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Abstract Long-term control of viral replication relies on the efficient differentiation of memory T cells into effector T cells during secondary immune responses. Recent findings have identified T cell precursors for both memory and exhausted T cells, suggesting the existence of progenitor-like effector T cells. These cells can persist without antigenic challenge but expand and acquire effector functions upon recall immune responses. In this study, we demonstrate that the combination of SLAMF7 with either CD27 or TCF-1 effectively identifies progenitor-like effector CD8 T cells, while SLAMF7 with GPR56 or TOX defines effector CD8 T cells. These markers allow for the clear segregation of these distinct cell subsets. SLAMF7+ CD8T cells are dynamically modulated during viral infections, including HIV, HCV, CMV, and SARS-CoV-2, as well as during aging. We further characterize the SLAMF7 signature at both phenotypic and transcriptional levels. Notably, during aging, the SLAMF7 pathway becomes dysregulated, resulting in persistent phosphorylation of STAT1. Additionally, SLAMF7 ligation in the presence of IL-15 induces TCF-1 expression, which promotes the homeostatic proliferation of progenitor-like effector CD8 T cells.

Summary: Background: Among people living with HIV-1 (PHIV), immunological non-responders (INR) experience incomplete immune recovery despite suppressive antiretroviral treatment (ART), facing more severe non-AIDS events than immunological responders (IR) due to higher chronic immune activation and inflammation (cIA/I). We analyzed the HIV-1 reservoir and immunometabolism in monocytes as a source of cIA/I. Methods: Cross-sectional study in which 110 participants were enrolled: 25 treatment-naïve; 35 INR; 40 IR; and 10 healthy controls. Cell-associated HIV-1-DNA (HIV-DNA) and -RNA (HIV-RNA) were measured in FACS-isolated monocytes using digital droplet PCR. Intact, 5′ deleted, and 3′ deleted proviruses were quantified by the intact proviral DNA assay. Systemic inflammation, monocyte immunophenotype, and immunometabolism were characterized by immunoassays, flow cytometry, and real-time cellular bioenergetics measurements, respectively. Findings: Monocytes from INR harbor higher HIV-RNA and HIV-DNA levels than IR. HIV-RNA was found in 14/21 treatment-naïve [2512 copies/106 TBP (331–4666)], 17/33 INR [240 (148–589)], and 15/28 IR [144 (15–309)], correlating directly with sCD163, IP-10, GLUT1high cells and glucose uptake, and inversely with the CD4+/CD8+ ratio. HIV-DNA was identified in all participants with detectable HIV-RNA, with intact provirus in 9/12 treatment-naïve [13 copies/106 monocytes (7–44)], 8/14 INR [46 (18–67)], and 9/13 IR [9 (7–24)]. INR presented glucose metabolism alterations and mitochondrial impairment; decreased coupling efficiency and BHI, and increased mitochondrial dysfunction inversely correlating with the CD4+/CD8+ ratio. Interpretation: HIV-RNA, more than HIV-DNA, in monocytes and their altered metabolism are factors associated with the higher cIA/I that characterize INR. Funding: This work was supported by the European Regional Development Fund, ISCIII, grant PI20/01646. Other funding sources: Instituto de Salud Carlos III through the Subprogram Miguel Servet (CP19/00159) to AGV, PFIS contracts (FI19/00304) to EMM, (FI21/00165) to ASA, and (FI19/00083) to CGC, and a mobility grant (MV21/00103) to EMM, from the Ministerio de Ciencia e Innovación, Spain. AJM was granted by a CSL Centenary Award.

Plasma cytokine levels were quantified among 30 persons with HIV (PWH) identified as elite controllers (15 transient controllers [studied a median of 1.38 years before losing viral control] and 15 persistent controllers). Thirty antiretroviral therapy (ART)-naive PWH, 30 ART-treated PWH with undetectable viremia, and 30 HIV-uninfected controls also were studied. Higher levels of cytokines were recognized among PWH than among controls, with EC displaying the highest levels. Elevated levels of IP-10 and MIG were identified among transient controllers as predictors of the loss of viral control. These findings offer feasible biomarkers for predicting virologic outcome and loss of control in EC.

[This corrects the article DOI: 10.1371/journal.pone.0269875.].

Summary: Some HIV controllers experience immunologic progression with CD4+ T cell decline. We aimed to identify genetic factors associated with CD4+ T cell lost in HIV controllers. A total of 561 HIV controllers were included, 442 and 119 from the International HIV controllers Study Cohort and the Swiss HIV Cohort Study, respectively. No SNP or gene was associated with the long-term non-progressor HIV spontaneous control phenotype in the individual GWAS or in the meta-analysis. However, SNPs previously associated with natural HIV control linked to HLA-B (rs2395029 [p = 0.005; OR = 1.70], rs59440261 [p = 0.003; OR = 1.78]), MICA (rs112243036 [p = 0.011; OR = 1.45]), and PSORS1C1 loci (rs3815087 [p = 0.017; OR = 1.39]) showed nominal association with this phenotype. Genetic factors associated with the long-term HIV controllers without risk of immunologic progression are those previously related to the overall HIV controller phenotype.

Summary: Background: Plasmacytoid dendritic cells (pDCs) sense viral and bacterial products through Toll-like receptor (TLR)-7 and -9 and translate this sensing into Interferon-α (IFN-α) production and T-cell activation. The understanding of the mechanisms involved in pDCs stimulation may contribute to HIV-cure immunotherapeutic strategies. The objective of the present study was to characterize the immunomodulatory effects of TLR agonist stimulations in several HIV-1 disease progression phenotypes and in non HIV-1 infected donors. Methods: pDCs, CD4 and CD8 T-cells were isolated from 450 ml of whole blood from non HIV-1 infected donors, immune responders (IR), immune non responders (INR), viremic (VIR) and elite controller (EC) participants. pDCs were stimulated overnight with AT-2, CpG-A, CpG-C and GS-9620 or no stimuli. After that, pDCs were co-cultured with autologous CD4 or CD8 T-cells and with/without HIV-1 (Gag peptide pool) or SEB (Staphylococcal Enterotoxin B). Cytokine array, gene expression and deep immunophenotyping were assayed. Findings: pDCs showed an increase of activation markers levels, interferon related genes, HIV-1 restriction factors and cytokines levels after TLR stimulation in the different HIV-disease progression phenotypes. This pDC activation was prominent with CpG-C and GS-9620 and induced an increase of HIV-specific T-cell response even in VIR and INR comparable with EC. This HIV-1 specific T-cell response was associated with the upregulation of HIV-1 restriction factors and IFN-α production by pDC. Interpretation: These results shed light on the mechanisms associated with TLR-specific pDCs stimulation associated with the induction of a T-cell mediated antiviral response which is essential for HIV-1 eradication strategies. Funding: This work was supported by Gilead fellowship program, the Instituto de Salud Carlos III (Fondo Europeo de Desarrollo Regional, FEDER, “a way to make Europe”) and the Red Temática de Investigación Cooperativa en SIDA and by the Spanish National Research Council (CSIC).

Abstract Background Long-Term Non-Progressors (LTNPs) are untreated Human Immunodeficiency virus type 1 (HIV-1) infected individuals able to control disease progression for prolonged periods. However, the LTNPs status is temporary, as viral load increases followed by decreases in CD4 + T-cell counts. Control of HIV-1 infection in LTNPs viremic controllers, have been associated with effective immunodominant HIV-1 Gag-CD8 + T-cell responses restricted by protective HLA-B alleles. Individuals carrying HLA-B*14:02 control HIV-1 infection is related to an immunodominant Env-CD8 + T-cell response. Limited data are available on the contribution of HLA-B*14:02 CD8 + T -cells in LTNPs. Results In this study, we performed a virological and immunological detailed analysis of an HLA-B*14:02 LNTP individual that lost viral control (LVC) 27 years after HIV-1 diagnosis. We analysed viral evolution and immune escape in HLA-B*14:02 restricted CD8 + T -cell epitopes and identified viral evolution at the Env-EL9 epitope selecting the L592R mutation. By IFN-γ ELISpot and immune phenotype, we characterized HLA- B*14:02 HIV-1 CD8 + T cell responses targeting, Gag-DA9 and Env-EL9 epitopes before and after LVC. We observed an immunodominant response against the Env-EL9 epitope and a decreased of the CD8 T + cell response over time with LVC. Loss of Env-EL9 responses was concomitant with selecting K588R + L592R mutations at Env-EL9. Finally, we evaluated the impact of Env-EL9 escape mutations on HIV-1 infectivity and Env protein structure. The K588R + L592R escape variant was directly related to HIV-1 increase replicative capacity and stability of Env at the LVC. Conclusions These findings support the contribution of immunodominant Env-EL9 CD8 + T-cell responses and the imposition of immune escape variants with higher replicative capacity associated with LVC in this LNTP. These data highlight the importance of Env-EL9 specific-CD8 + T-cell responses restricted by the HLA-B*14:02 and brings new insights into understanding long-term HIV-1 control mediated by Env mediated CD8 + T-cell responses.

The COVID-19 pandemic represents a valuable opportunity to carry out cohort studies that allow us to advance our knowledge on pathophysiological mechanisms of neuropsychiatric diseases. One of these opportunities is the study of the relationships between inflammation, brain development and an increased risk of suffering neuropsychiatric disorders. Based on the hypothesis that neuroinflammation during early stages of life is associated with neurodevelopmental disorders and confers a greater risk of developing neuropsychiatric disorders, we propose a cohort study of SARS-CoV-2-infected pregnant women and their newborns. The main objective of SIGNATURE project is to explore how the presence of prenatal SARS-CoV-2 infection and other non-infectious stressors generates an abnormal inflammatory activity in the newborn. The cohort of women during the COVID-19 pandemic will be psychological and biological monitored during their pregnancy, delivery, childbirth and postpartum. The biological information of the umbilical cord (foetus blood) and peripheral blood from the mother will be obtained after childbirth. These samples and the clinical characterisation of the cohort of mothers and newborns, are tremendously valuable at this time. This is a protocol report and no analyses have been conducted yet, being currently at, our study is in the recruitment process step. At the time of this publication, we have identified 1,060 SARS-CoV-2 infected mothers and all have already given birth. From the total of identified mothers, we have recruited 537 SARS-COV-2 infected women and all of them have completed the mental health assessment during pregnancy. We have collected biological samples from 119 mothers and babies. Additionally, we have recruited 390 non-infected pregnant women.

BackgroundCoronavirus-19 (COVID-19) disease is driven by an unchecked immune response to the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus which alters host mitochondrial-associated mechanisms. Compromised mitochondrial health results in abnormal reprogramming of glucose metabolism, which can disrupt extracellular signalling. We hypothesized that examining mitochondrial energy-related signalling metabolites implicated in host immune response to SARS-CoV-2 infection would provide potential biomarkers for predicting the risk of severe COVID-19 illness.MethodsWe used a semi-targeted serum metabolomics approach in 273 patients with different severity grades of COVID-19 recruited at the acute phase of the infection to determine the relative abundance of tricarboxylic acid (Krebs) cycle-related metabolites with known extracellular signaling properties (pyruvate, lactate, succinate and α-ketoglutarate). Abundance levels of energy-related metabolites were evaluated in a validation cohort (n=398) using quantitative fluorimetric assays.ResultsIncreased levels of four energy-related metabolites (pyruvate, lactate, a-ketoglutarate and succinate) were found in critically ill COVID-19 patients using semi-targeted and targeted approaches (p

The immune factors associated with impaired SARS-CoV-2 vaccine response in elderly people are mostly unknown. We studied individuals older than 60 and younger than 60 years, who had been vaccinated with SARS-CoV-2 BNT162b2 mRNA, before and after the first and second dose. Aging was associated with a lower anti–RBD IgG levels and a decreased magnitude and polyfunctionality of SARS-CoV-2–specific T cell response. The dramatic decrease in thymic function in people > 60 years, which fueled alteration in T cell homeostasis, and their lower CD161+ T cell levels were associated with decreased T cell response 2 months after vaccination. Additionally, deficient DC homing, activation, and TLR-mediated function, along with a proinflammatory functional profile in monocytes, were observed in the > 60-year-old group, which was also related to lower specific T cell response after vaccination. These findings might be relevant for the improvement of the current vaccination strategies and for the development of new vaccine prototypes.

Abstract Between 15% and 30% of HIV‐infected subjects fail to increase their CD4+ T‐cell counts despite continuous viral suppression (immunological nonresponders [INRs]). These subjects have a higher morbidity and mortality rate, but there are no effective treatments to reverse this situation so far. This study used data from an interrupted phase I/II clinical trial to evaluate safety and immune recovery after INRs were given four infusions, at baseline and at weeks 4, 8, and 20, with human allogeneic mesenchymal stromal cells from adipose tissue (Ad‐MSCs). Based on the study design, the first 5 out of 15 INRs recruited received unblinded Ad‐MSC infusions. They had a median CD4+ nadir count of 16/μL (range, 2‐180) and CD4+ count of 253 cells per microliter (171‐412) at baseline after 109 (54‐237) months on antiretroviral treatment and 69 (52‐91) months of continuous undetectable plasma HIV‐RNA. After a year of follow‐up, an independent committee recommended the suspension of the study because no increase of CD4+ T‐cell counts or CD4+/CD8+ ratios was observed. There were also no significant changes in the phenotype of different immunological lymphocyte subsets, percentages of natural killer cells, regulatory T cells, and dendritic cells, the inflammatory parameters analyzed, and cellular associated HIV‐DNA in peripheral blood mononuclear cells. Furthermore, three subjects suffered venous thrombosis events directly related to the Ad‐MSC infusions in the arms where the infusions were performed. Although the current study is based on a small sample of participants, the findings suggest that allogeneic Ad‐MSC infusions are not effective to improve immune recovery in INR patients or to reduce immune activation or inflammation. ClinicalTrials.gov identifier: NCT0229004. EudraCT number: 2014‐000307‐26.

In most HIV-infected persons, the natural history of untreated infection is one of sustained viremia, progressive CD4 T cell depletion with resultant morbidity and mortality. The advent of effective combination antiretroviral therapy (ART) that controls HIV replication has altered this landscape dramatically. Yet a rare population of HIV-infected persons—elite controllers (EC)—can control HIV replication such that plasma levels of virus are “undetectable” without ART. The EC phenotype is heterogeneous, with some subjects durably controlling the virus—persistent elite controllers—and some eventually losing viral control—transient elite controllers. Overall, EC tend to have robust HIV-specific T cell responses and in some cases, mainly in transient elite controllers, elevated activation and inflammation indices that diminish with ART suggesting that endogenous defenses against this persistent pathogen come at the cost of heightened activation/inflammation. A limited data set suggests that cardiovascular disease risk as well as the occurrence of other morbid events may be greater in the overall EC population than in treated HIV infection. ART in EC decreases activation indices but does not appear to increase circulating CD4 T cell numbers nor do we know if it alters clinical outcomes. Thus, it is difficult to recommend or discourage a decision to start ART in the EC population but the authors lean toward treatment particularly in those EC whose activation indices are high and those who are progressively losing circulating CD4 T cell numbers. Biomarkers that can reliably predict loss of virologic control and immune failure are needed.

Aging is associated with immune attrition that may impact the effectiveness of the immune system to protect the host from pathogens. Here the authors show that immune aging is associated with alterations in the Wnt/β-catenin signaling and reduced stem cell memory T lymphocytes, hinting the Wnt/β-catenin pathway as a potential therapy target.

Abstract Elite controllers (EC) represent a small subset of HIV-1-infected people that spontaneously control viral replication. However, natural virological suppression and absence of immune dysfunction are not always long-term sustained. We define exceptional EC (EEC) as HIV-1 subjects who maintain the EC characteristics without disease progression for more than 25 years. We analyzed three EEC, diagnosed between 1988 and 1992, who never showed signs of clinical disease progression in absence of any antiretroviral treatment. A comprehensive clinical, virological, and immunological study was performed. The individuals simultaneously exhibited ≥3 described host protective alleles, low levels of total HIV-1 DNA (0.50). Inflammation levels of EEC were similar to HIV-1 negative donors. Remarkably, they showed an exceptional lack of viral evolution and 8-fold lower genetic diversity (

Abstract SARS‐CoV‐2 specific T‐cell response has been associated with disease severity, immune memory and heterologous response to endemic coronaviruses. However, an integrative approach combining a comprehensive analysis of the quality of SARS‐CoV‐2 specific T‐cell response with antibody levels in these three scenarios is needed. In the present study, we found that, in acute infection, while mild disease was associated with high T‐cell polyfunctionality biased to IL‐2 production and inversely correlated with anti‐S IgG levels, combinations only including IFN‐γ with the absence of perforin production predominated in severe disease. Seven months after infection, both non‐hospitalised and previously hospitalised patients presented robust anti‐S IgG levels and SARS‐CoV‐2 specific T‐cell response. In addition, only previously hospitalised patients showed a T‐cell exhaustion profile. Finally, combinations including IL‐2 in response to S protein of endemic coronaviruses were the ones associated with SARS‐CoV‐2 S‐specific T‐cell response in pre‐COVID‐19 healthy donors’ samples. These results could have implications for protective immunity against SARS‐CoV‐2 and recurrent COVID‐19 and may help for the design of new prototypes and boosting vaccine strategies.

Long-term elite controllers (LTECs) are a fascinating small subset of HIV individuals with viral and immunological HIV control in the long term that have been designated as models of an HIV functional cure. However, data on the LTEC phenotype are still scarce, and hence, the metabolomics and lipidomics signatures in the LTEC-extreme phenotype, LTECs with more than 10 years of viral and immunological HIV control, could be pivotal to finding the keys for functional HIV remission. Metabolomics and lipidomics analyses were performed using high-resolution mass spectrometry (ultra-high-performance liquid chromatography–electrospray ionization–quadrupole time of flight [UHPLC-(ESI) qTOF] in plasma samples of 13 patients defined as LTEC-extreme, a group of 20 LTECs that lost viral and/or immunological control during the follow-up study (LTEC-losing) and 9 EC patients with short-term viral and immunological control (less than 5 years; no-LTEC patients). Long-term viral and immunological HIV-1 control was found to be strongly associated with elevated tricarboxylic acid (TCA) cycle function. Interestingly, of the nine metabolites identified in the TCA cycle, α-ketoglutaric acid (p = 0.004), a metabolite implicated in the activation of the mTOR complex, a modulator of HIV latency and regulator of several biological processes, was found to be a key metabolite in the persistent control. On the other hand, a lipidomics panel combining 45 lipid species showed an optimal percentage of separation and an ability to differentiate LTEC-extreme from LTEC-losing, revealing that an elevated lipidomics plasma profile could be a predictive factor for the reignition of viral replication in LTEC individuals.

BackgroundThe SARS-CoV-2 pandemic has overwhelmed hospital services due to the rapid transmission of the virus and its severity in a high percentage of cases. Having tools to predict which patients can be safely early discharged would help to improve this situation.MethodsPatients confirmed as SARS-CoV-2 infection from four Spanish hospitals. Clinical, demographic, laboratory data and plasma samples were collected at admission. The patients were classified into mild and severe/critical groups according to 4-point ordinal categories based on oxygen therapy requirements. Logistic regression models were performed in mild patients with only clinical and routine laboratory parameters and adding plasma pro-inflammatory cytokine levels to predict both early discharge and worsening.Results333 patients were included. At admission, 307 patients were classified as mild patients. Age, oxygen saturation, Lactate Dehydrogenase, D-dimers, neutrophil-lymphocyte ratio (NLR), and oral corticosteroids treatment were predictors of early discharge (area under curve (AUC), 0.786; sensitivity (SE) 68.5%; specificity (S), 74.5%; positive predictive value (PPV), 74.4%; and negative predictive value (NPV), 68.9%). When cytokines were included, lower interferon-γ-inducible protein 10 and higher Interleukin 1 beta levels were associated with early discharge (AUC, 0.819; SE, 91.7%; S, 56.6%; PPV, 69.3%; and NPV, 86.5%). The model to predict worsening included male sex, oxygen saturation, no corticosteroids treatment, C-reactive protein and Nod-like receptor as independent factors (AUC, 0.903; SE, 97.1%; S, 68.8%; PPV, 30.4%; and NPV, 99.4%). The model was slightly improved by including the determinations of interleukine-8, Macrophage inflammatory protein-1 beta and soluble IL-2Rα (CD25) (AUC, 0.952; SE, 97.1%; S, 98.1%; PPV, 82.7%; and NPV, 99.6%).ConclusionsClinical and routine laboratory data at admission strongly predict non-worsening during the first two weeks; therefore, these variables could help identify those patients who do not need a long hospitalization and improve hospital overcrowding. Determination of pro-inflammatory cytokines moderately improves these predictive capacities.

Elite controllers (ECs) are an exceptional group of people living with HIV (PLWH) who maintain undetectable viral loads (VLs) despite not being on antiretroviral therapy (ART). However, this phenotype is heterogeneous, with some of these subjects losing virological control over time. In this longitudinal retrospective study, serum acute-phase glycoprotein profile assessed by proton nuclear magnetic resonance (1H-NMR) was determined in 11 transient controllers (TCs) who spontaneously lost virological control and 11 persistent controllers (PCs) who persistently maintained virological control over time. Both PCs and TCs showed similar acute-phase glycoprotein profiles, even when TCs lost the virological control (GlycB, p = 0.824 and GlycA, p = 0.710), and the serum acute-phase glycoprotein signature in PCs did not differ from that in HIV-negative subjects (GlycB, p = 0.151 and GlycA, p = 0.243). Differences in serum glycoproteins A and B were significant only in ECs compared to HIV-typical progressors (TPs) with < 100 CD4+ T-cells (p < 0.001). 1H-NMR acute-phase glycoprotein profile does not distinguish TCs form PCs before the loss of viral control. ECs maintain a low-grade inflammatory state compared to TPs. PCs revealed a closer serum signature to HIV-negative subjects, reaffirming this phenotype as a closer model of functional control of HIV.

Background: Approximately 25% of elite controllers (ECs) lose their virological control by mechanisms that are only partially known. Recently, immunovirological and proteomic factors have been associated to the loss of spontaneous control. Our aim was to perform a metabolomic approach to identify the underlying mechanistic pathways and potential biomarkers associated with this loss of control. Methods: Plasma samples from EC who spontaneously lost virological control (Transient Controllers, TC, n = 8), at two and one year before the loss of control, were compared with a control group of EC who persistently maintained virological control during the same follow-up period (Persistent Controllers, PC, n = 8). The determination of metabolites and plasma lipids was performed by GC-qTOF and LC-qTOF using targeted and untargeted approaches. Metabolite levels were associated with the polyfunctionality of HIV-specific CD8+T-cell response. Findings: Our data suggest that, before the loss of control, TCs showed a specific circulating metabolomic profile characterized by aerobic glycolytic metabolism, deregulated mitochondrial function, oxidative stress and increased immunological activation. In addition, CD8+ T-cell polyfunctionality was strongly associated with metabolite levels. Finally, valine was the main differentiating factor between TCs and PCs. Interpretation: All these metabolomic differences should be considered not only as potential biomarkers but also as therapeutic targets in HIV infection. Fund: This work was supported by grants from Fondo de Investigación Sanitaria, Instituto de Salud Carlos III, Fondos FEDER; Red de Investigación en Sida, Gilead Fellowship program, Spanish Ministry of Education and Spanish Ministry of Economy and Competitiveness. Keywords: Elite controllers, Energy metabolism, HIV-1, Immunometabolism, Loss of control, Metabolomic profile

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread around the globe causing coronavirus disease 2019 (COVID-19). Because it affects the respiratory system, common symptoms are cough and breathing difficulties with fever and fatigue. Also, some cases progress to acute respiratory distress syndrome (ARDS). The acute phase of COVID-19 has been also related to nervous system symptoms, including loss of taste and smell as well as encephalitis and cerebrovascular disorders. However, it remains unclear if neurological complications are due to the direct viral infection of the nervous system, or they appear as a consequence of the immune reaction against the virus in patients who presented pre-existing deficits or had a certain detrimental immune response. Importantly, the medium and long-term consequences of the infection by SARS-CoV-2 in the nervous system remain at present unknown. This review article aims to give an overview of the current neurological symptoms associated with COVID-19, as well as attempting to provide an insight beyond the acute affectation.

Abstract Background Maraviroc-containing combined antiretroviral therapy (MVC-cART) improved the response to the hepatitis B virus (HBV) vaccine in HIV-infected subjects younger than 50 years old. We aimed here to explore the effect of this antiretroviral therapy on different immunological parameters that could account for this effect. Methods We analysed baseline samples of vaccinated subjects under 50 years old (n = 41). We characterized the maturational subsets and the expression of activation, senescence and prone-to-apoptosis markers on CD4 T-cells; we also quantified T-regulatory cells (Treg) and dendritic cell (DC) subsets. We used binary logistic regression to evaluate the immunological impact of MVC-cART, correlation with MVC exposure and linear regression for association with the magnitude of the HBV vaccine response. Results HIV-infected subjects on MVC-cART prior to vaccination showed increased recent thymic emigrants levels and reduced myeloid-DC levels. A longer exposure to MVC-cART was associated with lower frequencies of Tregs and activated and proliferating CD4 T-cells. Furthermore, the frequencies of activated and proliferating CD4 T-cells were inversely associated with the magnitude of the HBV vaccine response. Conclusion The beneficial effect of MVC-cART in the HBV vaccine response in subjects below 50 years old could be partially mediated by its reducing effect on the frequencies of activated and proliferating CD4 T-cells prior to vaccination.

Abstract Background Despite long-lasting HIV replication control, a significant proportion of elite controller (EC) patients may experience CD4 T-cell loss. Discovering perturbations in immunological parameters could help our understanding of the mechanisms that may be operating in those patients experiencing loss of immunological control. Methods A case–control study was performed to evaluate if alterations in different T-cell homeostatic parameters can predict CD4 T-cell loss in ECs by comparing data from EC patients showing significant CD4 decline (cases) and EC patients showing stable CD4 counts (controls). The partial least-squares–class modeling (PLS-CM) statistical methodology was employed to discriminate between the two groups of patients, and as a predictive model. Results Herein, we show that among T-cell homeostatic alterations, lower levels of naïve and recent thymic emigrant subsets of CD8 cells and higher levels of effector and senescent subsets of CD8 cells as well as higher levels of exhaustion of CD4 cells, measured prior to CD4 T-cell loss, predict the loss of immunological control. Conclusions These data indicate that the parameters of T-cell homeostasis may identify those EC patients with a higher proclivity to CD4 T-cell loss. Our results may open new avenues for understanding the mechanisms underlying immunological progression despite HIV replication control, and eventually, for finding a functional cure through immune-based clinical trials.

Intra-host evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported in cases with persistent coronavirus disease 2019 (COVID-19). In this study, we describe a severely immunosuppressed individual with HIV-1/SARS-CoV-2 coinfection with a long-term course of SARS-CoV-2 infection. A 28-year-old man was diagnosed with HIV-1 infection (CD4+ count: 3 cells/µL nd 563000 HIV-1 RNA copies/mL) and simultaneous Pneumocystis jirovecii pneumonia, disseminated Mycobacterium avium complex infection and SARS-CoV-2 infection. SARS-CoV-2 real-time reverse transcription polymerase chain reaction positivity from nasopharyngeal samples was prolonged for 15 weeks. SARS-CoV-2 was identified as variant Alpha (PANGO lineage B.1.1.7) with mutation S:E484K. Spike-specific T-cell response was similar to HIV-negative controls although enriched in IL-2, and showed disproportionately increased immunological exhaustion marker levels. Despite persistent SARS-CoV-2 infection, adaptive intra-host SARS-CoV-2 evolution, was not identified. Spike-specific T-cell response protected against a severe COVID-19 outcome and the increased immunological exhaustion marker levels might have favoured SARS-CoV-2 persistence.

Viral and host immune kinetics during acute COVID-19 and after remission of acute symptoms need better characterization. SARS-CoV-2 RNA, anti-SARS-CoV-2 IgA, IgM, and IgG antibodies, and proinflammatory cytokines were measured in sequential samples from hospitalized COVID-19 patients during acute infection and six months following diagnosis. Twenty four laboratory confirmed COVID-19 patients with mild/moderate and severe COVID-19 were included. Most were males (83%) with a median age of 61 years. Twenty one percent were admitted to the intensive care unit (ICU) and eight of them (33.3%) met the criteria for severe COVID-19 disease. A delay in SARS-CoV-2 levels’ decline during the first six days of follow up, and viral load persistence until month 3 were related to severe COVID-19, but not viral load levels at the diagnosis. Higher levels of anti-SARS-CoV-2 IgA, IgM, IgG and the cytokines IL-6, IL-8 and MIP-1β at the diagnosis time were related to the severe COVID-19 outcome. Higher levels of MIP-1β, IL-1β, MIP-1α and IFN-γ were observed at month 1 and 3 during mild/moderate disease, compared to severe COVID-19. IgG persisted at low levels after six months of diagnosis. In conclusion, higher concentrations of IgA, IgM, and IgG, and IL-6, IL-8 and MIP-1β are identified as early predictors of COVID-19 severity, whereas no significant association is found between baseline SARS-COV-2 viral load and COVID-19 severity.

Immune cells are, by default, migratory cells that traverse tissue for the purpose of carrying out recognition and recruitment in pathologic inflammation and infection. Members of the LDL receptor family (LDL-RFMs) interact with human leukocyte elastase on the cell surface (HLE-CS) in complex with the abundant blood protein α1proteinase inhibitor (α1PI, α1-antitrypsin, Alpha-1), a process that induces internalization of aggregated functionally-related receptors, including CD4 and the T cell antigen receptor, while simultaneously promoting cellular locomotion. We sought to determine whether augmenting α1PI blood concentration would promote the locomotion of immature T cells through the thymus and generate new CD4+ T cells. Two small clinical trials (NCT01370018, NCT01731691, https://clinicaltrials.gov) were conducted in which HIV-1 infected and uninfected individuals were augmented with α1PI and compared with placebo-treated subjects and untreated controls. Blood cell phenotypes were monitored weekly. We found that CD4/CD8 ratio was significantly increased by α1PI augmentation in both uninfected and HIV-1 infected individuals. We found that maturation of CD4+CD8+ T cells to become immunologically competent CD4+ T cells was regulated by α1PI. We propose a strategy targeting HLE-CS for treating secondary immunodeficiency for which there is currently no direct treatment. Treatment to directly elevate T cells in patients with secondary immunodeficiency, including HIV disease, can be provided by alpha-1 antitrypsin augmentation or small molecules that target HLE-CS. Because individuals infected with HIV-1 produce a monoclonal antibody, 3F5, which binds to and inactivates α1PI, a process that prevents α1PI from binding to HLE-CS, thereby blocking locomotion of immature T cells through the thymus to generate CD4+ T cells, we further propose that HIV-1 vaccination should include induction of an antibody that binds to and blocks 3F5 activity, thereby preventing AIDS in addition to the current vaccine strategy for preventing HIV-1 infection.

HIV-elite controllers are a minority group of HIV-infected patients with the ability to maintain undetectable HIV viremia for long time periods without antiretroviral treatment. A small group of HIV-controllers are also able to spontaneously clear the hepatitis C virus (HCV) whom we can refer to as “supercontrollers.” There are no studies that explore immune correlates looking for the mechanisms implicated in this extraordinary phenomenon. Herein, we have analyzed HCV- and HIV-specific T-cell responses, as well as T, dendritic and NK cell phenotypes. The higher HCV-specific CD4 T-cell polyfunctionality, together with a low activation and exhaustion T-cell phenotype was found in supercontrollers. In addition, the frequency of CD8 CD161high T-cells was related with HIV- and HCV-specific T-cells polyfunctionality. Interesting features regarding NK and plasmacytoid dendritic cells (pDCs) were found. The study of the supercontroller's immune response, subjects that spontaneously controls both chronic viral infections, could provide further insights into virus-specific responses needed to develop immunotherapeutic strategies in the setting of HIV cure or HCV vaccination.

The ability of the CD300a inhibitory receptor to modulate immune cell functions and its involvement in the pathogenesis of many diseases has aroused a great interest in this molecule. Within human CD4+ T lymphocytes from healthy donors, the inhibitory receptor CD300a is differentially expressed among different T helper subsets. However, there are no data about the expression and regulation of CD300a receptor on CD4+ T cells from human immunodeficiency virus (HIV)-1-infected patients. The objective of this study was to investigate the expression of CD300a on CD4+ T cells from HIV-infected patients on suppressive combined antiretroviral therapy (cART) and cART naïve patients. Our results have demonstrated that the expression levels of this inhibitory receptor were higher on CD4+ T cells from HIV-1 infected subjects compared with healthy donors, and that cART did not reverse the altered expression of CD300a receptor in these patients. We have observed an increase of CD300a expression on both PD1+CD4+ and CD38+CD4+ T cells from HIV-1 infected people. Interestingly, a triple positive (CD300a+PD1+CD38+) subset was expanded in naïve HIV-1 infected patients, while it was very rare in healthy donors and patients on cART. Finally, we found a negative correlation of CD300a expression on CD4+ T lymphocytes and some markers associated with HIV-1 disease progression. Thus, our results show that HIV-1 infection has an impact in the regulation of CD300a inhibitory receptor expression levels, and further studies will shed light into the role of this cell surface receptor in the pathogenesis of HIV infection.

HIV controllers (HICs) spontaneously maintain HIV viral replication at low level without antiretroviral therapy (ART), a small number of whom will eventually lose this ability to control HIV viremia. The objective was to identify factors associated with loss of virological control.HICs were identified in COHERE on the basis of ≥5 consecutive viral loads (VL) ≤500 copies/mL over ≥1 year whilst ART-naive, with the last VL ≤500 copies/mL measured ≥5 years after HIV diagnosis. Loss of virological control was defined as 2 consecutive VL >2000 copies/mL. Duration of HIV control was described using cumulative incidence method, considering loss of virological control, ART initiation and death during virological control as competing outcomes. Factors associated with loss of virological control were identified using Cox models. CD4 and CD8 dynamics were described using mixed-effect linear models.We identified 1067 HICs; 86 lost virological control, 293 initiated ART, and 13 died during virological control. Six years after confirmation of HIC status, the probability of losing virological control, initiating ART and dying were 13%, 37%, and 2%. Current lower CD4/CD8 ratio and a history of transient viral rebounds were associated with an increased risk of losing virological control. CD4 declined and CD8 increased before loss of virological control, and before viral rebounds.Expansion of CD8 and decline of CD4 during HIV control may result from repeated low-level viremia. Our findings suggest that in addition to superinfection, other mechanisms, such as low grade viral replication, can lead to loss of virological control in HICs.