe COVID-19 include several comorbidities, but age was the most striking one since elderly people were disproportionately affected by SARS-Cov-2. Major drivers that can explain this markedly unfavourable response in the elderly are inflammaging and immunosenescence. Recent reports have shown that the relationship between immunosenescence and COVID-19 can be bidirectional, since hospitalized patients with severe COVID-19 have an accumulation of senescent T cells suggesting that immunosenescence can be also exacerbated by SARS-CoV-2 infection. Therefore, the present work was designed to examine the emergence of immunosenescence in a longitudinal study in two distinct cohorts of COVID-19 patients, and to determine whether the senescence alterations were restricted to severe cases of the disease. Our data, with patients from Portugal and Brazil, identified their distinctive inflammatory profile and provided evidence of increased frequencies of senescent and exhausted T cells within a seven-day period in patients with mild to severe COVID-19. These results support the view that SARS-CoV2 infection can accelerate immunosenescence in both CD4 and CD8 T cell compartments in a short period of time.
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