Slow progression of pediatric HIV associates with early CD8+ T cell PD-1 expression and a stem-like phenotype

HIV non-progression despite persistent viraemia is rare among antiretroviral therapy (ART)-naïve adults, but relatively common among ART-naïve children. Previous studies indicate that ART-naïve paediatric slow-progressors (PSPs) adopt immune evasion strategies similar to those described in the SIV natural hosts. However, the mechanisms underlying this immunophenotype are not well understood. In a cohort of early-treated infants who underwent analytical treatment interruption (ATI) after 12 months of ART, expression of PD-1 on CD8+ T-cells immediately prior to ATI was the main predictor of slow progression during ATI (r=0.77, p=0.002). PD-1+ CD8+ T-cell frequency was also negatively correlated with CCR5 (r=-0.74, p=0.005) and HLA-DR (r=-0.63, p=0.02) expression on CD4+ T-cells and predicted stronger HIV-specific T-lymphocyte responses. In the CD8+ T-cell compartment of PSPs, we identified an enrichment of stem-like TCF-1+PD-1+ memory cells, whereas paediatric progressors and viraemic adults were populated with a terminally exhausted PD-1+CD39+ population. TCF-1+PD-1+ expression on CD8+ T-cells was associated with higher proliferative activity (r=0.41, p=0.03) and stronger Gag-specific effector functionality. These data prompt the hypothesis that the proliferative burst potential of stem-like HIV-specific cytotoxic cells could be exploited in therapeutic strategies to boost the antiviral response and facilitate remission in early-ART-treated infants with a preserved and non-exhausted T-cell compartment

Slow progression of pediatric HIV associates with early CD8 + T cell PD-1 expression and a stem-like phenotype

HIV nonprogression despite persistent viremia is rare among adults who are naive to antiretroviral therapy (ART) but relatively common among ART-naive children. Previous studies indicate that ART-naive pediatric slow progressors (PSPs) adopt immune evasion strategies similar to those described in natural hosts of SIV. However, the mechanisms underlying this immunophenotype are not well understood. In a cohort of early-treated infants who underwent analytical treatment interruption (ATI) after 12 months of ART, expression of PD-1 on CD8 + T cells immediately before ATI was the main predictor of slow progression during ATI. PD-1 + CD8 + T cell frequency was also negatively correlated with CCR5 and HLA-DR expression on CD4 + T cells and predicted stronger HIV-specific T lymphocyte responses. In the CD8 + T cell compartment of PSPs, we identified an enrichment of stem-like TCF-1 + PD-1 + memory cells, whereas pediatric progressors and viremic adults had a terminally exhausted PD-1 + CD39 + population. TCF-1 + PD-1 + expression on CD8 + T cells was associated with higher proliferative activity and stronger Gag-specific effector functionality. These data prompted the hypothesis that the proliferative burst potential of stem-like HIV-specific cytotoxic cells could be exploited in therapeutic strategies to boost the antiviral response and facilitate remission in infants who received early ART with a preserved and nonexhausted T cell compartment

Role of CD8+ T cells in adult and paediatric HIV infection

Infection with HIV is a continuing global health problem. Antiretroviral therapy effectively suppresses viraemia, but the viral reservoir in latently infected CD4+ T-cells persists for decades and is the main obstacle to HIV eradication. The central role of CD8+ T-cellmediated immune control of natural adult HIV infection has long been established and recent studies suggest that CD8+ T-cells are likely to be crucial in eliminating reactivated reservoirs. However, the questions of what constitutes an effective anti-HIV CD8+ T-cell response and how to induce it therapeutically are outstanding. Moreover, even less is known about the antiviral function of CD8+ T-cells in paediatric HIV infection. Although outnumbered by adult infections, paediatric infection may offer opportunities to achieve HIV cure that could be more widely applicable to cure strategies in adults. Here, I explore the specific aspects of the interplay between host and virus in order to gain a better understanding of the optimal CD8+ T-cell-mediated immune responses. I demonstrate that in contrast to the Gag-specific response that mediates viral control in the context of HLA-B&amp;ast;57, among HLA-B&amp;ast;14-restricted responses, Env-specific cells are more potent than those targeting Gag. This is associated with higher antigen sensitivity and stronger selection pressure in the Env-specific population. I define two broadly distinct phenotypes of HIV non-progression in children. These are characterised by differential protein specificity of the antiviral CD8+ T-cell response but children of both phenotypes demonstrate strong selection pressure exerted on the virus by CD8+ T-cells in the first weeks of life. Next, in the context of the HIV vaccine tested in the Phambili trial, I report an HLA-specific effect of vaccine on disease progression, as a result of altering the natural CD8+ T-cell immunodominance hierarchy. Finally, I demonstrate a new method which allows to selectively deplete human HIV-specific CD8+ T-cell in vitro, and thereby to evaluate the contribution and efficacy of particular CD8+ T-cell specificities to viral inhibition – a critical question to HIV vaccine design and reservoir eradication studies. The work described here adds important insights to our understanding of the HIV-specific CD8+ T-cell responses that are generated from birth through childhood and into adulthood and is relevant to the future studies directed at harnessing the most effective CD8+ T-cell response to achieve HIV cure.</p

Subdominant Gag-specific anti-HIV efficacy in an HLA-B*57-positive elite controller

Despite the discovery of HIV over three decades ago, the 2008 ‘Berlin patient’ is the only case of sustained HIV remission. Other cases of apparent ‘cure’ eventually relapsed [1] and although early antiretroviral therapy (ART) has recently gained traction as a factor contributing to remission [2,3], most cases are likely to relapse [4]. In contrast, relapse in ‘elite controllers’ of HIV infection is less common. These are ART-naïve individuals who spontaneously suppress viremia to undetectable levels. Approximately 40% of elite controllers express HLA-B*57 [5], an example being the original 1999 ‘Berlin patient’, in whom virologic control has been maintained for &gt;15 years to date [6]

Phosphorylation in the amino terminus of tau prevents inhibition of anterograde axonal transport

Alzheimer\u27s disease (AD) and other tauopathies are characterized by fibrillar inclusions composed of the microtubule-associated protein, tau. Recently, we demonstrated that the N-terminus of tau (amino acids [aa] 2-18) in filamentous aggregates or N-terminal tau isoforms activate a signaling cascade involving protein phosphatase 1 and glycogen synthase kinase 3 that results in inhibition of anterograde fast axonal transport (FAT). We have termed the functional motif comprised of aa 2-18 in tau the phosphatase-activating domain (PAD). Here, we show that phosphorylation of tau at tyrosine 18, which is a fyn phosphorylation site within PAD, prevents inhibition of anterograde FAT induced by both filamentous tau and 6D tau. Moreover, Fyn-mediated phosphorylation of tyrosine 18 is reduced in disease-associated forms of tau (e.g., tau filaments). A novel PAD-specific monoclonal antibody revealed that exposure of PAD in tau occurs before and more frequently than tyrosine 18 phosphorylation in the evolution of tangle formation in AD. These results indicate that N-terminal phosphorylation may constitute a regulatory mechanism that controls tau-mediated inhibition of anterograde FAT in AD

Post-treatment control or treated controllers? Viral remission in treated and untreated primary HIV infection

Objective(s): An HIV cure will impose aviraemia that is sustained following the withdrawal of antiretroviral therapy (ART). Understanding the efficacy of novel interventions aimed at curing HIV requires characterization of both natural viral control and the effect of ART on viral control after treatment interruption. Design: Analysis of transient viral control in recent seroconverters in the Short Pulse AntiRetroviral Therapy at Acute Seroconversion trial. Methods: We compared untreated and treated HIV seroconverters (n = 292) and identified periods of control (plasma HIV RNA < 400 copies/ml for ≥16 weeks off therapy) in 7.9% of ART-naive participants, and in 12.0% overall. HIV DNA was measured by qPCR, and HIV-specific CD8+ responses were measured by enzyme-linked immunosorbent spot assay (ELISpot). T-cell activation and exhaustion were measured by flow cytometry. Results: At baseline, future controllers had lower HIV DNA, lower plasma HIV RNA, higher CD4+ : CD8+ ratios (all P < 0.001) and higher CD4+ cell counts (P < 0.05) than noncontrollers. Among controllers, the only difference between the untreated and those who received ART was higher baseline HIV RNA in the latter (P = 0.003), supporting an added ART effect. Conclusion: Consideration of spontaneous remission in untreated individuals will be critical to avoid overestimating the effect size of new interventions used in HIV cure studies

Lower Viral Loads and Slower CD4+ T-Cell Count Decline in MRKAd5 HIV-1 Vaccinees Expressing Disease-Susceptible HLA-B*58:02

Background. HLA strongly influences human immunodeficiency virus type 1 (HIV-1) disease progression. A major contributory mechanism is via the particular HLA-presented HIV-1 epitopes that are recognized by CD8+ T-cells. Different populations vary considerably in the HLA alleles expressed. We investigated the HLA-specific impact of the MRKAd5 HIV-1 Gag/Pol/Nef vaccine in a subset of the infected Phambili cohort in whom the disease-susceptible HLA-B*58:02 is highly prevalent. Methods. Viral loads, CD4+ T-cell counts, and enzyme-linked immunospot assay–determined anti-HIV-1 CD8+ T-cell responses for a subset of infected antiretroviral-naive Phambili participants, selected according to sample availability, were analyzed. Results. Among those expressing disease-susceptible HLA-B*58:02, vaccinees had a lower chronic viral set point than placebo recipients (median, 7240 vs 122 500 copies/mL; P = .01), a 0.76 log10 lower longitudinal viremia level (P = .01), and slower progression to a CD4+ T-cell count of <350 cells/mm3 (P = .02). These differences were accompanied by a higher Gag-specific breadth (4.5 vs 1 responses; P = .04) and magnitude (2300 vs 70 spot-forming cells/106 peripheral blood mononuclear cells; P = .06) in vaccinees versus placebo recipients. Conclusions. In addition to the known enhancement of HIV-1 acquisition resulting from the MRKAd5 HIV-1 vaccine, these findings in a nonrandomized subset of enrollees show an HLA-specific vaccine effect on the time to CD4+ T-cell count decline and viremia level after infection and the potential for vaccines to differentially alter disease outcome according to population HLA composition. Clinical Trials Registration. NCT00413725, DOH-27-0207-1539