Chronic HIV-infected children suffer from premature aging and aging-related diseases. Viral replication induces an ongoing inflammation process, with the release of pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), the activation of the immune system, and the production of proinflammatory cytokines. Although combined highly active antiretroviral therapy (ART) has significantly modified the natural course of HIV infection, normalization of T and B cell phenotype is not completely achievable; thus, many HIV-infected children display several phenotypical alterations, including higher percentages of activated cells, that favor an accelerated telomere attrition, and higher percentages of exhausted and senescent cells. All these features ultimately lead to the clinical manifestations related to premature aging and comorbidities typically observed in older general population, including non-AIDS-related malignancies. Therefore, even under effective treatment, the premature aging process of HIV-infected children negatively impacts their quality and length of life. This review examines the available data on the impact of HIV and ART on immune and biological senescence of HIV-infected children.

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IntroductionPersistence of HIV‐1, causing chronic immune activation, is a key determinant of premature senescence. Early antiretroviral therapy (ART) has been associated with a reduced HIV‐1 reservoir in children with perinatally acquired HIV‐1 (PHIV), but its impact on the senescence process is an open question. We investigated the association between HIV‐1 reservoir and biological and immune ageing profile in PHIV enrolled in the multicentre cross‐sectional study CARMA (Child and Adolescent Reservoir Measurements on early suppressive ART) conducted within the EPIICAL (Early treated Perinatally HIV Infected individuals: Improving Children's Actual Life) consortium.MethodsBetween September 2017 and June 2018, CARMA enrolled 40 PHIV who started ART before 2 years of age and had undetectable viremia for at least 5 years before sampling date. Samples from 37 children with a median age of 13.8 years were available for this study. HIV‐1 DNA copies on CD4 cells, relative telomere length (marker of cellular senescence) and levels of T‐cell receptor rearrangement excision circle (TREC, marker of thymic output) on CD4 and CD8 cells were quantified by qPCR. Immunological profile was assessed by flow cytometry. Associations between molecular and phenotypic markers, HIV‐1 reservoir and age at ART initiation were explored using a multivariable Poisson regression.ResultsHigher HIV‐1 reservoir was associated (p<0.001) with telomere shortening (incidence rate ratio [IRR] = 0.15 [0.13–0.17]), immunosenescence (CD28–CD57+, IRR = 1.23 [1.21–1.26]) and immunoactivation (CD38+ HLADR+, IRR = 7.29 [6.58–8.09]) of CD4 cells. Late ART initiation (after 6 months of age) correlated with higher HIV‐1 reservoir levels (552 [303–1001] vs. 89 [56–365] copies/106 CD4 cells, p = 0.003) and percentage of CD4 senescent cells (2.89 [1.95–6.31] vs. 1.02 [0.45–2.69, p = 0.047). TREC levels in CD8 cells were inversely associated with HIV‐1 reservoir (IRR = 0.77 [0.76–0.79]) and were significantly lower in late treated PHIV (1128 [486–1671] vs. 2278 [1425–3314], p = 0.042).ConclusionsLater ART initiation is associated with higher HIV‐1 reservoir size, which correlates with increased telomere shortening and senescence of CD4 cells. Timing of ART initiation in infancy has long‐term consequences on the immune and biological ageing profile of children with perinatally acquired HIV‐1.

Besides its canonical role in stabilizing telomeres, telomerase reverse transcriptase (TERT) may promote tumor growth/progression through extra-telomeric functions. Our previous in vitro studies demonstrated that short-term TERT inhibition by BIBR1532 (BIBR), an inhibitor of TERT catalytic activity, negatively impacts cell proliferation and viability via telomeres’ length-independent mechanism. Here we evaluate the anti-proliferative and pro-apoptotic effects of short-term telomerase inhibition in vivo in wild-type (wt) and tert mutant (terthu3430/hu3430; tert−/−) zebrafish embryos, and in malignant human B cells xenografted in casper zebrafish embryos. Short-term Tert inhibition by BIBR in wt embryos reduced cell proliferation, induced an accumulation of cells in S-phase and ultimately led to apoptosis associated with the activation of DNA damage response; all these effects were unrelated to telomere shortening/dysfunction. BIBR treatment showed no effects in tert−/− embryos. Xenografted untreated malignant B cells proliferated in zebrafish embryos, while BIBR pretreated cells constantly decreased and were significantly less than those in the controls from 24 to up to 72 h after xenotransplantation. Additionally, xenografted tumor cells, treated with BIBR prior- or post-transplantation, displayed a significant higher apoptotic rate compared to untreated control cells. In conclusion, our data demonstrate that short-term telomerase inhibition impairs proliferation and viability in vivo and in human malignant B cells xenografted in zebrafish, thus supporting therapeutic applications of TERT inhibitors in human malignancies.

Coelimycin P1 and argimycins P are two types of polyketide alkaloids produced by Streptomyces coelicolor and Streptomyces argillaceus, respectively. Their biosynthesis pathways share some early steps that render very similar aminated polyketide chains, diverging the pathways afterwards. By F I G U R E 2 Analysis of PKS modules and biosynthesis steps of coelimycin P1 and argimycins P. (A) coelimycin P1, (B) argimycins P and (C) proposed biosynthesis of hybrid argimycin compounds. ARP, argimycins P; CPK, coelimycin P1.