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Science Translational Medicine May 2023Early initiation of antiretroviral therapy (ART) alters viral rebound kinetics after analytic treatment interruption (ATI) and may play a role in promoting HIV-1...
Early initiation of antiretroviral therapy (ART) alters viral rebound kinetics after analytic treatment interruption (ATI) and may play a role in promoting HIV-1 remission. Autologous neutralizing antibodies (aNAbs) represent a key adaptive immune response in people living with HIV-1. We aimed to investigate the role of aNAbs in shaping post-ATI HIV-1 rebound variants. We performed single-genome amplification of HIV-1 from pre-ART and post-ATI plasma samples of 12 individuals who initiated ART early after infection. aNAb activity was quantified using pseudoviruses derived from the most common plasma variant, and the serum dilution that inhibited 50% of viral infections was determined. aNAb responses matured while participants were on suppressive ART, because on-ART plasma and purified immunoglobulin G (IgG) demonstrated improved neutralizing activity against pre-ART HIV-1 strains when compared with pre-ART plasma or purified IgG. Post-ATI aNAb responses exerted selective pressure on the rebounding viruses, because the post-ATI HIV-1 strains were more resistant to post-ATI plasma neutralization compared with the pre-ART virus. Several pre-ATI features distinguished post-treatment controllers from noncontrollers, including an infecting HIV-1 sequence that was more similar to consensus HIV-1 subtype B, more restricted proviral diversity, and a stronger aNAb response. Post-treatment control was also associated with the evolution of distinct N-glycosylation profiles in the HIV-1 envelope. In summary, aNAb responses appeared to mature after early initiation of ART and applied selective pressure on rebounding viruses. The combination of aNAb activity with select HIV-1 sequence and reservoir features identified individuals with a greater chance of post-treatment control.
Topics: Humans; Antibodies, Neutralizing; Anti-Retroviral Agents; HIV Infections; Proviruses; Immunoglobulin G; HIV Antibodies; Viral Load
PubMed: 37163616
DOI: 10.1126/scitranslmed.abq4490 -
Trends in Immunology Mar 2021'Reverse vaccinology 2.0' aims to rationally reproduce template antibody responses, such as broadly neutralizing antibodies against human immunodeficiency virus-1. While... (Review)
Review
'Reverse vaccinology 2.0' aims to rationally reproduce template antibody responses, such as broadly neutralizing antibodies against human immunodeficiency virus-1. While observations of antibody convergence across individuals support the assumption that responses may be replicated, the diversity of humoral immunity and the process of antibody selection are rooted in stochasticity. Drawing from experience with in vitro antibody engineering by directed evolution, we consider how antibody selection may be driven, as in germline-targeting vaccine approaches to elicit broadly neutralizing antibodies and illustrate the potential consequences of over-defining a template antibody response. We posit that the prospective definition of template antibody responses and the odds of replicating them must be considered within the randomness of humoral immunity.
Topics: Antibodies, Neutralizing; Antibody Formation; HIV Antibodies; HIV-1; Humans; Prospective Studies
PubMed: 33514459
DOI: 10.1016/j.it.2021.01.001 -
Current Opinion in HIV and AIDS Sep 2020Immunotherapy strategies alternative to current antiretroviral therapies will need to address viral diversity while increasing the immune system's ability to efficiently... (Review)
Review
PURPOSE OF REVIEW
Immunotherapy strategies alternative to current antiretroviral therapies will need to address viral diversity while increasing the immune system's ability to efficiently target the latent virus reservoir. Antibody-based molecules can be designed based on broadly neutralizing and non-neutralizing antibodies that target free virions and infected cells. These multispecific molecules, either by IgG-like or non-IgG-like in structure, aim to target several independent HIV-1 epitopes and/or engage effector cells to eliminate the replicating virus and infected cells. This detailed review is intended to stimulate discussion on future requirements for novel immunotherapeutic molecules.
RECENT FINDINGS
Bispecific and trispecific antibodies are engineered as a single molecules to target two or more independent epitopes on the HIV-1 envelope (Env). These antibody-based molecules have increased avidity for Env, leading to improved neutralization potency and breadth compared with single parental antibodies. Furthermore, bispecific and trispecific antibodies that engage cellular receptors with one arm of the molecule help concentrate inhibitory molecules to the sites of potential infection and facilitate engagement of immune effector cells and Env-expressing target cells for their elimination.
SUMMARY
Recently engineered antibody-based molecules of different sizes and structures show promise in vitro or in vivo and are encouraging candidates for HIV treatment.
Topics: Antibodies, Neutralizing; Epitopes; HIV Antibodies; HIV Infections; HIV-1; Humans; env Gene Products, Human Immunodeficiency Virus
PubMed: 32732551
DOI: 10.1097/COH.0000000000000640 -
Cell Chemical Biology May 2022Highly active antiretroviral therapy currently used for HIV/AIDS has significantly increased the life expectancy of HIV-infected individuals. It has also improved the... (Review)
Review
Highly active antiretroviral therapy currently used for HIV/AIDS has significantly increased the life expectancy of HIV-infected individuals. It has also improved the quality of life, reduced mortality, and decreased the incidence of AIDS and HIV-related conditions. Currently, however, affected individuals are typically on a lifetime course of several therapeutic drugs, all with the potential for associated toxicity and emergence of resistance. This calls for development of novel, potent, and broad anti-HIV agents able to stop the spread of HIV/AIDS. Significant progress has been made toward identification of anti-HIV-1 broadly neutralizing antibodies (bNAbs). However, antibody-based drugs are costly to produce and store. Administration (by injection only) and other obstacles limit clinical use. In recent years, several highly promising small-molecule HIV-1 entry inhibitors targeting the epitopes of bNAbs have been developed. These newly developed compounds are the focus of the present article.
Topics: Antibodies, Neutralizing; Broadly Neutralizing Antibodies; Epitopes; HIV Antibodies; HIV Infections; HIV-1; Humans; Quality of Life; env Gene Products, Human Immunodeficiency Virus
PubMed: 35353988
DOI: 10.1016/j.chembiol.2022.03.009 -
Journal of Chemical Information and... Jan 2022The use of broadly neutralizing antibodies against human immunodeficiency virus type 1 (HIV-1) has been shown to be a promising therapeutic modality in the prevention of...
The use of broadly neutralizing antibodies against human immunodeficiency virus type 1 (HIV-1) has been shown to be a promising therapeutic modality in the prevention of HIV infection. Understanding the b12-gp120 binding mechanism under physiological conditions may assist the development of more broadly effective antibodies. In this work, the main conformations and interactions between the receptor-binding domain (RBD) of spike glycoprotein gp120 of HIV-1 and the IgG1-b12 mAb are studied. Accelerated molecular dynamics (aMD) and ab initio hybrid molecular dynamics have been combined to determine the most persistent interactions between the most populated conformations of the antibody-antigen complex under physiological conditions. The results show the most persistent receptor-binding mapping in the conformations of the antibody-antigen interface in solution. The binding-free-energy decomposition reveals a small enhancement in the contribution played by the CDR-H3 region to the b12-gp120 interface compared to the crystal structure.
Topics: Amino Acid Sequence; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Immunoglobulin G
PubMed: 34971312
DOI: 10.1021/acs.jcim.1c01143 -
Science (New York, N.Y.) Dec 2019Vaccine induction of broadly neutralizing antibodies (bnAbs) to HIV remains a major challenge. Germline-targeting immunogens hold promise for initiating the induction of...
Vaccine induction of broadly neutralizing antibodies (bnAbs) to HIV remains a major challenge. Germline-targeting immunogens hold promise for initiating the induction of certain bnAb classes; yet for most bnAbs, a strong dependence on antibody heavy chain complementarity-determining region 3 (HCDR3) is a major barrier. Exploiting ultradeep human antibody sequencing data, we identified a diverse set of potential antibody precursors for a bnAb with dominant HCDR3 contacts. We then developed HIV envelope trimer-based immunogens that primed responses from rare bnAb-precursor B cells in a mouse model and bound a range of potential bnAb-precursor human naïve B cells in ex vivo screens. Our repertoire-guided germline-targeting approach provides a framework for priming the induction of many HIV bnAbs and could be applied to most HCDR3-dominant antibodies from other pathogens.
Topics: AIDS Vaccines; Adoptive Transfer; Amino Acid Sequence; Animals; B-Lymphocytes; Broadly Neutralizing Antibodies; Complementarity Determining Regions; Directed Molecular Evolution; Disease Models, Animal; HEK293 Cells; HIV Antibodies; Humans; Immunogenicity, Vaccine; Mice; Mice, Knockout; Precursor Cells, B-Lymphoid; env Gene Products, Human Immunodeficiency Virus
PubMed: 31672916
DOI: 10.1126/science.aax4380 -
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 -
Current Opinion in HIV and AIDS Jul 2019Rare patients naturally control HIV replication without antiretroviral therapy. Understanding the mechanisms implicated in natural HIV control will inform the... (Review)
Review
PURPOSE OF REVIEW
Rare patients naturally control HIV replication without antiretroviral therapy. Understanding the mechanisms implicated in natural HIV control will inform the development of immunotherapies against HIV. Elite controllers are known for developing efficient antiviral T-cell responses, but recent findings suggest that antibody responses also play a significant role in HIV control. We review the key studies that uncovered a potent memory B-cell response and highly functional anti-HIV antibodies in elite controllers, and explore the mechanisms that may account for the distinct properties of their humoral response.
RECENT FINDINGS
Elite controllers maintain a large HIV-specific memory B-cell pool that is sustained by efficient T follicular helper function. Neutralizing antibody rarely show high titers in controllers, but seem capable, at least in certain cases, of neutralizing contemporaneous viral strains. In addition, elite controllers display a unique HIV-specific antibody profile in terms of isotype, antigen specificity, and glycosylation pattern, resulting in polyfunctional antibody effector functions that may promote infected cell lysis and prime effectors of the antiviral immune response.
SUMMARY
Lessons from elite controller studies argue for the importance of integrating the many parameters defining a polyfunctional antibody response when evaluating candidate vaccines and immunotherapeutic approaches directed at HIV.
Topics: Animals; B-Lymphocytes; HIV Antibodies; HIV Infections; Humans; Immunologic Memory; T-Lymphocytes, Helper-Inducer
PubMed: 30973420
DOI: 10.1097/COH.0000000000000554 -
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