Clonal succession after prolonged antiretroviral therapy rejuvenates CD8 T cell responses against HIV-1.

Human immunodeficiency virus 1 (HIV-1) infection is characterized by a dynamic and persistent state of viral replication that overwhelms the host immune system in the absence of antiretroviral therapy (ART). The impact of prolonged treatment on the antiviral efficacy of HIV-1-specific CD8 T cells has nonetheless remained unknown. Here, we used single-cell technologies to address this issue in a cohort of aging individuals infected early during the pandemic and subsequently treated with continuous ART.

Cytokine profile of anti-spike CD4T cells predicts humoral and CD8T cell responses after anti-SARS-CoV-2 mRNA vaccination.

Coordinating immune responses - humoral and cellular - is vital for protection against severe Covid-19. Our study evaluates a multicytokine CD4T cell signature's predictive for post-vaccinal serological and CD8T cell responses. A cytokine signature composed of four cytokines (IL-2, TNF-α, IP10, IL-9) excluding IFN-γ, and generated through machine learning, effectively predicted the CD8T cell response following mRNA-1273 or BNT162b2 vaccine administration.

Age differentially impacts adaptive immune responses induced by adenoviral versus mRNA vaccines against COVID-19.

Adenoviral and mRNA vaccines encoding the viral spike (S) protein have been deployed globally to contain severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Older individuals are particularly vulnerable to severe infection, probably reflecting age-related changes in the immune system, which can also compromise vaccine efficacy. It is nonetheless unclear to what extent different vaccine platforms are impacted by immunosenescence.

Immune response to the recombinant herpes zoster vaccine in people living with HIV over 50 years of age compared to non-HIV age-/gender-matched controls (SHINGR'HIV): a multicenter, international, non-randomized clinical trial study protocol.

Background: The burden of herpes zoster (shingles) virus and associated complications, such as post-herpetic neuralgia, is higher in older adults and has a significant impact on quality of life. The incidence of herpes zoster and post-herpetic neuralgia is increased in people living with HIV (PLWH) compared to an age-matched general population, including PLWH on long-term antiretroviral therapy (ART) with no detectable viremia and normal CD4 counts. PLWH - even on effective ART may- exhibit sustained immune dysfunction, as well as defects in cells involved in the response to vaccines.

Hepatitis B surface antigen reduction is associated with hepatitis B core-specific CD8 T cell quality.

Despite treatment, hepatitis B surface antigen (HBsAg) persists in patients with chronic hepatitis B (CHB), suggesting the likely presence of the virus in the body. CD8 T cell responses are essential for managing viral replication, but their effect on HBsAg levels remains unclear. We studied the traits of activated CD8 T cells and HBV-specific CD8 T cells in the blood of CHB patients undergoing nucleos(t)ide analog (NUC) therapy.

CD8 + T-cell priming is quantitatively but not qualitatively impaired in people with HIV-1 on antiretroviral therapy.

Background: The induction of de novo CD8 + T-cell responses is essential for protective antiviral immunity, but this process is often impaired in people with HIV-1 (PWH). We investigated the extent to which the immune competence of naive CD8 + T cells, a key determinant of priming efficacy, could be preserved or restored in PWH via long-term antiretroviral therapy (ART).

Methods: We used flow cytometry, molecular analyses of gene transcription and telomere length, and a fully validated priming assay to characterize naive CD8 + T cells ex vivo and evaluate the induction of antigen-specific effector/memory CD8 + T cells in vitro , comparing age-matched healthy uninfected donors (HUDs), PWH on ART, and natural HIV-1 controllers (HICs).

Primary role of type I interferons for the induction of functionally optimal antigen-specific CD8 T cells in HIV infection.

Background: CD8 T cells equipped with a full arsenal of antiviral effector functions are critical for effective immune control of HIV-1. It has nonetheless remained unclear how best to elicit such potent cellular immune responses in the context of immunotherapy or vaccination. HIV-2 has been associated with milder disease manifestations and more commonly elicits functionally replete virus-specific CD8 T cell responses compared with HIV-1.

Mechanisms of systemic low-grade inflammation in HIV patients on long-term suppressive antiretroviral therapy: the inflammasome hypothesis.

Objective: We aimed to determine the contribution of inflammasome activation in chronic low-grade systemic inflammation observed in patients with HIV (PWH) on long-term suppressive antiretroviral therapy (ART) and to explore mechanisms of such activation.

Design: Forty-two PWH on long-term suppressive ART (HIV-RNA < 40 copies/ml) were compared with 10 HIV-negative healthy controls (HC).

Methods: Inflammasome activation was measured by dosing mature interleukin (IL)-1β and IL-18 cytokines in patient serum.

Ageing Curtails the Diversity and Functionality of Nascent CD8 T Cell Responses against SARS-CoV-2.

Age-related changes in the immune system are thought to underlie the vulnerability of elderly individuals to emerging viral diseases, such as coronavirus disease 2019 (COVID-19). In this study, we used a fully validated approach to determine how age impacts the generation of CD8 T cell responses against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19. Our data revealed a generalized deficit in the ability of elderly individuals to prime the differentiation of naïve precursors into effector CD8 T cells defined by the expression of interferon (IFN)-γ and the transcription factor T-bet.

Model for predicting age-dependent safety and immunomodulatory effects of STING ligands in non-human primates.

Stimulator of interferon genes (STING) is a cytoplasmic dinucleotide sensor used as an immunomodulatory agent for cancer treatment. The efficacy of the STING ligand (STING-L) against various tumors has been evaluated in mouse models; however, its safety and efficacy in non-human primates have not been reported. We examined the effects of escalating doses of cyclic-di-adenosine monophosphate (c-di-AMP) or cyclic [G (3',5')pA (3',5'p] (3'-3'-cGAMP) administered intramuscularly or intravenously to cynomolgus macaques.

Does Inflammation Contribute to Cancer Incidence and Mortality during Aging? A Conceptual Review.

Aging is associated with chronic low-grade inflammation, cancer incidence and mortality. As inflammation contributes to cancer initiation and progression, one could hypothesize that age-associated chronic low-grade inflammation contributes to the increase in cancer incidence and/or mortality observed during aging. Here, we review the evidence supporting this hypothesis: (1) epidemiological associations between biomarkers of systemic inflammation and cancer incidence and mortality in older people, (2) therapeutic clues suggesting that targeting inflammation could reduce cancer incidence and mortality and (3) experimental evidence from animal models highlighting inflammation as a link between various mechanisms of aging and cancer initiation and progression.

Epitope length variants balance protective immune responses and viral escape in HIV-1 infection.

Cytotoxic T lymphocyte (CTL) and natural killer (NK) cell responses to a single optimal 10-mer epitope (KK10) in the human immunodeficiency virus type-1 (HIV-1) protein p24Gag are associated with enhanced immune control in patients expressing human leukocyte antigen (HLA)-B27:05. We find that proteasomal activity generates multiple length variants of KK10 (4-14 amino acids), which bind TAP and HLA-B27:05. However, only epitope forms ≥8 amino acids evoke peptide length-specific and cross-reactive CTL responses.

Primary immune responses are negatively impacted by persistent herpesvirus infections in older people: results from an observational study on healthy subjects and a vaccination trial on subjects aged more than 70 years old.

Background: Advanced age is accompanied by a decline of immune functions, which may play a role in increased vulnerability to emerging pathogens and low efficacy of primary vaccinations in elderly people. The capacity to mount immune responses against new antigens is particularly affected in this population. However, its precise determinants are not fully understood.

Impaired Priming of SARS-CoV-2-Specific Naive CD8 T Cells in Older Subjects.

Advanced age is associated with severe symptoms and death upon SARS-CoV-2 infection. Virus-specific CD8 T-cell responses have shown to be protective toward critical COVID-19 manifestations, suggesting that suboptimal cellular immunity may contribute to the age-pattern of the disease. The induction of a CD8 T-cell response against an emerging pathogen like SARS-CoV-2 relies on the activation of naive T cells.

Use of a Novel Peptide Welding Technology Platform for the Development of B- and T-Cell Epitope-Based Vaccines.

Peptide vaccines incorporating B- and T-cell epitopes have shown promise in the context of various cancers and infections. These vaccines are relatively simple to manufacture, but more immunogenic formulations are considered a priority. We developed tetrabranched derivatives for this purpose based on a novel peptide welding technology (PWT).

New chimeric TLR7/NOD2 agonist is a potent adjuvant to induce mucosal immune responses.

Background: PRR (Pattern Recognition Receptor) agonists have been widely tested as potent vaccine adjuvants. TLR7 (Toll-Like Receptor 7) and NOD2 (nucleotide-binding oligomerization domain 2) are key innate receptors widely expressed at mucosal levels.

Methods: Here, we evaluated the immunostimulatory properties of a novel hybrid chemical compound designed to stimulate both TLR7 and NOD2 receptors.

The TLR9 ligand CpG ODN 2006 is a poor adjuvant for the induction of de novo CD8 T-cell responses in vitro.

Toll-like receptor 9 (TLR9) agonists have gained traction in recent years as potential adjuvants for the induction of adaptive immune responses. It has nonetheless remained unclear to what extent such ligands can facilitate the priming events that generate antigen-specific effector and/or memory CD8 T-cell populations. We used an established in vitro model to prime naive precursors from human peripheral blood mononuclear cells in the presence of various adjuvants, including CpG ODN 2006, a synthetic oligonucleotide TLR9 ligand (TLR9L).

CTL Clonotypes with Higher TCR Affinity Have Better Ability to Reduce the HIV Latent Reservoir.

The success of the shock and kill strategy for the HIV cure depends both on the reactivation of the latent reservoir and on the ability of the immune system to eliminate infected cells. As latency reversal alone has not shown any impact in the size of the latent reservoir, ensuring that effector CTLs are able to recognize and kill HIV-infected cells could contribute to reservoir reduction. In this study, we investigated which functional aspects of human CTLs are associated with a better capacity to kill HIV-infected CD4 T cells.

Assessing T Lymphocyte Aging Using Telomere Length and Telomerase Activity Measurements in Low Cell Numbers.

As T lymphocytes proliferate and differentiate in vivo or in vitro, their functional capacity can change dramatically. In particular, extensive cell division is often associated with telomere shortening and the onset of cellular senescence, thus impacting the proliferative potential of the cells. Telomere length and integrity represent therefore key molecular markers of the status and aging of the cells.

HIV-mediated immune aging in young adults infected perinatally or during childhood.

Background: HIV-infected patients progressing towards disease present a premature immune aging profile, characterized by the exhaustion of lymphopoiesis. The development of these anomalies may be prevented in young HIV-infected patients owing to their robust immune resources and lymphocyte regeneration capacities.

Methods: An immunomonitoring substudy was designed for young adults aged between 18 and 25 years, living with HIV since childhood included in the national ANRS Co19 COVERTE Cohort.

Phenotypic and Functional Differences between Human Herpesvirus 6- and Human Cytomegalovirus-Specific T Cells.

Human herpesvirus 6 (HHV-6) infects >90% of the population and establishes a latent infection with asymptomatic episodes of reactivation. However, HHV-6 reactivation is associated with morbidity and sometimes mortality in immunocompromised patients. To date, control of the virus in healthy virus carriers and the failure to control it in patients with disease remain poorly understood.