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Virologie (Montrouge, France) Aug 2019The establishment of latent infection in long-lived cells is the main obstacle to HIV cure or sustained remission without antiretroviral therapy. The most developed... (Review)
Review
The establishment of latent infection in long-lived cells is the main obstacle to HIV cure or sustained remission without antiretroviral therapy. The most developed therapeutic strategies, in current clinical trials are mainly based on the concept of "shock and kill". They include latency reversing agents (LRAs) to re-activate HIV transcription that can be associated with immunomodulatory treatments. The objective is to eliminate virus-producing cells or to induce the control of HIV after anti-retroviral therapy cessation. HIV reservoir or cancer cells have a number of mechanisms in common. They can escape the immune system and persist by overexpressing survival molecules. This review presents a synthesis of current therapeutic approaches as well as the therapeutic perspectives related to the field of oncology.
Topics: Anti-HIV Agents; Antibodies, Monoclonal; Antibodies, Neutralizing; Apoptosis; Chemotaxis, Leukocyte; Disease Reservoirs; Gene Expression Regulation, Viral; HIV Antibodies; HIV Infections; Histone Deacetylase Inhibitors; Histone Methyltransferases; Humans; Immune Evasion; Immunotherapy; Immunotherapy, Adoptive; T-Lymphocytes; Toll-Like Receptors; Transcription Factors; Transcription, Genetic; Virus Activation; Virus Latency
PubMed: 31414662
DOI: 10.1684/vir.2019.0786 -
Frontiers in Cellular and Infection... 2022The ability to efficiently isolate antigen-specific B cells in high throughput will greatly accelerate the discovery of therapeutic monoclonal antibodies (mAbs) and...
The ability to efficiently isolate antigen-specific B cells in high throughput will greatly accelerate the discovery of therapeutic monoclonal antibodies (mAbs) and catalyze rational vaccine development. Traditional mAb discovery is a costly and labor-intensive process, although recent advances in single-cell genomics using emulsion microfluidics allow simultaneous processing of thousands of individual cells. Here we present a streamlined method for isolation and analysis of large numbers of antigen-specific B cells, including next generation antigen barcoding and an integrated computational framework for B cell multi-omics. We demonstrate the power of this approach by recovering thousands of antigen-specific mAbs, including the efficient isolation of extremely rare precursors of VRC01-class and IOMA-class broadly neutralizing HIV mAbs.
Topics: Antibodies, Neutralizing; B-Lymphocytes; HIV Antibodies; Antigens; Antibodies, Monoclonal; HIV-1
PubMed: 36968243
DOI: 10.3389/fcimb.2022.962945 -
Expert Review of Vaccines Aug 2021: An efficacious vaccine for HIV-1 has been sought for over 30 years to eliminate the virus from the human population. Many challenges have occurred in the attempt to... (Review)
Review
: An efficacious vaccine for HIV-1 has been sought for over 30 years to eliminate the virus from the human population. Many challenges have occurred in the attempt to produce a successful immunogen, mainly caused by the basic biology of the virus. Immunogens have been developed focusing on inducing one or more of the following types of immune responses; neutralizing antibodies, non-neutralizing antibodies, and T-cell mediated responses. One way to better present and develop an immunogen for HIV-1 is through the use of nanotechnology and nanoparticles.: This article gives a basic overview of the HIV-1 vaccine field, as well as nanotechnology, specifically nanovaccines. It then covers the application of nanovaccines made from biological macromolecules to HIV-1 vaccine development for neutralizing antibodies, non-neutralizing antibodies, and T-cell-mediated responses.: Nanovaccines are an area that is ripe for further exploration in HIV-1 vaccine field. Not only are nanovaccines capable of carrying and presenting antigens in native-like conformations, but they have also repeatedly been shown to increase immunogenicity over recombinant antigens alone. Only through further research can the true role of nanovaccines in the development of an efficacious HIV-1 vaccine be established.
Topics: AIDS Vaccines; Antibodies, Neutralizing; HIV Antibodies; HIV-1; Humans; Vaccine Development; Vaccines
PubMed: 34184607
DOI: 10.1080/14760584.2021.1945448 -
MMW Fortschritte Der Medizin May 2022
Topics: COVID-19; HIV Antibodies; HIV Infections; HIV-1; Humans
PubMed: 35513674
DOI: 10.1007/s15006-022-1134-2 -
Nature Communications Nov 2023HIV-1 broadly neutralizing antibodies (bNAbs) are able to suppress viremia and prevent infection. Their induction by vaccination is therefore a major goal. However, in...
HIV-1 broadly neutralizing antibodies (bNAbs) are able to suppress viremia and prevent infection. Their induction by vaccination is therefore a major goal. However, in contrast to antibodies that neutralize other pathogens, HIV-1-specific bNAbs frequently carry uncommon molecular characteristics that might prevent their induction. Here, we perform unbiased sequence analyses of B cell receptor repertoires from 57 uninfected and 46 chronically HIV-1- or HCV-infected individuals and learn probabilistic models to predict the likelihood of bNAb development. We formally show that lower probabilities for bNAbs are predictive of higher HIV-1 neutralization activity. Moreover, ranking bNAbs by their probabilities allows to identify highly potent antibodies with superior generation probabilities as preferential targets for vaccination approaches. Importantly, we find equal bNAb probabilities across infected and uninfected individuals. This implies that chronic infection is not a prerequisite for the generation of bNAbs, fostering the hope that HIV-1 vaccines can induce bNAb development in uninfected people.
Topics: Humans; Broadly Neutralizing Antibodies; HIV Infections; HIV Antibodies; HIV-1; Antibodies, Neutralizing; AIDS Vaccines
PubMed: 37932288
DOI: 10.1038/s41467-023-42906-y -
Vaccine Jan 2020The potential advantages and unique challenges of the early life immune system for the development of HIV-specific broadly neutralizing antibodies were discussed during... (Review)
Review
The potential advantages and unique challenges of the early life immune system for the development of HIV-specific broadly neutralizing antibodies were discussed during a workshop entitled "Immunological Mechanisms of Inducing HIV Immunity in Infants" sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) in conjunction with the 2018 HIVR4P Conference held in Madrid, Spain. A safe and effective HIV vaccine remains a critical need in the fight against the HIV pandemic, especially to prevent emerging infections in infants, adolescents, and young adults. To successfully target these populations, a vaccine should ideally induce protective immune responses during childhood. Interestingly, several recent studies highlighting differences in immune responses between adults and children have suggested that the early life immune system could present advantages for the elicitation of broadly neutralizing antibodies (bnAbs), a response highly desired for an HIV vaccine. Notably, HIV-infected children develop bnAbs responses earlier and more frequently than infected adults; with emerging evidence that the pathways of elicitation of bnAb lineages may differ between adults and children. Moreover, there is precedent for the prevention of lifelong infections with pediatric immunization, and early life provides a unique window of opportunity for the administration of a multi-dose HIV vaccine that will likely be needed to achieve protective immunity. Further understanding of how the distinct early life immune system can be harnessed to trigger bnAb lineages for induction of durable and polyfunctional HIV-specific immunity is warranted. This strategy will include testing promising HIV vaccine candidates in pediatric populations in preclinical and clinical studies. Novel approaches to identify molecular markers of protection are also key to guide and accelerate pediatric HIV vaccine development.
Topics: AIDS Vaccines; Antibodies, Neutralizing; Education; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunization; Infant; Infant, Newborn
PubMed: 31761501
DOI: 10.1016/j.vaccine.2019.11.011 -
Current Opinion in HIV and AIDS Nov 2023Nonhuman primates (NHPs) are seen as the closest animal model to humans in terms of anatomy and immune system makeup. Here, we review how preclinical studies in this... (Review)
Review
PURPOSE OF THE REVIEW
Nonhuman primates (NHPs) are seen as the closest animal model to humans in terms of anatomy and immune system makeup. Here, we review how preclinical studies in this model system are teaching the field of HIV vaccinology the basic immunology that is needed to induce broadly neutralizing antibodies (bnAbs) with vaccination and elicit protective T cell responses. These lessons are being translated into clinical trials to advance towards protective active vaccination against HIV-1 infection.
RECENT FINDINGS
Preclinical vaccination studies in NHPs have shown that highly engineered HIV-1 immunogens can initiate bnAb precursors providing proof of concept for Phase I clinical trials. Additionally, NHP models of HIV-1 infection are elucidating the pathways for bnAb development while serving as systems to evaluate vaccine protection. Innovative immunization strategies have increased affinity maturation of HIV-1 antibodies in long-lived germinal centers. Preclinical studies in macaques have defined the protective level of neutralizing antibodies and have shown that T cell responses can synergize with antibody-mediated immunity to provide protection in the presence of lower neutralizing antibody titers.
SUMMARY
The NHP model provides vaccine regimens and desired antibody and T cell responses that serve as benchmarks for clinical trials, accelerating HIV vaccine design.
Topics: Animals; Humans; HIV Infections; HIV-1; Broadly Neutralizing Antibodies; HIV Antibodies; Antibodies, Neutralizing; Primates; Vaccines; AIDS Vaccines
PubMed: 37712825
DOI: 10.1097/COH.0000000000000819 -
Viruses Jul 2021The entry of HIV-1 into host cells is initiated by the interaction of the viral envelope (Env) spike with the CD4 receptor. During this process, the spike undergoes a... (Review)
Review
The entry of HIV-1 into host cells is initiated by the interaction of the viral envelope (Env) spike with the CD4 receptor. During this process, the spike undergoes a series of conformational changes that eventually lead to the exposure of the fusion peptide located at the N-terminus of the transmembrane glycoprotein, gp41. Recent structural and functional studies have provided important insights into the interaction of Env with CD4 at various stages. However, a fine elucidation of the earliest events of CD4 contact and its immediate effect on the Env conformation remains a challenge for investigation. Here, we summarize the discovery of the quaternary nature of the CD4-binding site in the HIV-1 Env and the role of quaternary contact in the functional interaction with the CD4 receptor. We propose two models for this initial contact based on the current knowledge and discuss how a better understanding of the quaternary interaction may lead to improved immunogens and antibodies targeting the CD4-binding site.
Topics: Antibodies, Neutralizing; Binding Sites, Antibody; CD4 Antigens; Cell Line; HIV Antibodies; HIV Envelope Protein gp120; HIV Envelope Protein gp41; Humans; Models, Molecular; Protein Binding; Protein Conformation; Protein Multimerization; Protein Structure, Quaternary; Virus Internalization
PubMed: 34372611
DOI: 10.3390/v13071405 -
Current HIV/AIDS Reports Oct 2020The application of immunotherapies to HIV presents a new horizon of treatment options, but little is known about what impact they may have on the central nervous system... (Review)
Review
PURPOSE OF REVIEW
The application of immunotherapies to HIV presents a new horizon of treatment options, but little is known about what impact they may have on the central nervous system (CNS). Here we review the most promising immunotherapeutic strategies that can be used to target HIV in the CNS and focus on identifying their potential benefits while exploring the challenges that remain in their application.
RECENT FINDINGS
We have identified five immunotherapeutic strategies that hold potential in managing CNS disease among HIV-infected patients. These include broadly neutralizing antibodies, multi-affinity antibodies, CAR-T cell therapy, checkpoint inhibitors, and therapeutic vaccines. Each class of immunotherapy presents unique mechanisms by which CNS viremia and latency may be addressed but are faced with several challenges. CAR-T cell therapy and multi-affinity antibodies seem to hold promise, but combination therapy is likely to be most effective. However, more human trials are needed before the clinical benefits of these therapies are realized.
Topics: Antibodies, Neutralizing; Central Nervous System; Combined Modality Therapy; HIV Antibodies; HIV Infections; Humans; Immune Checkpoint Inhibitors; Immunotherapy, Adoptive; Viral Vaccines; Viremia
PubMed: 32671567
DOI: 10.1007/s11904-020-00519-w -
Proceedings of the National Academy of... Mar 2023Binding to the host cell receptors, CD4 and CCR5/CXCR4, triggers large-scale conformational changes in the HIV-1 envelope glycoprotein (Env) trimer [(gp120/gp41)] that...
Binding to the host cell receptors, CD4 and CCR5/CXCR4, triggers large-scale conformational changes in the HIV-1 envelope glycoprotein (Env) trimer [(gp120/gp41)] that promote virus entry into the cell. CD4-mimetic compounds (CD4mcs) comprise small organic molecules that bind in the highly conserved CD4-binding site of gp120 and prematurely induce inactivating Env conformational changes, including shedding of gp120 from the Env trimer. By inducing more "open," antibody-susceptible Env conformations, CD4mcs also sensitize HIV-1 virions to neutralization by antibodies and infected cells to antibody-dependent cellular cytotoxicity (ADCC). Here, we report the design, synthesis, and evaluation of novel CD4mcs based on an indoline scaffold. Compared with our current lead indane scaffold CD4mc, BNM-III-170, several indoline CD4mcs exhibit increased potency and breadth against HIV-1 variants from different geographic clades. Viruses that were selected for resistance to the lead indane CD4mc, BNM-III-170, are susceptible to inhibition by the indoline CD4mcs. The indoline CD4mcs also potently sensitize HIV-1-infected cells to ADCC mediated by plasma from HIV-1-infected individuals. Crystal structures indicate that the indoline CD4mcs gain potency compared to the indane CD4mcs through more favorable π-π overlap from the indoline pose and by making favorable contacts with the vestibule of the CD4-binding pocket on gp120. The rational design of indoline CD4mcs thus holds promise for further improvements in antiviral activity, potentially contributing to efforts to treat and prevent HIV-1 infection.
Topics: Humans; HIV-1; HIV Seropositivity; HIV Infections; Antibody-Dependent Cell Cytotoxicity; HIV Envelope Protein gp120; CD4 Antigens; HIV Antibodies
PubMed: 36961924
DOI: 10.1073/pnas.2222073120