Size of HIV‐1 reservoir is associated with telomere shortening and immunosenescence in early‐treated European children with perinatally acquired HIV‐1

Abstract

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.

Progress Note 2024: Curing HIV; Not in My Lifetime or Just Around the Corner?

“…While there is optimism regarding the potential of combination approaches, it is important to acknowledge that a scalable, clinically well-tolerated therapeutic strategy to either cure or control HIV in the absence of ART is unlikely to occur in the same timescale as has been proposed to end the HIV epidemic (ie, by 2030) [ 6 , 8 ]. As such, an emerging area of concern is to address how age-related perturbations in immune function and HIV-associated immunosenescence [ 162 – 164 ] intersect with the maintenance of infected cells during long-term ART [ 165 ], with the risk of co-morbidities [ 166 - 168 ], and with responsiveness to immune-based cure strategies [ 169 – 171 ]. Moreover, a portfolio of experimental and FDA-approved drugs are under investigation for their ability to either eliminate (ie, senolytics) or alter the function (ie, senomorphic) of senescent cells, including Bcl-2 inhibitors (Venetoclax), JAK1/JAK2 inhibitors (ruxolitinib), mTOR inhibitors (rapamycin), and tyrosine kinase inhibitors (dasatinib) among others [ 172 , 173 ]; however, further study is required to evaluate these agents for their utility in attenuating or reversing HIV-induced immunosenescence and affecting HIV persistence.…”

Factors Associated with Periodontitis in Patients with and without HIV

“…As already mentioned, periodontitis is a chronic inflammatory disease modulated by the immune system that can be associated with a series of risk factors, similar to those shared by aging. Additionally, chronic medication use, comorbidities, immunosenescence, and alteration of the inflammatory and immune responses resulting from aging can influence the onset and progression of periodontitis [ 38 , 39 ]. In our sample, it was possible to observe a significant correlation between periodontitis and older age (OR A = 4.674).…”

“…Furthermore, studies have shown the influence of HIV and antiretroviral medication on accelerating the aging process in people living with HIV. The mechanisms by which HIV can influence accelerated immunosenescence in young individuals can be explained by chronic immune activation, high profile of inflammation played by B cells, replicative senescence of CD4 and CD8 T-cells, frequencies of naïve cells, and the innate immune response presented by infected individuals [ 39 , 49 ].…”

“…Some viral proteins such as Nef, Tat, or Vpr can induce T-cell apoptosis, interfere with autophagy, and promote cell aging. HIV infection itself causes depletion of mitochondrial DNA levels, which induces the production of reactive oxygen species and deregulates the methylome in several locations [ 13 , 33 , 39 ].…”

CD8+ T Cell Senescence: Lights and Shadows in Viral Infections, Autoimmune Disorders and Cancer

“…Indeed, HIV-1 persistence contributes to a premature immune-senescence [ 36 ], often exacerbated by CMV coinfection [ 37 , 38 ], and a higher susceptibility to age-associated multi-morbidity [ 39 ]. Interestingly, children with perinatally acquired HIV-1 (PHIV) also face a premature T cell senescence that could be limited by an early administration of ART, which prevents viremia explosion [ 40 , 41 ].…”