Conformational transitions of membrane-bound HIV-1 fusion peptide

AbstractThe human immunodeficiency virus type-1 (HIV-1) fusion peptide (FP) functions as a non-constitutive membrane anchor that translocates into membranes during envelope glycoprotein-induced fusion. Here, by means of infrared spectroscopy (IR) and of various bilayer-perturbation assays, we describe the peptide conformations that are accessible to its membrane-bound state and the transitions occurring between them. The peptide underwent a conformational transition from a predominantly α-helical structure to extended β-type strands by increasing peptide concentration in 1-palmitoyl-2-oleoylphosphatidylglycerol (POPG) vesicles. A comparable transition was observed at a fixed 1:100 peptide-to-lipid ratio when calcium was added to vesicles containing prebound α-helical peptide. Cation binding induced an increase in the amount of H-bonded carbonyls within the interfacial region of POPG. Calcium-promoted α→β conversion in membranes correlated with the closure of preformed lytic pores and took place in dispersed (nonaggregated) vesicles doped with poly(ethylene glycol)–lipid conjugates, showing that the conformational transition was independent of vesicle aggregation. We conclude that the target membrane conditions modulate the eventual structure adopted by the HIV-1 FP. Conformational polymorphism of the inserted peptide may contribute to the flexibility of the fusogenic complex during the fusion reaction cycle, and/or may be related to target membrane perturbation at the fusion locus

Highlights from the Inaugural HIV Reservoirs and Immune Control Conference, October 1st–4th 2023, Malahide Ireland

The inaugural FASEB HIV Reservoirs and Immune Control Conference brought researchers together from across the globe to discuss reservoir dynamics in clinical cohorts. It extended over 4 days in the seaside town of Malahide, Ireland. The scientific sessions covered a broad range of topics, including: 1) HIV pathogenesis and control, 2) reservoirs and viral expression, 3) pediatric reservoirs, 4) innate immunity and B cell responses, 5) environmental factors affecting pathogenesis, 6) loss of virologic control, and 7) HIV-2. The following article provides a brief summary of the meeting proceedings and includes a supplementary document with the meeting abstracts.

Persistent resistance to HIV-1 infection in CD4 T cells from exposed uninfected Vietnamese individuals is mediated by entry and post-entry blocks

BACKGROUND: We have previously reported that CD4 T cells from some exposed uninfected (EU) Vietnamese intravenous drug users are relatively resistant to HIV infection in vitro. Here, we further characterized the restriction of viral replication in CD4 T cells from five EUs and assessed its persistence in serial samples. RESULTS: CD4 T cells and/or PBMC sampled during a period of between 2 and 6 years were challenged with replication-competent HIV-1 and other retroviral particles pseudotyped with envelope proteins of various tropisms. CCR5 expression and function in resistant CD4 T cells was evaluated. The step at which HIV-1 replication is restricted was investigated by real-time PCR quantification of HIV-1 reverse transcripts. We identified three patterns of durable HIV-1 restriction in EU CD4 T cells. CD4 T cells from four of the five EU subjects were resistant to HIV-1 R5 infection. In two cases this resistance was associated with low CCR5 surface expression, which was itself associated with heterozygous CCR5 mutations. In the other two cases, CD4 T cells were resistant to HIV-1 R5 infection despite normal CCR5 expression and signaling function, and normal β-chemokine secretion upon CD4 T cell activation. Instead, restriction appeared to be due to enhanced CD4 T cell sensitivity to β-chemokines in these two subjects. In the fifth EU subject the restriction involved post-entry steps of viral replication and affected not only HIV-1 but also other lentiviruses. The restriction was not overcome by a high viral inoculum, suggesting that it was not mediated by a saturable inhibitory factor. CONCLUSION: Various constitutive mechanisms of CD4 T cell resistance to HIV-1 infection, affecting entry or post-entry steps of viral replication, are associated with resistance to HIV-1 in subjects who remain uninfected despite long-term high-risk behavior

Dendritic Cells from HIV Controllers Have Low Susceptibility to HIV-1 Infection In Vitro but High Capacity to Capture HIV-1 Particles

ANRS CO21 CODEX cohortInternational audienceHIV controllers (HICs), rare HIV-1 infected individuals able to control viral replication without antiretroviral therapy, are characterized by an efficient polyfunctional and cytolytic HIV-specific CD8+ T cell response. The mechanisms underlying the induction and maintenance of such response in many HICs despite controlled viremia are not clear. Dendritic cells play a crucial role in the generation and reactivation of T cell responses but scarce information is available on those cells in HICs. We found that monocyte derived dendritic cells (MDDCs) from HICs are less permissive to HIV-1 infection than cells from healthy donors. In contrast MDDCs from HICs are particularly efficient at capturing HIV-1 particles when compared to cells from healthy donors or HIV-1 patients with suppressed viral load on antiretroviral treatment. MDDCs from HICs expressed on their surface high levels of syndecan-3, DC-SIGN and MMR, which could cooperate to facilitate HIV-1 capture. The combination of low susceptibility to HIV-1 infection but enhanced capacity to capture particles might allow MDDCs from HICs to preserve their function from the deleterious effect of infection while facilitating induction of HIV-specific CD8+ T cells by cross-presentation in a context of low viremia

Extremely low viral reservoir in treated chronically HIV-1-infected individuals

Altres ajuts: This research was sponsored in part by Grifols and by Merck Sharp & Dohme España, S.A. (IISP 54925). The funding organizations had no input in the design of the study; in the collection, analyses, or interpretation of the data; writing of the manuscript; or in the decision to submit the study for publication. NH received a post-doctoral grant from the Jaqueline Beytout Foundation. FG received the support of "José María Segovia de Arana" contracts (2019) and MMT from the NIH (R01AI143457).Small viral reservoirs are found predominantly in HIV-1 controllers and individuals treated during acute/early HIV-1 infection. However, other HIV + individuals could naturally also harbour low viral reservoirs. We screened 451 HIV-1-infected treated-individuals with suppressed plasma viremia for at least 3 years and stored cryopreserved peripheral blood mononuclear cells (PBMCs). Total HIV-DNA was analysed in PBMCs with ddPCR. Individuals with 50 HIV-DNA copies/10 6 PBMCs) to analyse total HIV-DNA, T-cell and NK-cell populations, HIV-1 specific antibodies, and plasma inflammation markers. We found that 9.3% of the individuals screened had <50 HIV-DNA copies/10 6 PBMCs. At least 66% initiated cART during the chronic phase of HIV-1 infection (cp-LoViReT). Cp-LoViReT harboured lower levels of HIV-DNA before cART and after treatment introduction the decays were greater compared to controls. They displayed a marked decline in quantity and avidity in HIV-specific antibodies after initiation of cART. Cp-LoViReT had fewer CD8 + T and T in the absence of cART, and higher CD8 + T after 18 months on therapy. Treated chronically HIV-1-infected LoViReT represent a new phenotype of individuals characterized by an intrinsically reduced viral reservoir, less impaired CD8 + T-cell compartment before cART, and low circulating HIV-1 antigens despite being treated in the chronic phase of infection. The identification of this unique group of individuals is of great interest for the design of future eradication studies. MSD Spai

Affinity for the Interface Underpins Potency of Antibodies Operating In Membrane Environments

The contribution of membrane interfacial interactions to recognition of membrane-embedded antigens by antibodies is currently unclear. This report demonstrates the optimization of this type of antibodies via chemical modification of regions near the membrane but not directly involved in the recognition of the epitope. Using the HIV-1 antibody 10E8 as a model, linear and polycyclic synthetic aromatic compounds are introduced at selected sites. Molecular dynamics simulations predict the favorable interactions of these synthetic compounds with the viral lipid membrane, where the epitope of the HIV-1 glycoprotein Env is located. Chemical modification of 10E8 with aromatic acetamides facilitates the productive and specific recognition of the native antigen, partially buried in the crowded environment of the viral membrane, resulting in a dramatic increase of its capacity to block viral infection. These observations support the harnessing of interfacial affinity through site-selective chemical modification to optimize the function of antibodies that target membrane-proximal epitopes.We are grateful to Professor Ueda (Kyushu University) for valuable advice. C.D. acknowledges RES (Red Espanola de Supercomputacio ' n) for providing computational resources. S.I. received a pre-doctoral fellowship from the Basque Government. P.C. acknowledges a research associate contract from the University of the Basque Country (DOCREC18/01) and a postdoctoral fellowship from the Basque Government (POS_2018_1_0066).This study was supported by the following grants: European Commission (790012 SI H2020MSCA-IF-2017 to E.R., J.-P.J., and J.L.N.); US NIAID (NIH) (R01 AI143563 to M.B.Z.); James B. Pendleton Charitable Trust (to M.B.Z.); Grant-in-Aid for Scientific Research on Innovative Areas "Chemistry for Multimolecular Crowding Biosystems, JSPS KAKENHI (JP17H06349 to A.O.); JSPS KAKENHI (15K06962 and 20H03228 to J.M.M.C.); Spanish MINECO (BIO2015-64421R and MINECO/AEI/FEDER, UE to J.L.N.); Spanish MCIU (RTI2018-095624B-C21 and MCIU/AEI/FEDER, UE to J.L.N.); and the Basque Government (IT1196-19) (to J.L.N.). C.E. acknowledges funding from Medical Research Council (MC_UU_12010/unit programs G0902418 and MC_UU_12025), Wolfson Foundation, Deutsche Forschungsgemeinschaft (Research unit 1905, Excellence Cluster Balance of the Microverse, Collaborative Research Centre 1278 Polytarget), Wellcome Institutional Strategic Support Fund, Oxford internal funds (EPA Cephalosporin Fund and John Fell Fund), and support from the Micron Oxford Advanced Bioimaging Unit (Wellcome Trust funding 107457/Z/15/Z). This research was undertaken, in part, thanks to funding from the CIFAR Azrieli Global Scholar program (to J.-P.J.) and the Canada Research Chairs program (950-231604 to J.-P.J.). This work was also supported by the Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research [BINDS] from AMED JP19am0101091)

International AIDS Society global scientific strategy: towards an HIV cure 2016

Antiretroviral therapy is not curative. Given the challenges in providing lifelong therapy to a global population of more than 35 million people living with HIV, there is intense interest in developing a cure for HIV infection. The International AIDS Society convened a group of international experts to develop a scientific strategy for research towards an HIV cure. This Perspective summarizes the group's strategy

Immunometabolism and HIV-1 pathogenesis: food for thought

International audienceAntiretroviral therapies efficiently block HIV-1 replication but need to be maintained for life. Moreover, chronic inflammation is a hallmark of HIV-1 infection that persists despite treatment. There is, therefore, an urgent need to better understand the mechanisms driving HIV-1 pathogenesis and to identify new targets for therapeutic intervention. In the past few years, the decisive role of cellular metabolism in the fate and activity of immune cells has been uncovered, as well as its impact on the outcome of infectious diseases. Emerging evidence suggests that immunometabolism has a key role in HIV-1 pathogenesis. The metabolic pathways of CD4+ T cells and macrophages determine their susceptibility to infection, the persistence of infected cells and the establishment of latency. Immunometabolism also shapes immune responses against HIV-1, and cell metabolic products are key drivers of inflammation during infection. In this Review, we summarize current knowledge of the links between HIV-1 infection and immunometabolism, and we discuss the potential opportunities and challenges for therapeutic interventions

HIV cure research: advances and prospects.

International audienceThirty years after the identification of HIV, a cure for HIV infection is still to be achieved. Advances of combined antiretroviral therapy (cART) in recent years have transformed HIV infection into a chronic disease when treatment is available. However, in spite of the favorable outcomes provided by the newer therapies, cART is not curative and patients are at risk of developing HIV-associated disorders. Moreover, universal access to antiretroviral treatment is restricted by financial obstacles. This review discusses the most recent strategies that have been developed in the search for an HIV cure and to improve life quality of people living with HIV