Paediatric HIV infection in the 'omics era: defining transcriptional signatures of viral control and vaccine responses

Modern technologies and their increased accessibility have shifted 'benchtop' medical research to the larger dimension of 'omics. The huge amount of data derived from gene expression and sequencing experiments has propelled physicians, basic scientists and bioinformaticians towards a common goal to transform 'big data' into predictive constructs that are readily available and will offer clinical utility. Although most of the studies available in the literature have been performed on healthy subjects and in peripheral blood mononuclear cells (PBMC), which are a heterogenous and extremely variable pool of cells, scientists are now trying to address mechanistic questions in purified cell subsets in pathological conditions. In the field of HIV, few attempts have been made to comprehensively evaluate gene-expression profiles of infected patients with different disease status. With the view of discovering a path towards remission or viral eradication, perinatally HIV-infected children represent a unique model. In fact the well-defined time of infection and the resulting opportunity to start early treatment, thereby generating a smaller size of viral reservoir and a more intact immune system, allow for investigation of therapeutic strategies to defeat the virus. In this scenario, 'transcriptomic' or gene expression technologies and supporting bioinformatics applications need to be strategically integrated to provide novel information about immune correlates of virus control following treatment interruption. Here we review modern techniques for gene expression analysis and discuss the best transcriptomic strategies applicable to the field of functional cure in paediatric HIV infection

Opioids exacerbate inflammation in people with well-controlled HIV

IntroductionPeople with HIV (PWH) are known to have underlying inflammation and immune activation despite virologic control. Substance use including opioid dependence is common in this population and is associated with increased morbidity and reduced lifespan. The primary objective of the present study termed opioid immunity study (OPIS), was to investigate the impact of chronic opioids in PWH.MethodsThe study recruited people with and without HIV who had opioid use disorder (OUD). Study participants (n=221) were categorized into four groups: HIV+OP+, n=34; HIV-OP+, n=66; HIV+OP-, n=55 and HIV-OP-, n=62 as controls. PWH were virally suppressed on ART and those with OUD were followed in a syringe exchange program with confirmation of OP use by urine drug screening. A composite cytokine score was developed for 20 plasma cytokines that are linked to inflammation. Cellular markers of immune activation (IA), exhaustion, and senescence were determined in CD4 and CD8 T cells. Regression models were constructed to examine the relationships of HIV status and opioid use, controlling for other confounding factors.ResultsHIV+OP+ participants exhibited highest inflammatory cytokines and cellular IA, followed by HIV-OP+ for inflammation and HIV+OP- for IA. Inflammation was found to be driven more by opioid use than HIV positivity while IA was driven more by HIV than opioid use. In people with OUD, expression of CD38 on CD28-CD57+ senescent-like T cells was elevated and correlated positively with inflammation.DiscussionGiven the association of inflammation with a multitude of adverse health outcomes, our findings merit further investigations to understand the mechanistic pathways involved

HIV and Aging in the Era of ART and COVID-19

Our understanding of HIV/AIDS has been reframed during the recent past because the use of novel antiretroviral therapy has enabled clinicians and patients to control the progression of the disease. This supplement provides an overview of the HIV and Aging in the Era of ART and COVID-19, a virtual symposium held on February 8-9, 2021, organized by the Miami Center for AIDS Research along with articles contributed by some of the speakers and members of the organizing committee and presentations by junior investigators

Interleukin-21 and T follicular helper cells in HIV infection: research focus and future perspectives

Interleukin (IL)-21 is a member of the γ chain-receptor cytokine family along with IL-2, IL-4, IL-7, IL-9, and IL-15. The effects of IL-21 are pleiotropic, owing to the broad cellular distribution of the IL-21 receptor. IL-21 is secreted by activated CD4 T cells and natural killer T cells. Within CD4 T cells, its secretion is restricted mainly to T follicular helper (Tfh) cells and Th17 cells to a lesser extent. Our research focus has been on the role of IL-21 and more recently of Tfh in immunopathogenesis of HIV infection. This review focuses on first the influence of IL-21 in regulation of T cell, B cell, and NK cell responses and its immunotherapeutic potential in viral infections and as a vaccine adjuvant. Second, we discuss the pivotal role of Tfh in generation of antibody responses in HIV-infected persons in studies using influenza vaccines as a probe. Lastly, we review data supporting ability of HIV to infect Tfh and the role of these cells as reservoirs for HIV and their contribution to viral persistence

Metabolic phenotype of B cells from young and elderly HIV individuals

Abstract 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

Role of IL-21 and IL-21 Receptor on B Cells in HIV Infection

Interleukin (IL)-21 is a member of a family of cytokines which includes IL-2, IL-4, IL-7, IL-9 and IL-15 all of which utilize a common γ chain in their individual receptor complexes for delivering intracellular signals in their target cells. IL-21 is produced by CD4(+) T cells, in particular T follicular helper cells, and is critically important in the regulation and maintenance of T cells and B cells in innate and adaptive immunity. Effects of IL-21 are pleiotropic, owing to the broad cellular distribution of the IL-21 receptor and it plays a critical role in T cell-dependent and independent human B cell differentiation for generating humoral immune responses. This chapter reviews current knowledge about the importance of IL-21 and IL-21 receptor interaction in human B cell responses, immune defects of B cells and IL-21 in HIV infection and the potential applicability of IL-21 in vaccines/immunotherapeutic approaches to augment relevant immune responses

Serosurvey of Immunity to Monkeypox (Mpox) Virus Antigens in People Living with HIV in South Florida

Mpox is an infectious disease caused by the monkeypox virus (MPXV) belonging to the Orthopoxvirus (OPXV) genus, which includes smallpox and vaccinia virus (VACV). A global mpox outbreak which began in May 2022 has infected more than 88,000 people. VACV-based vaccines provide protection against mpox disease but complicate the use of serological assays for disease surveillance. We tested the reactivity of serum IgG from Modified Vaccinia Ankara-Bavarian Nordic (MVA-BN)-vaccinated (n = 12) and convalescent mpox-infected (n = 5) individuals and uninfected, non-vaccinated controls (n = 32) to MPXV/VACV proteins A27, A29, A30, A35, B16, B21, C19, D6, E8, H3, I1, and L1. Using a subset of MPXV antigen-based assays (A35, B16, E8, H3, and I1), we conducted a mpox antibody survey of serum from 214 individuals, including 117 (54.7%) people with HIV (PWH) collected between June 2022 and January 2023, excluding individuals who reported recent mpox vaccination or infection, and 32 young, pre-pandemic controls. The convalescent sera reacted strongly to most tested antigens. Vaccine sera responses were limited to A35, E8, H3, and I1. IgG antibody to E8 was markedly elevated in all vaccinated individuals. B16 IgG showed high sensitivity (100% [95% CI: 56.55–100.0%]) and specificity (91.67% [64.61–99.57%]) for distinguishing infection from MVA-BN vaccination, while E8 IgG showed 100% [75.75–100] sensitivity and 100% [79.61–100] specificity for detecting and distinguishing vaccinated individuals from controls. We identified 11/214 (5.1%) recent serum samples and 1/32 (3.1%) young, pre-pandemic controls that were seropositive for ≥2 MPXV antibodies, including 6.8% of PWH. Seropositivity was 10/129 (7.8%) among males compared to 1/85 (1.2%) among females. Our findings provide insight into the humoral immune response to mpox and demonstrate the usefulness of inexpensive, antigen-based serosurveillance in identifying asymptomatic or unreported infections

Role of IL-21 and IL-21 receptor on B cells in HIV infection

Interleukin (IL)-21 is a member of a family of cytokines that includes IL-2, IL-4, IL-7, IL-9, and IL-15, all of which utilize a common γ chain in their individual receptor complexes for delivering intracellular signals in their target cells. IL-21 is produced by CD4+ T-cells, in particular follicular T-helper cells, and is critically important in the regulation and maintenance of T cells and B cells in innate and adaptive immunity. The effects of IL-21 are pleiotropic because of the broad cellular distribution of the IL-21 receptor, and it plays a critical role in T cell-dependent and -independent human B cell differentiation for generating humoral immune responses. This article reviews the current knowledge about the importance of IL-21 and IL-21 receptor interaction in human B cell responses, immune defects of B cells and IL-21 in HIV infection, and the potential applicability of IL-21 in vaccines/immunotherapeutic approaches to augment relevant immune responses

Effects of Aging on Metabolic Characteristics of Human B Cells

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

T Follicular Helper Cells and B Cell Dysfunction in Aging and HIV-1 Infection

T follicular helper (Tfh) cells are a subset of CD4 T cells that provide critical signals to antigen-primed B cells in germinal centers to undergo proliferation, isotype switching, and somatic hypermutation to generate long-lived plasma cells and memory B cells during an immune response. The quantity and quality of Tfh cells therefore must be tightly controlled to prevent immune dysfunction in the form of autoimmunity and, on the other hand, immune deficiency. Both Tfh and B cell perturbations appear during HIV infection resulting in impaired antibody responses to vaccines such as seasonal trivalent influenza vaccine, also seen in biologic aging. Although many of the HIV-associated defects improve with antiretroviral therapy (ART), excess immune activation and antigen-specific B and T cell responses including Tfh function are still impaired in virologically controlled HIV-infected persons on ART. Interestingly, HIV infected individuals experience increased risk of age-associated pathologies. This review will discuss Tfh and B cell dysfunction in HIV infection and highlight the impact of chronic HIV infection and aging on Tfh–B cell interactions