Elite Controllers Research Articles

NK and CD8+ T cell phenotypes predict onset and control of CMV viremia after kidney transplant.

CMV causes mostly asymptomatic but lifelong infection. Primary infection or reactivation in immunocompromised individuals can be life-threatening. CMV viremia often occurs in solid organ transplant recipients and associates with decreased graft survival and higher mortality. Furthering understanding of impaired immunity that allows CMV reactivation is critical to guiding antiviral therapy and examining the effect of CMV on solid organ transplant outcomes. This study characterized longitudinal immune responses to CMV in 31 kidney transplant recipients with CMV viremia and matched, nonviremic recipients. Recipients were sampled 3 and 12 months after transplant, with additional samples 1 week and 1 month after viremia. PBMCs were stained for NK and T cell markers. PBMC transcriptomes were characterized by RNA-Seq. Plasma proteins were quantified by Luminex. CD8+ T cell transcriptomes were characterized by single-cell RNA-Seq. Before viremia, patients had high levels of IL-15 with concurrent expansion of immature CD56bright NK cells. After viremia, mature CD56dim NK cells and CD28–CD8+ T cells upregulating inhibitory and NK-associated receptors were expanded. Memory NK cells and NK-like CD28–CD8+ T cells were associated with control of viremia. These findings suggest that signatures of innate activation may be prognostic for CMV reactivation after transplant, while CD8+ T cell functionality is critical for effective control of CMV.

Nef-specific CD107a+ CD4+ T-cell responses in a rhesus macaque (Macaca mulatta) showing partial simian immunodeficiency virus control following passive neutralizing antibody infusion.

Acute-phase neutralizing antibody (NAb) passive immunization in simian immunodeficiency virus (SIV)-infected rhesus macaques (Macaca mulatta) can confer stringent viremia control with T-cell augmentation. In one NAb-infused SIV partial controller, we identify chronic-phase Nef-specific CD107a+ CD4+ T-cell response maintenance, implicating that NAb infusion modulates long-term T-cell responses even within viremic control.

Diminished Peripheral CD29hi Cytotoxic CD4+ T Cells Are Associated With Deleterious Effects During SIV Infection.

Cytotoxic CD4+ T cells (CD4+ CTLs) limit HIV pathogenesis, as evidenced in elite controllers (a subset of individuals who suppress the virus without the need for therapy). CD4+ CTLs have also been shown to kill HIV-infected macrophages. However, little is known about their contribution towards HIV persistence, how they are affected following exposure to immune modulators like morphine, and what factors maintain their frequencies and function. Further, the lack of robust markers to identify CD4+ CTLs in various animal models limits understanding of their role in HIV pathogenesis. We utilized various PBMC samples obtained from SIV infected and cART treated rhesus macaques exposed to morphine or saline and subjected to flow cytometry evaluations. Thereafter, we compared and correlated the expression of CD4+ CTL-specific markers to viral load and viral reservoir estimations in total CD4+ T cells. We found that CD29 could be reliably used as a marker to identify CD4+ CTLs in rhesus macaques since CD29hi CD4+ T cells secrete higher cytotoxic and proinflammatory cytokines following PMA/ionomycin or gag stimulation. In addition, this immune cell subset was depleted during untreated SIV infection. Strikingly, we also observed that early initiation of cART reconstitutes depleted CD29hi CD4+ T cells and restores their function. Furthermore, we noted that morphine exposure reduced the secretion of proinflammatory cytokines/cytotoxic molecules in CD29hi CD4+ T cells. Lastly, increased functionality of CD29hi CD4+ T cells as depicted by elevated levels of either IL-21 or granzyme B hi T Bet+ gag specific responses were linked to limiting the size of the replication-competent reservoir during cART treatment. Collectively, our data suggest that CD4+ CTLs are crucial in limiting SIV pathogenesis and persistence.

MARCO+ lymphatic endothelial cells sequester arthritogenic alphaviruses to limit viremia and viral dissemination.

Viremia in the vertebrate host is a major determinant of arboviral reservoir competency, transmission efficiency, and disease severity. However, immune mechanisms that control arboviral viremia are poorly defined. Here, we identify critical roles for the scavenger receptor MARCO in controlling viremia during arthritogenic alphavirus infections in mice. Following subcutaneous inoculation, arthritogenic alphavirus particles drain via the lymph and are rapidly captured by MARCO+ lymphatic endothelial cells (LECs) in the draining lymph node (dLN), limiting viral spread to the bloodstream. Upon reaching the bloodstream, alphavirus particles are cleared from the circulation by MARCO-expressing Kupffer cells in the liver, limiting viremia and further viral dissemination. MARCO-mediated accumulation of alphavirus particles in the draining lymph node and liver is an important host defense mechanism as viremia and viral tissue burdens are elevated in MARCO-/- mice and disease is more severe. In contrast to prior studies implicating a key role for lymph node macrophages in limiting viral dissemination, these findings exemplify a previously unrecognized arbovirus-scavenging role for lymphatic endothelial cells and improve our mechanistic understanding of viremia control during arthritogenic alphavirus infection.

Autophagy-dependent glutaminolysis drives superior IL21 production in HIV-1-specific CD4 T cells

ABSTRACT The maintenance of a strong IL21 production in memory CD4 T cells, especially in HIV-1-specific cells, represents a major correlate of natural immune protection against the virus. However, the molecular mechanisms underlying IL21 production during HIV-1 infection, which is only elevated among the naturally protected elite controllers (EC), are still unknown. We recently found out that lipophagy is a critical immune mediator that control an antiviral metabolic state following CD8A T cell receptor engagement, playing an important role in the natural control of HIV-1 infection. This led us to investigate whether the beneficial role of a strong macroautophagy/autophagy, could also be used to ensure effective IL21 production as well. Herein, we confirm that after both polyclonal and HIV-1-specific activation, memory CD4 T cells (Mem) from EC display enhanced activity of the autophagy-mediated proteolysis compared to ART. Our results indicate that the enhanced autophagy activity in EC was controlled by the energy-sensing PRKAA1 (protein kinase AMP-activated catalytic subunit alpha 1). We further confirmed the critical role of the autophagy-mediated proteolysis in the strong IL21 production in EC by using BECN1 gene silencing as well as protease, PRKAA1, and lysosomal inhibitors. Finally, we established that high autophagy-mediated proteolysis in EC fuels their cellular rates of mitochondrial respiration due to glutaminolysis. Our data confirm the critical role of autophagy in dictating the metabolic input, which is required not only to ensure protective cytotoxic CD8A T cell responses, but also to provide strong IL21 production among antiviral CD4 T cells. Abbreviations: AKG: alpha-ketoglutarate; ART: patients under antiretroviral therapy; ATG7: autophagy related 7; BaF: bafilomycin A1; BECN1: beclin 1; Chloro.: chloroquine; EC: elite controllers; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; FOXO3: forkhead box O3; GLS: glutaminase; GLUD1: glutamate dehydrogenase 1; HIVneg: HIV-1-uninfected control donors; IFNG/IFN-γ: interferon gamma; IL21: interleukin 21; MTOR: mechanistic target of rapamycin kinase; PBMC: peripheral blood mononuclear cells; PRKAA1: protein kinase AMP-activated catalytic subunit alpha 1; SQSTM1: sequestosome 1; TCA: tricarboxylic acid cycle; ULK1: unc-51 like autophagy activating kinase

Robust HIV-specific CD4+ and CD8+ T-cell responses distinguish elite control in adolescents living with HIV from viremic nonprogressors.

Background:Elite controllers are therapy-naive individuals living with HIV capable of spontaneous control of plasma viraemia for at least a year. Although viremic nonprogressors are more common in vertical HIV-infection than in adults’ infection, elite control has been rarely characterized in the pediatric population.Design:We analyzed the T-cell immunophenotype and the HIV-specific response by flow cytometry in four pediatric elite controllers (PECs) compared with age-matched nonprogressors (PNPs), progressors and HIV-exposed uninfected (HEUs) adolescents.Results:PECs T-cell populations had lower immune activation and exhaustion levels when compared with progressors, reflected by a more sustained and preserved effector function. The HIV-specific T-cell responses among PECs were characterized by high-frequency Gag-specific CD4+ T-cell activity, and markedly more polyfunctional Gag-specific CD8+ activity, compared with PNPs and progressors. These findings were consistently observed even in the absence of protective HLA-I molecules such as HLA-B∗27/57/81.Conclusion:Pediatric elite control is normally achieved after years of infection, and low immune activation in PNPs precedes the increasing ability of CD8+ T-cell responses to achieve immune control of viraemia over the course of childhood, whereas in adults, high immune activation in acute infection predicts subsequent CD8+ T-cell mediated immune control of viremia, and in adult elite controllers, low immune activation is therefore the consequence of the rapid CD8+ T-cell mediated immune control generated after acute infection. This distinct strategy adopted by PECs may help identify pathways that facilitate remission in posttreatment controllers, in whom protective HLA-I molecules are not the main factor.

IMMUNE RECONSTITUTION INFLAMMATORY SYNDROME AFTER USE OF ANTI-RETROVIRAL THERAPY IN COVID-19

TOPIC: Chest Infections TYPE: Global Case Reports INTRODUCTION: COVID-19 is still an emerging topic and co-existence in HIV patients presents its unique challenge. These patients can range from elite controllers to Acquired immunodeficiency syndrome (T cell CD4 < 200). Throughout our management, we noticed certain trends in our population. Those patients with CD4 T cell < 200 were rarely admitted to hospital with severe cases of COVID-19, requiring if anything minimal oxygen requirements. However, HIV patients who were admitted did not fare well after initiating their anti-retroviral therapy (ART) therapy during index hospitalization. We describe two such cases one in which ART was maintained and one in which ART was help with different outcomes. CASE PRESENTATION: Both patients on admission were admitted for progressive dyspnea with COVID PCR positive, started on ART therapy, given a 10-day course of Dexamethasone 6mg and 5 doses of Remdisivir.Case 1 - 55year old Hispanic male with a history of non-compliance on Triumeq (CD4 count of 34), lymphoma in remission after chemotherapy, and sulfa allergy. On admission he was started on Triumeq, Azithromycin, Clindamycin, Primaquine. Over next 3 days he experienced progressive hypoxia and worsening chest imaging eventually requiring mechanical ventilation.Case 2 - 66year old female non-compliant on ART, and polysubstance abuse. She was also noted to have MSSA pneumonia. She was started on Emricitabine, Tenofovir, Ritonavir, and Atazanorvir. Within 48 hours of ART initiation her oxygen requirement increased. At this time, her antiretrovirals were stopped and started on Solumedrol 40mg twice daily for suspected IRIS. Her respiratory status improved and her oxygen requirements were back to baseline. Upon restarting ART 2 weeks post treatment for IRIS, patient again required an increase in oxygen supplementation. ART was held for an extended period while maintaining opportunistic infection prophylaxis. DISCUSSION: We pose this discussion for the community, as COVID-19 pathophysiology has been hypothesized to be an inflammatory response mitigated by Interleukins and Interferon-gamma, released by CD4 and CD8 T cells {3} Theoretically those with lower CD4 T cells, such as those with AIDs, should produce a lesser inflammatory response;and therefore, be less symptomatic. IRIS is typically determined from clinical context and is seen more frequently in those with CD4 < 100. {1} Treatment is typically steroids with a prolonged taper, with an ongoing discussion on whether ART should be held. {4} CONCLUSIONS: Currently there are no guidelines regarding utilization of ART in HIV patients infected with COVID;which leads to following questions of whether ART be held transiently until the COVID-19 pneumonia has been sufficiently treated? When should ART be restarted in these patients? If a patient's condition is deteriorating, should the patient's ART be held and started on opportunistic infection prophylaxis? REFERENCE #1: Bosamiya, S.S. The immune reconstitution inflammatory syndrome (2011) 56(5) 476-9, Indian J Dermatology. doi : 10.4103/0019-5154.87114 REFERENCE #2: Brown, L.B, Spinelli, M.A., and Gandhi, M. The interplay between HIV and COVID-19: summary of the data and responses to date. (2021) 16(1) 63-73, Current opinion of HIV and AIDs. REFERENCE #3: Kalfaoglu, B., Almeida-Santos, J., Tye, C.A., Satou, Y., and Ono, M. T cell dysregulation in COVID-19 (2020) 29(530) 204-210, Biochem Biophys Res Commun. doi: 10.1016/j.bbrc.2020.10.079 DISCLOSURES: No relevant relationships by Obed Adarkwah, source=Web Response no disclosure on file for Anjali Bakshi;No relevant relationships by Louis Gerolemou, source=Web Response No relevant relationships by Aneeta Kumari, source=Web Response No relevant relationships by Nabil Mesiha, source=Web Response No relevant relationships by Steven Miller, source=Web Response No relevant relationships by Kunal Nangrani, source=Web Response No relevant relationships by Jose Orsini, source=Web Response No relevant relationships by Gaurav Parhar, source=We Response no disclosure on file for Dhruv Patel;No relevant relationships by Jason Ravidas, source=Web Response No relevant relationships by jad sargi, source=Web Response No relevant relationships by Viswanath Vasudevan, source=Web Response No relevant relationships by Kiran Zaman, source=Web Response No relevant relationships by John Zeibeq, source=Web Response

Evolution of Serum Acute-Phase Glycoproteins Assessed by 1H-NMR in HIV Elite Controllers.

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.

Elite and viremic HIV-1 controllers in West Africa.

Background:Data on HIV-1 controllers in Africa are scarce. We report the proportion of HIV-1 controllers in a group of adults prospectively monitored with frequent viral load measurements as part of a clinical trial in West Africa.Methods:For the Temprano trial, antiretroviral therapy (ART)-naive HIV-1 infected adults with no criteria for starting ART were randomized to start ART immediately or defer ART until the WHO starting criteria were met. Plasma viral load was measured every 6 months. The trial follow-up was 30 months. We considered all Temprano participants randomized to defer ART. Patients with all semestrial viral <2000 copies/ml and still off ART at month 30 were defined as HIV-1 controllers. Controllers with all viral loads <50 copies/ml were defined as elite controllers, the rest as viremic controllers.Results:Of the 1023 HIV-1-infected adults randomized in the Temprano deferred-ART group, 18 (1.8%) met the criteria for classification as HIV controllers, of whom seven (0.7%) were elite controllers and 11 (1.1%) viremic controllers. The HIV-1 controllers had low peripheral blood mononuclear cell HIV-1 DNA and low inflammatory marker levels. They maintained high CD4+ cell count and percentages and had a low morbidity rate.Discussion:HIV controllers exist in Africa at a proportion close to that reported elsewhere. They represent a small fraction of all HIV-1-infected patients but raise important questions. Further studies should assess whether starting ART might represent more risk than benefit for some controllers, and where it does, how to identify these patients before they start ART.

Functional impairment of HIV-specific CD8+ T cells precedes aborted spontaneous control of viremia

Spontaneous control of HIV infection has been repeatedly linked to antiviral CD8+ Tcells but is not always permanent. To address mechanisms of durable and aborted control of viremia, we evaluated immunologic and virologic parameters longitudinally among 34 HIV-infected subjects with differential outcomes. Despite sustained recognition of autologous virus, HIV-specific proliferative and cytolytic Tcell effector functions became selectively and intrinsically impaired prior to aborted control. Longitudinal transcriptomic profiling of functionally impaired HIV-specific CD8+ Tcells revealed altered expression of genes related to activation, cytokine-mediated signaling, and cell cycle regulation, including increased expression of the antiproliferative transcription factor KLF2 but not of genes associated with canonical exhaustion. Lymphoid HIV-specific CD8+ Tcells also exhibited poor functionality during aborted control relative to durable control. Our results identify selective functional impairment of HIV-specific CD8+ Tcells as prognostic of impending aborted HIV control, with implications for clinical monitoring and immunotherapeutic strategies.

Prevalence of undetectable and suppressed viral load in HIV-infected pregnant women initiating Option B+\u2009in Uganda: an observational study nested within a randomized controlled trial

BackgroundViral load (VL) testing is key in monitoring adherence to antiretroviral therapy (ART) and documenting HIV treatment response. As per HIV treatment guidelines in Uganda, the first VL test is recommended 6 months after initiation of ART. Undetectable VL (uVL) at ART initiation may be helpful in detecting elite controllers in the absence of previous ART use. We investigated viral suppression at ART initiation among a cohort of HIV-positive pregnant women enrolled in the Friends for Life Circles (FLC) for Option B+ randomized controlled trial (RCT).MethodsPregnant women ≥ 18 years of age testing positive for HIV at their first antenatal care visit and starting on ART Option B+ as per the National PMTCT Program guidelines were enrolled into the FLC for Option B+ RCT in urban Kampala and rural Mityana districts of Uganda. Each participant had whole blood samples collected at enrolment to assess baseline VL. Plasma HIV-1 RNA was quantified using COBAS Ampliprep /COBAS Taqman. Baseline VL below 400 RNA copies/ml was considered as viral suppression while baseline VL below 20 RNA copies/ml was considered uVL.ResultsThe mean duration from the date of ART initiation to time of sample collection for baseline VL assessment was 4.4 days (SD 3.6). Of the 532 HIV-positive pregnant women enrolled in the FLC for Option B+ study and newly starting Option B+ without a self-reported history of prior ART use, 29 (5.5%) had uVL and 113 (21.4%) had suppressed VL at baseline. There was no association between participants’ age, gravidity, marital status, mean monthly income, educational level, disclosure of HIV status to partner, and uVL or viral suppression at baseline. However, non-disclosure of HIV status to any other person was associated with decreased odds of viral suppression at baseline (OR 0.640; 0.416–0.982).ConclusionTwenty-one percent of HIV-positive Ugandan pregnant women initiating ART (Option B+) showed virological suppression at baseline and were presumed to be “elite controllers” or to have misreported being ART-naive. Further studies are needed to better understand the biologic mechanisms of elite controllers among pregnant women as well as to differentiate elite controllers from concealed ART use.Trial Registration The trial was registered as NCT02515370 (04/08/2015) on Clinicaltrials.gov.

Dynamics and epigenetic signature of regulatory T-cells following antiretroviral therapy initiation in acute HIV infection.

BackgroundHIV infection promotes the expansion of immunosuppressive regulatory T-cells (Tregs), contributing to immune dysfunction, tissue fibrosis and disease progression. Early antiretroviral treatment (ART) upon HIV infection improves CD4 count and decreases immune activation. However, Treg dynamics and their epigenetic regulation following early ART initiation remain understudied.MethodsTreg subsets were characterized by flow cytometry in 103 individuals, including untreated HIV-infected participants in acute and chronic phases, ART-treated in early infection, elite controllers (ECs), immunological controllers (ICs), and HIV-uninfected controls. The methylation status of six regulatory regions of the foxp3 gene was assessed using MiSeq technology.FindingsTotal Treg frequency increased overtime during HIV infection, which was normalized in early ART recipients. Tregs in untreated individuals expressed higher levels of activation and immunosuppressive markers (CD39, and LAP(TGF-β1)), which remained unchanged following early ART. Expression of gut migration markers (CCR9, Integrin-β7) by Tregs was elevated during untreated HIV infection, while they declined with the duration of ART but not upon early ART initiation. Notably, gut-homing Tregs expressing LAP(TGF-β1) and CD39 remained higher despite early treatment. Additionally, the increase in LAP(TGF-β1)+ Tregs overtime were consistent with higher demethylation of conserved non-coding sequence (CNS)-1 in the foxp3 gene. Remarkably, LAP(TGF-β1)-expressing Tregs in ECs were significantly higher than in uninfected subjects, while the markers of Treg activation and gut migration were not different.InterpretationEarly ART initiation was unable to control the levels of immunosuppressive Treg subsets and their gut migration potential, which could ultimately contribute to gut tissue fibrosis and HIV disease progression.FundingThis study was funded by the Canadian Institutes of Health Research (CIHR, grant MOP 142294) and in part by the AIDS and Infectious Diseases Network of the Réseau SIDA et maladies infectieuses du Fonds de recherche du Québec-Santé (FRQ-S).

Exome Sequencing Reveals a Putative Role for HLA-C*03:02 in Control of HIV-1 in African Pediatric Populations.

Human leucocyte antigen (HLA) class I molecules present endogenously processed antigens to T-cells and have been linked to differences in HIV-1 disease progression. HLA allelotypes show considerable geographical and inter-individual variation, as does the rate of progression of HIV-1 disease, with long-term non-progression (LTNP) of disease having most evidence of an underlying genetic contribution. However, most genetic analyses of LTNP have occurred in adults of European ancestry, limiting the potential transferability of observed associations to diverse populations who carry the burden of disease. This is particularly true of HIV-1 infected children. Here, using exome sequencing (ES) to infer HLA allelotypes, we determine associations with HIV-1 LTNP in two diverse African pediatric populations. We performed a case-control association study of 394 LTNPs and 420 rapid progressors retrospectively identified from electronic medical records of pediatric HIV-1 populations in Uganda and Botswana. We utilized high-depth ES to perform high-resolution HLA allelotyping and assessed evidence of association between HLA class I alleles and LTNP. Sixteen HLA alleles and haplotypes had significantly different frequencies between Uganda and Botswana, with allelic differences being more prominent in HLA-A compared to HLA-B and C allelotypes. Three HLA allelotypes showed association with LTNP, including a novel association in HLA-C (HLA-B∗57:03, aOR 3.21, Pc = 0.0259; B∗58:01, aOR 1.89, Pc = 0.033; C∗03:02, aOR 4.74, Pc = 0.033). Together, these alleles convey an estimated population attributable risk (PAR) of non-progression of 16.5%. We also observed novel haplotype associations with HLA-B∗57:03-C∗07:01 (aOR 5.40, Pc = 0.025) and HLA-B∗58:01-C∗03:02 (aOR 4.88, Pc = 0.011) with a PAR of 9.8%, as well as a previously unreported independent additive effect and heterozygote advantage of HLA-C∗03:02 with B∗58:01 (aOR 4.15, Pc = 0.005) that appears to limit disease progression, despite weak LD (r2 = 0.18) between these alleles. These associations remained irrespective of gender or country. In one of the largest studies of HIV in Africa, we find evidence of a protective effect of canonical HLA-B alleles and a novel HLA-C association that appears to augment existing HIV-1 control alleles in pediatric populations. Our findings outline the value of using multi-ethnic populations in genetic studies and offer a novel HIV-1 association of relevance to ongoing vaccine studies.

Peacebuilding with “Chinese Characteristics”? Insights from China's Engagement in Myanmar's Peace Process

AbstractThe unpreceded rise of China, amid the decline of the Western-led liberal world order, has brought questions about how China will engage with the various manifestations of that world order, including human rights, trade, and global peace and security regimes. Through the empirical example of Chinese engagement in Myanmar, this article offers an inductive analysis of China's engagement in the field of “peacebuilding”: a prominent manifestation of the liberal world order in post-conflict states. In doing so, the article first argues that China speaks a distinct vernacular of peace, which is characterized by five core features: a focus on stability, prioritisation of development, conditional adherence to state-centricity, prioritization of regional actors in the making of peace, and an aversion to templates and policies for engaging in peace processes. Secondly, the article also highlights that in deploying these features, Chinese engagement in conflict management in Myanmar not only generates tensions between the various features, but is also seen to overlook local needs, bolster elite control of the state, discount the political context of peace processes, and indeed fluctuate in accordance with Chinese strategic and economic interests: all issues that resonate with the dominant critique of liberal peacebuilding projects. In proffering these arguments, the article cautions that as the Chinese approach to peacebuilding matures and strengthens, the ironing out of these contradictions is likely to be challenging.

Gut Microbiome Changes Associated with Epithelial Barrier Damage and Systemic Inflammation during Antiretroviral Therapy of Chronic SIV Infection.

Gut dysbiosis is a common feature associated with the chronic inflammation of HIV infection. Toward understanding the interplay of chronic treated HIV infection, dysbiosis, and systemic inflammation, we investigated longitudinal fecal microbiome changes and plasma inflammatory markers in the nonhuman primate model. Following simian immunodeficiency virus (SIV) infection in rhesus macaques, significant changes were observed in several members of the phylum Firmicutes along with an increase in Bacteroidetes. Viral suppression with antiretroviral therapy (ART) resulted in an early but partial recovery of compositional changes and butyrate producing genes in the gut microbiome. Over the course of chronic SIV infection and long-term ART, however, the specific loss of Faecalibacterium prausnitzii and Treponema succinifaciens significantly correlated with an increase in plasma inflammatory cytokines including IL-6, G-CSF, I-TAC, and MIG. Further, the loss of T. succinifaciens correlated with an increase in circulating biomarkers of gut epithelial barrier damage (IFABP) and microbial translocation (LBP and sCD14). As F. prausnitzii and T. succinifaciens are major short-chain fatty acid producing bacteria, their sustained loss during chronic SV-ART may contribute to gut inflammation and metabolic alterations despite effective long-term control of viremia. A better understanding of the correlations between the anti-inflammatory bacterial community and healthy gut barrier functions in the setting of long-term ART may have a major impact on the clinical management of inflammatory comorbidities in HIV-infected individuals.

Does gender affect immune response in HIV patients?

Gender differences affect the frequency and course of many diseases. This study aimed to determine the gender distribution in HIV-infected patients and investigate the relationship between gender and immune response. The study included HIV-infected patients who followed up in our hospital in 2018. The patients were divided into HIV RNA negative patients (Group 1) and HIV RNA positive patients (Group 2). Patients with diseases that may affect the immune system and those using drugs that affect the immune system were excluded from the study. The evaluation was made of 549 patients, as 305 patients (45 females 14.75%) in Group 1 and 224 patients (23 females, 9.43%) in Group 2. When the CD4/CD8 ratio of male and female patients was compared in both groups, a lower rate was determined in females (0.71-0.58) than males (0.82-0.93). A negative correlation was determined between HIV RNA and the CD4/CD8 ratio in premenopausal females (p=0.045) and males (≤45 years p=0.0001). Clinical studies of HIV infection have demonstrated better initial viremia control in females with primary infection, faster disease progression, and stronger immune activation than males for the same level of viral replication.

CD8 Effector T Cells Function Synergistically With Broadly Neutralizing Antibodies to Enhance Suppression of HIV Infection

HIV-specific CD8 T cells and broadly neutralizing antibodies (bNAbs) both contribute to the control of viremia, but in most cases, neither can completely suppress viral replication. To date, therapeutic vaccines have not been successful in eliciting HIV-specific CD8 T cell or bNAb responses that are capable of preventing long-term viral rebound upon ART cessation. These challenges suggest that a combinatorial approach that harnesses both bNAbs and CD8 T cell responses may be necessary for long term control of viral replication. In this study we demonstrate a synergistic interaction between CD8 T cells and bNAbs using an in vitro model. Our data suggest that this combinatorial approach is very effective at suppressing viral replication in vitro and should be considered in future therapeutic studies.

Immunological effector mechanisms in HIV-1 elite controllers.

HIV-1 elite controllers encompass small populations of people infected with HIV-1 who can spontaneously control plasma viral loads below the limit of detection, in the absence of antiretroviral treatment. Antiviral immune responses are likely to contribute to such an impressive HIV-1 disease outcome. In this review, we discuss recent novel findings regarding antiviral innate and adaptive immune responses in elite controllers. Elite controllers maintain a pool of infected cells in which intact HIV-1 proviruses are more frequently integrated into noncoding regions of the host genome, likely conferring a state of deep latency. This atypical viral reservoir configuration is best explained by potent antiviral immune responses that can successfully eliminate virally infected cells in which proviruses are integrated into permissive chromatin. However, identifying the specific type and nature of this immune selection pressure represents a formidable challenge. Recent studies continue to support the role of HIV-1-specific CD8+ T cells as the main driver of elite immune control of HIV-1, however, increasing evidence suggests that their role is complemented by a fine-tuned interplay with innate immune cell subsets. Therefore, the combination of different immune effector mechanisms may shape antiviral immunity in elite controllers. Understanding the complex immune mechanisms responsible for natural, drug-free HIV-1 control represents a premier avenue to find and develop interventions for a cure of HIV-1 infection. Future single-cell assays designed to uncover the full genetic, epigenetic, transcriptional and functional complexity of antiviral immune responses in elite controllers may allow us to define correlates of antiviral immune protection in greater detail.

Opera houses: from democratization to plutocratic control? Lyric production, economic management, and elite control in the main Spanish opera houses during the period of austerity (2009–2018)

ABSTRACT For 20 years, the main cultural institutions in Europe have faced new challenges such as increasing their efficiency in terms of the use of public resources. However, while operas found themselves under financial pressure during the period of spending cuts starting in 2009, another logic emerged that undermined attempts to govern them in a democratizing way. Under this new paradigm, the dynamics of governance in the large operas were privatized in exchange for increased private patronage. Our analysis of the changes in the management processes of the two main opera houses in Spain showed that neither of them were private or public, but rather, they were both hybrid organizations at the service of plutocratic elites.

Fecal Metabolome Signature in the HIV-1 Elite Control Phenotype: Enrichment of Dipeptides Acts as an HIV-1 Antagonist but a Prevotella Agonist.

HIV-1 elite controllers (EC) are a rare group among HIV-1-infected individuals who can naturally control viral replication for a prolonged period. Due to their heterogeneous nature, no universal mechanism could be attributed to the EC status; instead, several host and viral factors have been discussed as playing a role. In this study, we investigated the fecal metabolome and microbiome in a Swedish cohort of EC (n = 14), treatment-naive viremic progressors (VP; n = 16), and HIV-negative individuals (HC; n = 12). Fecal untargeted metabolomics was performed by four ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). Molecular docking and biochemical microscale thermophoresis (MST) were used to describe the peptide-metabolite interactions. Single-cycle infectivity assays were performed in TZM-Bl cell lines using CCR5- and CXCR4-tropic HIV-1 strains. The microbiome analysis was performed using 16S rRNA sequencing. Th effects of metabolites on bacterial species viability were determined using several clinical isolates. We observed an enrichment of dipeptides in EC compared to VP and HC (adjusted P < 0.05). In silico analysis by molecular docking, in vitro biochemical assays, and ex vivo infection assays identified anti-HIV-1 properties for two dipeptides (WG and VQ) that could bind to the HIV-1 gp120, of which WG was more potent. The microbiome analysis identified enrichment of the genus Prevotella in EC, and these dipeptides supported bacterial growth of the genus Prevotella in vitro. The enrichments of the dipeptides and higher abundance of Prevotella have a distinct mechanism of elite control status in HIV-1 infection that influences host metabolism. IMPORTANCE HIV-1 elite controllers (EC) are a rare group among HIV-1-infected individuals who can naturally control viral replication for a prolonged period. Due to their heterogeneous nature, no universal mechanism could be attributed to the EC status; instead, several host and viral factors have been discussed as playing a role. In this study, we investigated the fecal metabolome and microbiome in a Swedish cohort of EC, treatment-naive viremic progressors (VP), and HIV-negative individuals (HC). We observed an enrichment of dipeptides in EC compared to the other two study groups. In silico and in vitro analyses identified anti-HIV-1 properties for two dipeptides that could bind to the HIV-1 gp120 and act as an HIV-1 antagonist. Furthermore, these dipeptides supported bacterial growth of the genus Prevotella in vitro that was enriched in EC, which influences host metabolism. Thus, increased levels of both dipeptides and Prevotella could provide beneficial effects for EC.