Study of Immune Senescence and Premature Aging in Two Populations at Higher Risk of Cancer: Elderly People and Perinatally Human Immunodeficiency Virus (HIV)-Infected Children

Immune senescence and premature aging are important tumor risk factors. Decline in immune functions and accumulation of DNA damages influence overall health and predispose to malignancies. As a result of longer life expectancy, the number of cancers in the elderly population is expected to increase significantly over the next years. Considering the effect of the growing geriatric population on cancer care, the need to develop prognostic markers for cancer onset and/or chemotherapy response for improved treatment in this frail population is becoming greater. Furthermore, several conditions, such as HIV infection, also appear to accelerate aging and immune senescence; chronic immune activation may play a critical role in these dysfunctions which, besides immune depression, may constitute important risk factors for the onset of HIV-associated tumors. The persistence of a higher incidence of malignancies in HIV-infected individuals compared with the age-matched general population, even after the introduction of antiretroviral therapy (ART), which can reduce HIV levels and partially restore the immune functions, indicates that other conditions than immune depression play a role in the cancerogenesis occurring in HIV-infected patients. This is of particular importance in the perinatally HIV-infected children in whom the immune system co-evolves with HIV from birth. After the introduction of ART, most perinatally HIV-infected children are entering into adolescence and young adulthood and, despite ART, they remain at high risk of malignancies. My PhD project focuses on the study of immune senescence and premature aging in two populations at higher risk of cancer: elderly people and perinatally HIV-infected children. 1. Immune senescence and cancer in elderly people This study analyzed thymic output, immunophenotypic profile of CD4+ and CD8+ lymphocytes and peripheral blood telomere length (TL) in cancer patients 70≥ years old. Fifty-two elderly cancer patients and 39 age-matched controls without personal history of cancer were enrolled. The percentages of CD8+ naïve and CD8+ recent thymic emigrant cells (RTE) cells and levels of TREC (T-cell receptor excision circles, a molecular marker to evaluate thymic output) were significantly lower in cancer patients than in controls (16.7% [9.3-25.2] vs 24.6% [14.7-33.5], p=0.003; 34.2% [24.7-46.4] vs 44.9% [36.0-50.7], p=0.004; 16.0 [7.7-31.5] vs 25.0 [14.0-56.0] TREC copies/105 PBMC, p=0.031; respectively). TLs in peripheral blood mononuclear cells (PBMC) were significantly shorter in cancer patients than they did in controls (p=0.046) and did not correlate with age in patients, whereas it did in controls (r=-0.354, p=0.031). Short telomere(≤median)/low TREC(≤median) profile was associated with a higher risk of cancer (OR=3.68 [95%CI 1.22-11.11]; p=0.021). A longitudinal substudy is in progress to evaluate the effect of these markers on chemotherapy response and/or disease outcome. Preliminary data from this longitudinal substudy showed that, after chemotherapy treatment, there was an increase in CD8+ terminally differentiated cells (p=0.031), and telomere shortening at follow-up tended to be greater in stage III patients than in those at stage II. In addition, analysis of DNA-damage in PBMC, before and after exposure to a source of y-radiation, suggested that the DNA repair process is less efficient in cancer patients than in controls. Taken together, these findings indicate that immune senescence is significantly worse in elderly cancer patients than in age-matched controls. The low thymic output and the short telomeres in peripheral blood cells of cancer patients may reflect a pre-existing condition which facilitates the onset of malignancies in elderly people and may affect the response to chemotherapy and disease outcome. 2. Premature aging in perinatally HIV-infected children Seventy-one HIV-infected (HIV+) children born to HIV-infected mothers, aged from 0-5 years, 65 HIV-exposed-uninfected (HEU) born to HIV-infected mothers and 56 HIV-unexposed-uninfected (HUU) age-matched children were studied. 42% of the HIV+ children were not on ART. TLs were significantly shorter in HIV+ than in HEU and HUU children (overall p<0.0001, adjusted for age); in addition, HIV+ ART-naïve children had shorter TLs than children on ART (median 2.11 [interquartile range (IQR) 1.75-2.37] vs 2.46 [2.07-2.68]; p=0.0029 adjusted for age). CD8+ RTE (CD45RA+CD31+) and TREC levels were significantly lower in the HIV+ group than in the HEU and HUU groups (overall, p=0.005 and p=0.0249, respectively), whereas percentages of CD8+ effector memory (CD45RA-CD27-) and terminally differentiated cells (CD45RA+CD27-) were higher in the former (overall, p=0.033, and p<0.001, respectively). CD8+ senescent cells (CD28-CD57+) were higher in HIV+ than in HEU and HUU children (25.8% [12.4-43.2] vs 8.5% [6.8-16.7] vs 9.7% [3.3-27.3]; p=0.004), as were CD8+ activated cells (CD38+HLA-DR+) (7.0% [5.2-12.2] vs 3.5% [3.9-7.6] vs 3.7% [2.4-6.7]; p<0.001) and CD8+PD-1+ cells (7.1% [5.0-12.4] vs 3.5% [2.1-5.9] vs 3.7% [2.4-5.3]; p<0.001). Within the CD4+ cell subset, percentages of senescent cells did not differ between HIV+ and controls, although PD-1 expression tended to be up-regulated in HIV+ children (overall, p=0.050). Overall, these data suggest that HIV-infected children exhibit premature aging and accelerated immune senescence, which particularly affects the CD8+ cell subset. HIV infection per se seems to influence the aging process, rather than exposure to ART for prophylaxis or treatment. The mechanism(s) by means of which HIV may affect these functions remain to be investigated; however, chronic immune activation due to viral antigen persistence may promote rapid proliferation of CD8+ cells, resulting in erosion of telomeres and immunosenescent phenotype. Conclusions Taken together these studies indicate that TL, TREC and immunophenotypic analysis are useful markers in monitoring premature aging and immune senescence. In elderly patients, low thymic output and short telomeres are significantly associated with tumor and may affect the response to chemotherapy. Thus, these markers may be useful in the elderly population to predict tumor onset and to plan therapeutic strategies. In the context of pediatric HIV infection, in addition to current assays, i.e. HIV plasmaviremia and CD4+ cell profile, our study indicates the need to analyze TL and CD8+ cell subsets to assess the status of premature aging and immune senescence in this population at high risk of cancer

Host factors and early treatments to restrict paediatric HIV infection and early disease progression

open6noA body of evidence indicates that a threshold level of the virus is required to establish systemic and persistent HIV infection in the host and that this level depends on virus-host interactions. Mother-to-child transmission (MTCT) of HIV is the main source of paediatric HIV infection and occurs when the host's immune system is still developing. Thus, innate resistance and immunity, rather than adaptive immune response, may be the main drivers in restricting the establishment of HIV reservoirs and the long-lived persistence of HIV infection in infants. Genetic variations in HIV co-receptors and their ligands, as well as in Toll-like receptors and defensins, key elements of innate immunity, have been demonstrated to influence the risk of perinatal HIV infection and disease progression in HIV-infected infants. Early treatments with combined antiretroviral therapy (cART) restrict paediatric infection by reducing the level of the transmitted/infecting virus to below the threshold required for the onset of immune response to the virus and also significantly reduce HIV reservoirs. However, despite long periods with no signs and symptoms of HIV infection, all early cART-treated children who later discontinued cART had a rebound of HIV, except for one case in whom a period of viral remission occurred. Which parameters predict viral remission or viral rebound after cART discontinuation? Could early cART prevent rather than just reduce the establishment of viral reservoirs? And, if so, how? Answers to these questions are also important in order to optimise the use of early cART in infants at high risk of HIV infection.openGianesin, Ketty; Petrara, Raffaella; Freguja, Riccardo; Zanchetta, Marisa; Giaquinto, Carlo; DE ROSSI, AnitaGianesin, Ketty; Petrara, Raffaella; Freguja, Riccardo; Zanchetta, Marisa; Giaquinto, Carlo; DE ROSSI, Anit

Differences in telomere length between sporadic and familial cutaneous melanoma

BACKGROUND: Several pieces of evidence indicate that a complex relationship exists between constitutional telomere length (TL) and the risk of cutaneous melanoma. Although the general perception is that longer telomeres increase melanoma risk, some studies do not support this association. We hypothesise that discordant data are due to the characteristics of the studied populations. OBJECTIVES: To evaluate the association of telomere length with familial and sporadic melanoma. METHODS: TL was measured by multiplex quantitative PCR in leukocytes from 310 melanoma patients according to familial/sporadic and single/multiple cancers and 216 age-matched controls. RESULTS: Patients with sporadic melanoma were found to have shorter telomeres as compared to those with familial melanoma. In addition, shorter telomeres, while tending to reduce the risk of familial melanoma regardless of single or multiple tumors, nearly trebled the risk of single sporadic melanoma. CONCLUSIONS: This is the first time that TL has been correlated to opposite effects on melanoma risk according to the presence or absence of familial predisposition. Individual susceptibility to melanoma should be taken into account when assessing the role of TL as a risk factor. This article is protected by copyright. All rights reserved

Pediatric Human Immunodeficiency Virus infection and cancer in the Highly Active Antiretroviral Treatment (HAART) era

Abstract Highly active antiretroviral therapy (HAART) changed the natural history of pediatric HIV infection. This review focuses on trends of HIV-associated cancers in childhood in the HAART era and analyses potential pathogenetic mechanisms. HAART reduced AIDS-defined-malignancies (ADM), but incidence of several non-ADM is increasing. HIV-associated immune activation and inflammation, promoting tumorigenesis, can only partially be reduced by HAART. In addition, HIV-infected children may undergo accelerated immune senescence that favors cancer development. How HAART affects this condition is an open question. Lastly, there is no evidence that prenatal exposure to HAART increases the risk of cancer in childhood, but long-term studies are needed

Premature aging and immune senescence in HIV-infected children

Objective: Several pieces of evidence indicate that HIV-infected adults undergo premature aging. The effect of HIV and antiretroviral therapy (ART) exposure on the aging process of HIV-infected children may be more deleterious since their immune system coevolves from birth with HIV. Design: Seventy-one HIV-infected (HIV+), 65 HIV-exposed-uninfected (HEU), and 56 HIV-unexposed-uninfected (HUU) children, all aged 0\u20135 years, were studied for biological aging and immune senescence. Methods: Telomere length and T-cell receptor rearrangement excision circle levels were quantified in peripheral blood cells by real-time PCR. CD4+ and CD8+ cells were analysed for differentiation, senescence, and activation/exhaustion markers by flow cytometry. Results: Telomere lengths were significantly shorter in HIV+ than in HEU and HUU children (overall, P < 0.001 adjusted for age); HIV+ ART-naive (42%) children had shorter telomere length compared with children on ART (P = 0.003 adjusted for age). T-cell receptor rearrangement excision circle levels and CD8+ recent thymic emigrant cells (CD45RA+CD31+) were significantly lower in the HIV+ than in control groups (overall, P = 0.025 and P = 0.005, respectively). Percentages of senescent (CD28-CD57+), activated (CD38+HLA-DR+), and exhausted (PD1+) CD8+ cells were significantly higher in HIV+ than in HEU and HUU children (P = 0.004, P < 0.001, and P < 0.001, respectively). Within the CD4+ cell subset, the percentage of senescent cells did not differ between HIV+ and controls, but programmed cell death receptor-1 expression was upregulated in the former. Conclusions: HIV-infected children exhibit premature biological aging with accelerated immune senescence, which particularly affects the CD8+ cell subset. HIV infection per se seems to influence the aging process, rather than exposure to ART for prophylaxis or treatmen

Premature aging and immune senescence in HIV-infected children.

Objective: Several pieces of evidence indicate that HIV-infected adults undergo premature aging. The effect of HIV and antiretroviral therapy (ART) exposure on the aging process of HIV-infected children may be more deleterious since their immune system coevolves from birth with HIV. Design: Seventy-one HIV-infected (HIV+), 65 HIV-exposed-uninfected (HEU), and 56 HIV-unexposed-uninfected (HUU) children, all aged 0-5 years, were studied for biological aging and immune senescence. Methods: Telomere length and T-cell receptor rearrangement excision circle levels were quantified in peripheral blood cells by real-time PCR. CD4+ and CD8+ cells were analysed for differentiation, senescence, and activation/exhaustion markers by flow cytometry. Results: Telomere lengths were significantly shorter in HIV+ than in HEU and HUU children (overall, P < 0.001 adjusted for age); HIV+ ART-naive (42%) children had shorter telomere length compared with children on ART (P = 0.003 adjusted for age). T-cell receptor rearrangement excision circle levels and CD8+ recent thymic emigrant cells (CD45RA+CD31+) were significantly lower in the HIV+ than in control groups (overall, P = 0.025 and P = 0.005, respectively). Percentages of senescent (CD28−CD57+), activated (CD38+HLA-DR+), and exhausted (PD1+) CD8+ cells were significantly higher in HIV+ than in HEU and HUU children (P = 0.004, P < 0.001, and P < 0.001, respectively). Within the CD4+ cell subset, the percentage of senescent cells did not differ between HIV+ and controls, but programmed cell death receptor-1 expression was upregulated in the former. Conclusions: HIV-infected children exhibit premature biological aging with accelerated immune senescence, which particularly affects the CD8+ cell subset. HIV infection per se seems to influence the aging process, rather than exposure to ART for prophylaxis or treatment. Keywords: immune activation, immune senescence, microbial translocation, pediatric HIV/AIDS, premature aging, telomere length, T-cell receptor rearrangement excision circl

Immune senescence and cancer in elderly patients: Results from an exploratory study

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Study of Immune Senescence and Premature Aging in Two Populations at Higher Risk of Cancer: Elderly People and Perinatally Human Immunodeficiency Virus (HIV)-Infected Children

Immune senescence and premature aging are important tumor risk factors. Decline in immune functions and accumulation of DNA damages influence overall health and predispose to malignancies. As a result of longer life expectancy, the number of cancers in the elderly population is expected to increase significantly over the next years. Considering the effect of the growing geriatric population on cancer care, the need to develop prognostic markers for cancer onset and/or chemotherapy response for improved treatment in this frail population is becoming greater. Furthermore, several conditions, such as HIV infection, also appear to accelerate aging and immune senescence; chronic immune activation may play a critical role in these dysfunctions which, besides immune depression, may constitute important risk factors for the onset of HIV-associated tumors. The persistence of a higher incidence of malignancies in HIV-infected individuals compared with the age-matched general population, even after the introduction of antiretroviral therapy (ART), which can reduce HIV levels and partially restore the immune functions, indicates that other conditions than immune depression play a role in the cancerogenesis occurring in HIV-infected patients. This is of particular importance in the perinatally HIV-infected children in whom the immune system co-evolves with HIV from birth. After the introduction of ART, most perinatally HIV-infected children are entering into adolescence and young adulthood and, despite ART, they remain at high risk of malignancies. My PhD project focuses on the study of immune senescence and premature aging in two populations at higher risk of cancer: elderly people and perinatally HIV-infected children. 1. Immune senescence and cancer in elderly people This study analyzed thymic output, immunophenotypic profile of CD4+ and CD8+ lymphocytes and peripheral blood telomere length (TL) in cancer patients 70≥ years old. Fifty-two elderly cancer patients and 39 age-matched controls without personal history of cancer were enrolled. The percentages of CD8+ naïve and CD8+ recent thymic emigrant cells (RTE) cells and levels of TREC (T-cell receptor excision circles, a molecular marker to evaluate thymic output) were significantly lower in cancer patients than in controls (16.7% [9.3-25.2] vs 24.6% [14.7-33.5], p=0.003; 34.2% [24.7-46.4] vs 44.9% [36.0-50.7], p=0.004; 16.0 [7.7-31.5] vs 25.0 [14.0-56.0] TREC copies/105 PBMC, p=0.031; respectively). TLs in peripheral blood mononuclear cells (PBMC) were significantly shorter in cancer patients than they did in controls (p=0.046) and did not correlate with age in patients, whereas it did in controls (r=-0.354, p=0.031). Short telomere(≤median)/low TREC(≤median) profile was associated with a higher risk of cancer (OR=3.68 [95%CI 1.22-11.11]; p=0.021). A longitudinal substudy is in progress to evaluate the effect of these markers on chemotherapy response and/or disease outcome. Preliminary data from this longitudinal substudy showed that, after chemotherapy treatment, there was an increase in CD8+ terminally differentiated cells (p=0.031), and telomere shortening at follow-up tended to be greater in stage III patients than in those at stage II. In addition, analysis of DNA-damage in PBMC, before and after exposure to a source of y-radiation, suggested that the DNA repair process is less efficient in cancer patients than in controls. Taken together, these findings indicate that immune senescence is significantly worse in elderly cancer patients than in age-matched controls. The low thymic output and the short telomeres in peripheral blood cells of cancer patients may reflect a pre-existing condition which facilitates the onset of malignancies in elderly people and may affect the response to chemotherapy and disease outcome. 2. Premature aging in perinatally HIV-infected children Seventy-one HIV-infected (HIV+) children born to HIV-infected mothers, aged from 0-5 years, 65 HIV-exposed-uninfected (HEU) born to HIV-infected mothers and 56 HIV-unexposed-uninfected (HUU) age-matched children were studied. 42% of the HIV+ children were not on ART. TLs were significantly shorter in HIV+ than in HEU and HUU children (overall p<0.0001, adjusted for age); in addition, HIV+ ART-naïve children had shorter TLs than children on ART (median 2.11 [interquartile range (IQR) 1.75-2.37] vs 2.46 [2.07-2.68]; p=0.0029 adjusted for age). CD8+ RTE (CD45RA+CD31+) and TREC levels were significantly lower in the HIV+ group than in the HEU and HUU groups (overall, p=0.005 and p=0.0249, respectively), whereas percentages of CD8+ effector memory (CD45RA-CD27-) and terminally differentiated cells (CD45RA+CD27-) were higher in the former (overall, p=0.033, and p<0.001, respectively). CD8+ senescent cells (CD28-CD57+) were higher in HIV+ than in HEU and HUU children (25.8% [12.4-43.2] vs 8.5% [6.8-16.7] vs 9.7% [3.3-27.3]; p=0.004), as were CD8+ activated cells (CD38+HLA-DR+) (7.0% [5.2-12.2] vs 3.5% [3.9-7.6] vs 3.7% [2.4-6.7]; p<0.001) and CD8+PD-1+ cells (7.1% [5.0-12.4] vs 3.5% [2.1-5.9] vs 3.7% [2.4-5.3]; p<0.001). Within the CD4+ cell subset, percentages of senescent cells did not differ between HIV+ and controls, although PD-1 expression tended to be up-regulated in HIV+ children (overall, p=0.050). Overall, these data suggest that HIV-infected children exhibit premature aging and accelerated immune senescence, which particularly affects the CD8+ cell subset. HIV infection per se seems to influence the aging process, rather than exposure to ART for prophylaxis or treatment. The mechanism(s) by means of which HIV may affect these functions remain to be investigated; however, chronic immune activation due to viral antigen persistence may promote rapid proliferation of CD8+ cells, resulting in erosion of telomeres and immunosenescent phenotype. Conclusions Taken together these studies indicate that TL, TREC and immunophenotypic analysis are useful markers in monitoring premature aging and immune senescence. In elderly patients, low thymic output and short telomeres are significantly associated with tumor and may affect the response to chemotherapy. Thus, these markers may be useful in the elderly population to predict tumor onset and to plan therapeutic strategies. In the context of pediatric HIV infection, in addition to current assays, i.e. HIV plasmaviremia and CD4+ cell profile, our study indicates the need to analyze TL and CD8+ cell subsets to assess the status of premature aging and immune senescence in this population at high risk of cancer.L’immunosenescenza e l’invecchiamento prematuro rappresentano importanti fattori di rischio per l’insorgenza di tumore; il deterioramento delle funzioni immunitarie e l’accumulo di danni al DNA con l’avanzare dell’età determinano un generale peggioramento dello stato di salute e predispongono alla malattia neoplastica. Come risultato della maggiore aspettativa di vita, è previsto che il numero di tumori nella popolazione anziana aumenterà significativamente nei prossimi anni. E’ sempre più importante, pertanto, trovare dei marcatori prognostici per l’insorgenza di cancro e/o di risposta alla terapia, anche al fine di migliorare il trattamento di questa popolazione più vulnerabile. Va inoltre sottolineato che certe condizioni, come l’infezione da HIV, sembrano accelerare il processo di invecchiamento e di immunosenescenza; l’attivazione cronica del sistema immunitario potrebbe giocare un ruolo critico in queste disfunzioni, che, oltre all’immunodepressione, potrebbero costituire un importante fattore di rischio per l’insorgenza dei tumori associati ad HIV. L’alta incidenza di tumore fra gli individui HIV-infetti, rispetto alla popolazione generale di pari età, anche dopo l’introduzione della terapia antiretrovirale (ART) che riduce i livelli di HIV e parzialmente ripristina il sistema immunitario, va a sostegno dell’ipotesi che altre condizioni, oltre all’immunodepressione, possano giocare un ruolo nel processo di cancerogenesi nelle persone HIV-infette. Questo è di particolare rilievo nei bambini con infezione perinatale da HIV, nei quali il sistema immunitario co-evolve dalla nascita con il virus. Dopo l’introduzione dell’ART, la maggior parte dei bambini HIV-infetti diventa adolescente ed entra nell’età adulta; nonostante la terapia, questi rimangono ad alto rischio di tumore. Il mio progetto di Dottorato si è focalizzato sullo studio dell’immunosenescenza e dell’invecchiamento prematuro in due popolazioni ad alto rischio di cancro: i soggetti anziani e i bambini con infezione perinatale da HIV. 1. Immunosenescenza e cancro negli anziani In questo studio sono stati analizzati l’output timico, il profilo immunofenotipico dei linfociti CD4+ e CD8+ e la lunghezza del telomero (TL) nel sangue periferico di pazienti con cancro di età superiore ai 70 anni. Sono stati arruolati 52 soggetti anziani con cancro e 39 controlli di pari età senza storia di cancro. Le percentuali di cellule C8+ naive e CD8+ di recente uscita timica e i livelli di TREC (“T-cell receptor excision circles”, marker molecolare per valutare l’output timico) erano significativamente più bassi nei pazienti con cancro che nei controlli (16.7% [9.3-25.2] vs 24.6% [14.7-33.5], p=0.003; 34.2% [24.7-46.4] vs 44.9% [36.0-50.7], p=0.004; 16.0 [7.7-31.5] vs 25.0 [14.0-56.0] TREC copies/105 PBMC, p=0.031; rispettivamente). La TL nelle cellule mononucleari di sangue periferico (PBMC) era significativamente più corta nei pazienti con cancro che nei controlli (p=0.046) e correlava con l’età solo in quest’ultimi (r=-0.354, p=0.031). Il profilo telomeri corti(≤mediana)/bassi livelli di TREC (≤mediana) era associato con un alto rischio di cancro (OR=3.68 [95%CI 1.22-11.11]; p=0.021). E’ in corso un sottostudio longitudinale al fine di valutare l’impatto di questi marcatori sulla risposta alla chemioterapia e/o sul decorso della malattia. Dati preliminari hanno mostrato, che dopo il trattamento chemioterapico, vi è un aumento delle cellule CD8+ differenziate allo stadio terminale (p=0.031), e che l’accorciamento del telomero durante il follow-up tende ad essere maggiore nei pazienti con malattia di stadio III rispetto a quelli di stadio II. Inoltre, l’analisi del danno al DNA nei PBMC, prima e dopo l’esposizione ad una sorgente di raggi gamma, ha suggerito che i pazienti con cancro hanno una ridotta efficienza nei processi di riparo del DNA. In generale, questi risultati indicano che l’immunosenescenza è significativamente più grave nei pazienti anziani con cancro rispetto ai controlli di pari età. Il basso output timico e i telomeri più corti nelle cellule di sangue periferico potrebbero riflettere una condizione pre-esistente, che facilita l’insorgenza di tumore nelle persone anziane e che potrebbe influenzare la risposta alla chemioterapia. 2. Invecchiamento prematuro nei bambini con infezione perinatale da HIV Sono stati studiati 71 bambini HIV-infetti (HIV+) nati da madre HIV-infetta, dai 0 ai 5 anni di età, 65 bambini esposti non infetti (HEU) nati da madre HIV-infetta e 56 non esposti non infetti (HUU) di pari età. Il 42% dei bambini HIV+ non era in ART. La TL era significativamente più corta nei bambini HIV+ rispetto ai bambini HEU e HUU (p<0.0001, dopo aggiustamento per età); inoltre, i bambini HIV+ ART-naive mostravano una TL più corta rispetto ai bambini in ART (mediana 2.11 [range interquartilico (IQR) 1.75-2.37 vs 2.46 [2.07-2.68]; p=0.0029, dopo aggiustamento per età). Le cellule CD8+ di recente uscita timica (CD45RA+CD31+) e i livelli di TREC erano significativamente più bassi nei bambini HIV+ rispetto ai bambini HEU e HUU (p=0.005 e p=0.0249, rispettivamente), mentre le percentuali delle cellule CD8+ di memoria effettrici (CD45RA-CD27-) e differenziate allo stadio terminale (CD45RA+CD27-) erano maggiori nei primi (p=0.033 e p<0.001, rispettivamente). Le cellule CD8+ senescenti (CD28-CD57+) erano maggiori negli HIV+ che nei bambini HEU e HUU (25.8% [12.4-43.2] vs 8.5% [6.8-16.7] vs 9.7% [3.3-27.3]; p=0.004), così come le cellule CD8+ attivate (CD38+HLA-DR+) (7.0% [5.2-12.2] vs 3.5% [3.9-7.6] vs 3.7 [2.4-6.7]; p<0.001) e le cellule CD8+PD-1+ (7.1% [5.0-12.4] vs 3.5% [2.1-5.9] vs 3.7% [2.4-5.3]; p<0.001). All’interno della sottopopolazione di cellule CD4+, la percentuale delle cellule senescenti non era significativamente diversa fra HIV+ e controlli, sebbene l’espressione di PD-1 tendesse ad essere maggiore negli HIV+ (p=0.050). Nell’insieme, questi dati suggeriscono che i bambini HIV-infetti mostrano un invecchiamento prematuro e uno stato di immunosenescenza accelerato che colpisce per lo più la sottopopolazione delle cellule CD8+. L’infezione da HIV per sé sembra influenzare il processo di invecchiamento, piuttosto che l’esposizione all’ART per profilassi o trattamento. I meccanismi attraverso i quali HIV potrebbe influenzare queste funzioni rimangono ancora da chiarire; comunque, l’attivazione cronica del sistema immunitario dovuta alla persistenza degli antigeni virali potrebbe promuovere la rapida proliferazione delle cellule CD8+ causando l’erosione dei telomeri e determinando il fenotipo immunosenescente. Conclusioni Nel complesso questi studi suggeriscono che la lunghezza dei telomeri, l’output timico e l’analisi immunofenotipica rappresentano dei marcatori utili per monitorare l’invecchiamento prematuro e l’immunosenescenza. Nei pazienti anziani, il basso output timico e i telomeri corti sono significativamente associati al tumore e potrebbero influenzare la risposta alla chemioterapia. Pertanto, questi marcatori potrebbero essere utili nella popolazione anziana per predire l’insorgenza di neoplasia e pianificare strategie terapeutiche. Nel contesto dell’infezione pediatrica da HIV, il nostro studio indica l’importanza di analizzare, in aggiunta agli esami correnti, come la plasmaviremia HIV e il profilo delle cellule CD4+, la lunghezza del telomero e le sottopopolazioni delle cellule CD8+, al fine di valutare lo stato di invecchiamento prematuro e l’immunosenescenza in questa popolazione ad alto rischio di cancro