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Introduction: HIV infection causes pathological changes in the natural killer (NK) cell compartment that can be only partially restored by antiretroviral therapy (ART). We investigated NK cells phenotype and function in children with perinatally acquired HIV (PHIV) and long-term viral control (five years) due to effective ART in a multicentre cross-sectional European study (CARMA, EPIICAL consortium). The impact of age at ART start and viral reservoir was also evaluated. Methods: Peripheral blood mononuclear cells (PBMCs) from 40 PHIV who started ART within two years of life (early treated patients (ET), 6 months), with at least five years of HIV-1 suppression ( Results: A significantly higher frequency of [CD56.sup.neg] NK cells was found in LT compared with ET. We further found in LT a positive correlation of [CD56.sup.neg] NK cells with HIV-1 DNA. LT also displayed increased expression of the NKG2D and NKp46 activating receptors and perforin compared with ET. Moreover, [CD107a.sup.+] and [IFN-[gamma].sup.+] frequencies in non-stimulated NK were associated with HIV-1 DNA in LT patients. Finally RNA-Seq analysis showed in LT an up-regulation of genes related to NKactivating pathways and susceptibility to apoptosis compared with ET. Conclusions: We show that early initiation of ART during infancy preserves the NK compartment and is associated with lower HIV-1 reservoir. Such condition persists over adolescence due to long-term viral control achieved through effective ART. Keywords: cohort studies; HIV care continuum; immunology; paediatrics; ARV; viral suppression Additional information may be found under the Supporting Information tab for this article., 1 | INTRODUCTION HIV-1-induced immunological impairment begins during acute infection and is only partially restored in children with perinatally acquired HIV (PHIV) if antiretroviral therapy (ART) is introduced during the [...]

Introduction: Latent tuberculosis infection (LTBI) is a common coinfection in people living with HIV (PWH). How LTBI and HIV exposure in utero influence the development of infant humoral immunity is not well characterized. To address this question, we assessed the relationship between maternal humoral responses in pregnant women with HIV or with HIV/LTBI on humoral responses in infants to BCG vaccination and TB acquisition. Methods: Plasma samples were obtained from mother infant pairs during pregnancy (14-34 wks gestation) and in infants at 12 and 44 wks of age from the IMPAACT P1078 clinical trial. LTBI was established by Interferon gamma release assay (IGRA). Progression to active TB (ATB) disease was observed in 5 women at various times after giving birth. All infants were BCG vaccinated at birth and tested for IGRA at 44 weeks. Mtb (PPD, ESAT6/CFP10, Ag85A, LAM), HIV (GP120), and Influenza (HA) specific IgG, IgM, and IgA were measured in plasma samples using a bead based Luminex assay with Flexmap 3D. Results: In maternal plasma there were no differences in Mtb-specific antibodies or viral antibodies in relation to maternal IGRA status. ATB progressors showed increases in Mtb-specific antibodies at diagnosis compared to study entry. However, when compared to the non-progressors at entry, progressors had higher levels of Ag85A IgG and reduced ESAT6/CFP10 IgG and LAM IgG, IgM, and IgA1. All infants showed a decrease in IgG to viral antigens (HIV GP120 and HA) from 12 to 44 weeks attributed to waning of maternally transferred antibody titers. However, Mtb-specific (PPD, ESAT6/CFP10, Ag85A, and LAM) IgG and IgM increased from 12 to 44 weeks. HIV and HA IgG levels in maternal and 12-week infant plasma were highly correlated, and ESAT6/CFP10 IgG and LAM IgG showed a relationship between maternal and infant Abs. Finally, in the subset of infants that tested IGRA positive at 44 weeks, we observed a trend for lower LAM IgM compared to IGRA- infants at 44 weeks. Discussion: The results from our study raise the possibility that antibodies to LAM are associated with protection from progression to ATB and support further research into the development of humoral immunity against TB through infection or vaccination. [ABSTRACT FROM AUTHOR]

People with HIV (PWH) frequently suffer from Opioid (OP) Use Disorder (OUD). In an investigation of the impact of OUD on underlying immune dysfunction in PWH, we previously reported that OP use exacerbates inflammation in virally controlled PWH followed in the Infectious Diseases Elimination Act (IDEA) Syringe Services Program (SSP). Unexpectedly, Flu vaccination-induced antibody responses in groups with OUD were superior to PWH without OUD. Here, we investigated the profile of 48 plasma biomarkers comprised of TNF and Ig superfamily (SF) molecules known to impact interactions between T and B cells in 209 participants divided into four groups: (1) HIV+OP+, (2) HIV−OP+, (3) HIV+OP−, and (4) HIV−OP−. The differential expression of the top eight molecules ranked by median values in individual Groups 1–3 in comparison to Group 4 was highly significant. Both OP+ groups 1 and 2 had higher co-stimulatory TNF SF molecules, including 4-1BB, OX-40, CD40, CD30, and 4-1BBL, which were found to positively correlate with Flu Ab titers. In contrast, HIV+OP− exhibited a profile dominant in Ig SF molecules, including PDL-2, CTLA-4, and Perforin, with PDL-2 showing a negative correlation with Flu vaccine titers. These findings are relevant to vaccine development in the fields of HIV and OUD. [ABSTRACT FROM AUTHOR]

Post vaccine immunity following COVID-19 mRNA vaccination may be driven by extrinsic, or controllable and intrinsic, or inherent health factors. Thus, we investigated the effects of extrinsic and intrinsic on the peak antibody response following COVID-19 primary vaccination and on the trajectory of peak antibody magnitude and durability over time. Participants in a longitudinal cohort attended visits every 3 months for up to 2 years following enrollment. At baseline, participants provided information on their demographics, recreational behaviors, and comorbid health conditions which guided our model selection process. Blood samples were collected for serum processing and spike antibody testing at each visit. Cross-sectional and longitudinal models (linear-mixed effects models) were generated to assess the relationship between selected intrinsic and extrinsic health factors on peak antibody following vaccination and to determine the influence of these predictors on antibody over time. Following cross-sectional analysis, we observed higher peak antibody titers after primary vaccination in females, those who reported recreational drug use, younger age, and prior COVID-19 history. Following booster vaccination, females and Hispanics had higher peak titers after the 3rd and 4th doses, respectively. Longitudinal models demonstrated that Moderna mRNA-1273 recipients, females, and those previously vaccinated had increased peak titers over time. Moreover, drug users and half-dose Moderna mRNA-1273 recipients had higher peak antibody titers over time following the first booster, while no predictive factors significantly affected post-second booster antibody responses. Overall, both intrinsic and extrinsic health factors play a significant role in shaping humoral immunogenicity after initial vaccination and the first booster. The absence of predictive factors for second booster immunogenicity suggests a more robust and consistent immune response after the second booster vaccine administration. [ABSTRACT FROM AUTHOR]

T follicular helper (Tfh) cells in germinal centers of secondary lymphoid organs are pivotal for B and T cell interactions required for induction of humoral immunity. It has long been debated whether Tfh cells exit from lymph nodes into the blood as circulating Tfh cells. In this issue of the JCI, Vella et al. have taken the bull by the horns and applied considerable technical muscle to answer this question. By analyzing phenotype, transcriptome, epigenetic profile, and T cell receptor clonotype, the authors provide evidence that a subset of cTfh cells do indeed originate in lymph nodes and traffic into the blood via the thoracic duct., A cell type of mysterious origin The center of antibody production lies in lymphoid germinal centers (GCs), the seat of the T follicular helper (Tfh) cell interaction with B cells. [...]

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.sup.+] 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.sup.+] volunteers on cART to investigate [CD4.sup.+] T follicular helper (Tfh) and B cell dynamics by flow cytometry and quantitative imaging analysis. Prior to vaccination, compared with those in HCs, [HIV.sup.+] LNs exhibited an altered follicular architecture, but harbored higher numbers of Tfh cells and increased [IgG.sup.+] 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.sup.+] 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.sup.+] 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., Introduction The introduction of combination antiretroviral therapy (cART) for the treatment of HIV infection has dramatically altered the course of HIV/AIDS, prolonging life span to nearly normal and minimizing the [...]

Introduction: People 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. Methods: The 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. Results: HIV+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. Discussion: Given the association of inflammation with a multitude of adverse health outcomes, our findings merit further investigations to understand the mechanistic pathways involved. [ABSTRACT FROM AUTHOR]

Aging people living with HIV (PWH) frequently manifest impaired antibody (Ab) responses to seasonal flu vaccination which has been attributed to ongoing inflammation and immune activation. We have recently reported a similar scenario in old simian immunodeficiency virus (SIV) infected rhesus macaques (RM) with controlled viremia and have been able to compensate for this deficiency by immunotherapy with interleukin (IL)‐21‐IgFc. To understand the underlying mechanisms of IL‐21‐induced immunomodulation leading to enhanced flu vaccine response in aging and SIV, we have investigated draining lymph node (LN) cells of IL‐21‐treated and ‐untreated animals at postvaccination. We observed IL‐21‐induced proliferation of flu‐specific LN memory CD4 T cells, expansion of B cells expressing IL‐21 receptor (IL‐21R), and modest expansion of T follicular helper cells (Tfh) co‐expressing T‐cell immunoreceptor with Ig and ITIM domains (TIGIT) and DNAX accessory molecule (DNAM‐1). Transcriptional analysis of LN cells of IL‐21‐treated animals revealed significant inhibition of germinal center (GC) Tfh and B‐cell interferon signaling pathways along with enhanced B‐cell development and antigen presentation pathways. We conclude that IL‐21 treatment at the time of flu vaccination in aging SIV‐infected animals modulates the inductive LN GC activity, to reverse SIV‐associated LN Tfh and B‐cell dysfunction. IL‐21 is a potential candidate molecule for immunotherapy to enhance flu vaccine responses in aging PWH who have deficient antibody responses. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

The objectives of this study were to (1) investigate the association between human blood type and COVID-19 in both inpatient and longitudinal populations and (2) identify the association between blood type and severity of COVID-19 via presence of cellular biomarkers of severe infection in hospitalized individuals at our institution in South Florida. This study consisted of (1) a single-center retrospective analysis of 669 out of 2741 COVID-19-positive, screened patients seen from 1 January 2020 until 31 March 2021 at the University of Miami Emergency Department (ED) who tested positive for COVID-19 and had a documented ABO blood type and (2) a longitudinal SARS-CoV-2 immunity study ("CITY") at the University of Miami Miller School of Medicine, consisting of 185 survey participants. In an inpatient setting, blood type appeared to be associated with COVID-19 severity and mortality. Blood type O sustained less risk of COVID-19 mortality, and blood type O- demonstrated less risk of developing COVID-19 pneumonia. Inpatients with O- blood type exhibited less biomarkers of severe infection than did other blood types. In a longitudinal setting, there was no association found between blood type and SARS-CoV-2 infection. [ABSTRACT FROM AUTHOR]

False positive reactive plasmin reagin (RPR) reactivity following a COVID-19 vaccine has been reported, and it is therefore conceivable that individuals who receive frequent coronavirus disease 2019 (COVID-19) vaccinations may exhibit durable RPR responses. Here, we sought to investigate the extent to which repeated mRNA COVID-19 vaccines can elicit chronic false RPR reactivity in a longitudinal cohort. Participants (n = 119) in an IRB-approved (#20201026), longitudinal SARS-CoV-2 cohort study were screened for RPR reactivity via manual RPR card assays. Samples with reactive results underwent additional testing, including follow-on RPR screening at additional timepoints, confirmatory fluorescent treponemal antibody (FTA-ABS) testing and anti-nuclear antibody (ANA) testing. Medical histories were collected. We observed (n = 2) screen-positive RPR results (1.7% [2/119]) following booster vaccination, for which two individuals exhibited chronic, vaccine-induced RPR reactivity for up to 9 months following booster vaccination. Both participants were ANA-negative. It is imperative for clinicians to be mindful of the potential immunologic interference of COVID-19 vaccines with standard infectious disease assays, including RPR testing. Detailed medical histories and clinical contexts, including recent vaccination, should be reviewed prior to proceeding with distressing and invasive workups. [ABSTRACT FROM AUTHOR]