Biological aging is associated with immune activation (IA) and declining immunity due to systemic inflammation. It is widely accepted that HIV infection causes persistent IA and premature immune senescence despite effective antiretroviral therapy and virologic suppression; however, the effects of combined HIV infection and aging are not well defined. Here, we assessed the relationship between markers of IA and inflammation during biological aging in HIV-infected and -uninfected populations. Antibody response to seasonal influenza vaccination was implemented as a measure of immune competence and relationships between IA, inflammation, and antibody responses were explored using statistical modeling appropriate for integrating high-dimensional data sets. Our results show that markers of IA, such as coexpression of HLA antigen D related (HLA-DR) and CD38 on CD4 ⁺ T cells, exhibit strong associations with HIV infection but not with biological age. Certain variables that showed a strong relationship with aging, such as declining naive and CD38 ⁺ CD4 and CD8 ⁺ T cells, did so regardless of HIV infection. Interestingly, the variable of biological age was not identified in a predictive model as significantly impacting vaccine responses in either group, while distinct IA and inflammatory variables were closely associated with vaccine response in HIV-infected and -uninfected populations. These findings shed light on the most relevant and persistent immune defects during virological suppression with antiretroviral therapy.

HIV infection changes the lymph node (LN) tissue architecture, potentially impairing the immunologic response to antigenic challenge. The tissue-resident immune cell dynamics in virologically suppressed HIV⁺ patients on combination antiretroviral therapy (cART) are not clear. We obtained LN biopsies before and 10 to 14 days after trivalent seasonal influenza immunization from healthy controls (HCs) and HIV⁺ volunteers on cART to investigate CD4⁺ T follicular helper (Tfh) and B cell dynamics by flow cytometry and quantitative imaging analysis. Prior to vaccination, compared with those in HCs, HIV⁺ LNs exhibited an altered follicular architecture, but harbored higher numbers of Tfh cells and increased IgG⁺ follicular memory B cells. Moreover, Tfh cell numbers were dependent upon preservation of the follicular dendritic cell (FDC) network and were predictive of the magnitude of the vaccine-induced IgG responses. Interestingly, postvaccination LN samples in HIV⁺ participants had significantly (P = 0.0179) reduced Tfh cell numbers compared with prevaccination samples, without evidence for peripheral Tfh (pTfh) cell reduction. We conclude that influenza vaccination alters the cellularity of draining LNs of HIV⁺ persons in conjunction with development of antigen-specific humoral responses. The underlying mechanism of Tfh cell decline warrants further investigation, as it could bear implications for the rational design of HIV vaccines.

Background: HIV infection induces inflammaging and chronic immune activation (IA), which are negatively associated with protective humoral immunity. Similar to HIV, aging is also associated with increased inflammaging and IA. The metabolic requirements of B cell responses in HIV infected (HIV+) individuals are not known, although metabolic abnormalities have been reported in these individuals. How these metabolic abnormalities are exacerbated by aging is also not known. Methods: B cells were isolated by magnetic sorting from the blood of young and elderly HIV + individuals, as well as from the blood of age-matched healthy controls. We evaluated the composition of the B cell pool by flow cytometry, the expression of RNA for pro-inflammatory and metabolic markers by qPCR and their metabolic status using a Seahorse XFp extracellular flux analyzer. Results: In this study we have evaluated for the first time the metabolic phenotype of B cells from young and elderly HIV + individuals as compared to those obtained from age-matched healthy controls. Results show that the B cell pool of HIV + individuals is enriched in pro-inflammatory B cell subsets, expresses higher levels of RNA for pro-inflammatory markers and is hyper-metabolic, as compared to healthy controls, and more in elderly versus young HIV + individuals, suggesting that this higher metabolic phenotype of B cells is needed to support B cell IA. We have identified the subset of Double Negative (DN) B cells as the subset mainly responsible for this hyper-inflammatory and hyper-metabolic profile. Conclusions: Our results identify a relationship between intrinsic B cell inflammation and metabolism in HIV + individuals and suggest that metabolic pathways in B cells from HIV + individuals may be targeted to reduce inflammaging and IA and improve B cell function and antibody responses.

Objective: Sexual minority men (e.g., gay, bisexual, and other men who have sex with men) experience stigma and sexual minority stress, which are theorized to drive negative health outcomes. Sexual minority men with treated HIV display persistent immune dysregulation, which could be amplified by sexual minority stress responses to potentiate cellular aging. Methods: This cross-sectional study included 52 sexual minority men living with HIV who had undetectable viral load (<40 copies/mL) and biologically confirmed recent methamphetamine use. Participants completed measures assessing sexual minority stress and openness about sexual minority status (i.e., outness). DNA methylation–derived outcomes included the following: the extrinsic epigenetic age acceleration clock, telomere length, naive CD4+ T-helper cells, and naive CD8+ T-cytotoxic/suppressor cells. Results: After adjusting for negative affect and recent stimulant use, higher sexual minority stress was associated with a faster extrinsic epigenetic age acceleration clock ( β = 0.29, p = .030), shorter telomere length ( β = −0.43, p = .002), and fewer naive CD4+ (β = −0.57, p < .001) and naive CD8+ T cells ( β = −0.57, p < .001). Greater outness was associated with higher naive CD4+ ( β = 0.32, p = .030) and naive CD8+ T cells ( β = 0.38, p = .008) as well as lower plasma interleukin 6 ( β = −0.33, p = .027). Conclusions: Sexual minority stress processes are associated with markers of cellular aging and inflammation in methamphetamine-using sexual minority men living with HIV. Longitudinal research should elucidate biobehavioral mechanisms linking sexual minority stress processes with accelerated cellular aging in those with and without HIV.

Natural aging and HIV infection are associated with chronic low-grade systemic inflammation, immune senescence, and impaired antibody responses to vaccines such as the influenza (flu) vaccine. We investigated the role of IL-21, a CD4 ⁺ T follicular helper cell (Tfh) regulator, on flu vaccine antibody response in nonhuman primates (NHPs) in the context of age and controlled SIV mac239 infection. Three doses of the flu vaccine with or without IL-21–IgFc were administered at 3-month intervals in aged SIV ⁺ NHPs following virus suppression with antiretroviral therapy. IL-21–treated animals demonstrated higher day 14–postboost antibody responses, which associated with expanded CD4 ⁺ T central memory cells and peripheral Tfh–expressing (pTfh–expressing) T cell immunoreceptor with Ig and ITIM domains (TIGIT), expanded activated memory B cells, and contracted CD11b ⁺ monocytes. Draining lymph node (LN) tissue from IL-21–treated animals revealed direct association between LN follicle Tfh density and frequency of circulating TIGIT ⁺ pTfh cells. We conclude that IL-21 enhances flu vaccine–induced antibody responses in SIV ⁺ aged rhesus macaques (RMs), acting as an adjuvant modulating LN germinal center activity. A strategy to supplement IL-21 in aging could be a valuable addition in the toolbox for improving vaccine responses in an aging HIV ⁺ population.

Metabolic changes represent the most common sign of aging and lead to increased risk of developing diseases typical of old age. Age-associated metabolic changes, such as decreased insulin sensitivity, decreased mitochondrial function, and dysregulated nutrient uptake, fuel the low-grade chronic systemic inflammation, known as inflammaging, a leading cause of morbidity and mortality, linked to the development of several diseases of old age. How aging affects the metabolic phenotype of immune cells, and B cells in particular, is not well known and is under intensive investigation by several groups. In this study, we summarized the few published results linking intrinsic B-cell metabolism and B-cell function in different groups of young and elderly individuals: healthy, with type-2 diabetes mellitus, or with HIV infection. Although preliminary, these results suggest the intriguing possibility that metabolic pathways can represent potential novel therapeutic targets to reduce inflammaging and improve humoral immunity.