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The Journal of Clinical Investigation Feb 2016Current antiretroviral drug therapies do not cure HIV-1 because they do not eliminate a pool of long-lived cells harboring immunologically silent but... (Review)
Review
Current antiretroviral drug therapies do not cure HIV-1 because they do not eliminate a pool of long-lived cells harboring immunologically silent but replication-competent proviruses - termed the latent reservoir. Eliminating this reservoir and stimulating the immune response to control infection in the absence of therapy remain important but unsolved goals of HIV-1 cure research. Recently discovered broadly neutralizing antibodies (bNAbs) exhibit remarkable breadth and potency in their ability to neutralize HIV-1 in vitro, and recent studies have demonstrated new therapeutic applications for passively administered bNAbs in vivo. This Review discusses the roles bNAbs might play in HIV-1 treatment regimens, including prevention, therapy, and cure.
Topics: Animals; Antibodies, Neutralizing; HIV Antibodies; HIV Infections; HIV-1; Humans; Remission Induction
PubMed: 26752643
DOI: 10.1172/JCI80561 -
PLoS Pathogens Feb 2020Antibody functions such as neutralization require recognition of antigen by the Fab region, while effector functions are additionally mediated by interactions of the Fc...
Antibody functions such as neutralization require recognition of antigen by the Fab region, while effector functions are additionally mediated by interactions of the Fc region with soluble factors and cellular receptors. The efficacy of individual antibodies varies based on Fab domain characteristics, such as affinity for antigen and epitope-specificity, and on Fc domain characteristics that include isotype, subclass, and glycosylation profile. Here, a series of HIV-specific antibody subclass and hinge variants were constructed and tested to define those properties associated with differential effector function. In the context of the broadly neutralizing CD4 binding site-specific antibody VRC01 and the variable loop (V3) binding antibody 447-52D, hinge truncation and extension had a considerable impact on the magnitude of phagocytic activity of both IgG1 and IgG3 subclasses. The improvement in phagocytic potency of antibodies with extended hinges could not be attributed to changes in either intrinsic antigen or antibody receptor affinity. This effect was specific to phagocytosis and was generalizable to different phagocytes, at different effector cell to target ratios, for target particles of different size and composition, and occurred across a range of antibody concentrations. Antibody dependent cellular cytotoxicity and neutralization were generally independent of hinge length, and complement deposition displayed variable local optima. In vivo stability testing showed that IgG molecules with altered hinges can exhibit similar biodistribution and pharmacokinetic profiles as IgG1. Overall, these results suggest that when high phagocytic activity is desirable, therapeutic antibodies may benefit from being formatted as human IgG3 or engineered IgG1 forms with elongated hinges.
Topics: Antibodies, Neutralizing; Antibody-Dependent Cell Cytotoxicity; HEK293 Cells; HIV Antibodies; HIV-1; Hinge Exons; Humans; Immunoglobulin G; Phagocytosis
PubMed: 32092122
DOI: 10.1371/journal.ppat.1008083 -
Microbial Biotechnology Jul 2022Preclinical studies have shown that the induction of secretory IgA (sIgA) in mucosa and neutralizing antibodies (NAbs) in sera is essential for designing vaccines that...
Preclinical studies have shown that the induction of secretory IgA (sIgA) in mucosa and neutralizing antibodies (NAbs) in sera is essential for designing vaccines that can effectively block the transmission of HIV-1. We previously showed that a vaccine consisting of bacterium-like particles (BLPs) displaying Protan-gp120AE-MTQ (PAM) could induce mucosal immune responses through intranasal (IN) immunization in mice and NAbs through intramuscular (IM) immunization in guinea pigs. Here, we evaluated the ability of this vaccine BLP-PAM to elicit HIV-1-specific mucosal and systemic immune responses through IN and IM immunization combination strategies in rhesus macaques. First, the morphology, antigenicity and epitope accessibility of the vaccine were analysed by transmission electron microscopy, bio-layer interferometry and ELISA. In BLP-PAM-immunized macaques, HIV-1-specific sIgA were rapidly induced through IN immunization in situ and distant mucosal sites, although the immune responses are relatively weak. Furthermore, the HIV-1-specific IgG and IgA antibody levels in mucosal secretions were enhanced and maintained, while production of serum NAbs against heterologous HIV-1 tier 1 and 2 pseudoviruses was elicited after IM boost. Additionally, situ mucosal responses and systemic T cell immune responses were improved by rAd2-gp120AE boost immunization via the IN and IM routes. These results suggested that BLP-based delivery in combination with the IN and IM immunization approach represents a potential vaccine strategy against HIV-1.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Guinea Pigs; HIV Antibodies; HIV-1; Immunoglobulin A, Secretory; Immunoglobulin G; Macaca mulatta; Mice; Mucous Membrane
PubMed: 35290714
DOI: 10.1111/1751-7915.14022 -
Retrovirology Jul 2018A central puzzle in HIV-1 research is the inability of vaccination or even infection to reliably elicit humoral responses against broadly neutralizing epitopes in the... (Review)
Review
A central puzzle in HIV-1 research is the inability of vaccination or even infection to reliably elicit humoral responses against broadly neutralizing epitopes in the HIV-1 envelope protein. In infected individuals, broadly neutralizing antibodies (bNAbs) do arise in a substantial minority, but only after 2 or more years of chronic infection. All known bNAbs possess at least one of three traits: a high frequency of somatic hypermutation, a long third complementarity determining region in the antibody heavy chain (HCDR3), or significant poly- or autoreactivity. Collectively, these observations suggest a plausible explanation for the rarity of many types of bNAbs: namely, that their generation is blocked by immunological tolerance or immune response checkpoints, thereby mandating that B cells take a tortuous path of somatic evolution over several years to achieve broadly neutralizing activity. In this brief review, we discuss the evidence for this tolerance hypothesis, its implications for HIV-1 vaccine design, and potential ways to access normally forbidden compartments of the antibody repertoire by modulating or circumventing tolerance controls.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Antibody Specificity; B-Lymphocytes; HIV Antibodies; HIV Infections; HIV-1; Humans; Immune Tolerance
PubMed: 30055635
DOI: 10.1186/s12977-018-0435-0 -
Frontiers in Immunology 2021Broadly neutralizing antibodies (bNAbs) are currently being assessed in clinical trials for their ability to prevent HIV infection. Single chain variable fragments...
Broadly neutralizing antibodies (bNAbs) are currently being assessed in clinical trials for their ability to prevent HIV infection. Single chain variable fragments (scFv) of bNAbs have advantages over full antibodies as their smaller size permits improved diffusion into mucosal tissues and facilitates vector-driven gene expression. We have previously shown that scFv of bNAbs individually retain significant breadth and potency. Here we tested combinations of five scFv derived from bNAbs CAP256-VRC26.25 (V2-apex), PGT121 (N332-supersite), 3BNC117 (CD4bs), 8ANC195 (gp120-gp41 interface) and 10E8v4 (MPER). Either two or three scFv were combined in equimolar amounts and tested in the TZM-bl neutralization assay against a multiclade panel of 17 viruses. Experimental IC and IC data were compared to predicted neutralization titers based on single scFv titers using the Loewe additive and the Bliss-Hill model. Like full-sized antibodies, combinations of scFv showed significantly improved potency and breadth compared to single scFv. Combinations of two or three scFv generally followed an independent action model for breadth and potency with no significant synergy or antagonism observed overall although some exceptions were noted. The Loewe model underestimated potency for some dual and triple combinations while the Bliss-Hill model was better at predicting IC titers of triple combinations. Given this, we used the Bliss-Hill model to predict the coverage of scFv against a 45-virus panel at concentrations that correlated with protection in the AMP trials. Using IC titers and concentrations of 1μg/mL, there was 93% coverage for one dual scFv combination (3BNC117+10E8v4), and 96% coverage for two of the triple combinations (CAP256.25+3BNC117+10E8v4 and PGT121+3BNC117+10E8v4). Combinations of scFv, therefore, show significantly improved breadth and potency over individual scFv and given their size advantage, have potential for use in passive immunization.
Topics: Broadly Neutralizing Antibodies; Genetic Engineering; HEK293 Cells; HIV Antibodies; HIV Envelope Protein gp160; HIV Infections; HIV-1; Humans; Immunization, Passive; Neutralization Tests; Single-Chain Antibodies
PubMed: 34603312
DOI: 10.3389/fimmu.2021.734110 -
Genes and Immunity Aug 2022The development of an effective vaccine against HIV is desperately needed. The successive failures of HIV vaccine efficacy trials in recent decades have shown the... (Review)
Review
The development of an effective vaccine against HIV is desperately needed. The successive failures of HIV vaccine efficacy trials in recent decades have shown the difficulty of inducing an appropriate protective immune response to fight HIV. Different correlates of antibody parameters associated with a decreased risk of HIV-1 acquisition have been identified. However, these parameters are difficult to reproduce and improve, possibly because they have an intricate and combined action. Here, we describe the numerous antibody (Ab) functions associated with HIV-1 protection and report the interrelated parameters regulating their complex functions. Indeed, besides neutralizing and Fc-mediated activity, additional factors such as Ab type, concentration and kinetics of induction, and Fc-receptor expression and binding capacity also influence the protective effect conferred by Abs. As these parameters were described to be associated with ethnicity, age and sex, these additional factors must be considered for the development of an effective immune response. Therefore, future vaccine designs need to consider these multifaceted Ab functions together with the demographic attributes of the patient populations.
Topics: AIDS Vaccines; Antibodies, Neutralizing; Antibody Formation; HIV Antibodies; HIV Infections; HIV-1; Humans; Receptors, Fc; Vaccination
PubMed: 35688931
DOI: 10.1038/s41435-022-00175-7 -
Current Opinion in HIV and AIDS May 2017Here we discuss recently developed HIV-1 entry inhibitors that can target multiple epitopes on the HIV-1 envelope glycoprotein (Env), with an emphasis on eCD4-Ig. Some... (Review)
Review
PURPOSE OF REVIEW
Here we discuss recently developed HIV-1 entry inhibitors that can target multiple epitopes on the HIV-1 envelope glycoprotein (Env), with an emphasis on eCD4-Ig. Some of these inhibitors are more potent and broader than any single antibody characterized to date. We also discuss the use of recombinant adeno-associated virus (rAAV) vectors as a platform for long-term expression of these inhibitors.
RECENT FINDINGS
Much of the exterior of HIV-1 Env can be targeted by broadly neutralizing antibodies (bNAbs). Recent studies combine the variable regions or Fabs from different bNAbs, often with the receptor-mimetic components, to create broad, potent, and hard-to-escape inhibitors. rAAV vectors can express these inhibitors for years in vivo, highlighting their ability to prevent or treat HIV-1 infection.
SUMMARY
By targeting multiple epitopes on Env, bispecific and antibody-like inhibitors can be broader and more potent than bNAbs. These inhibitors can provide long-term protection from, and perhaps suppression of, HIV-1 if they are administered by a delivery platform, like rAAV vectors, but only after rAAV limitations are addressed.
Topics: Animals; Anti-HIV Agents; Dependovirus; HIV Antibodies; HIV Infections; HIV-1; Humans; env Gene Products, Human Immunodeficiency Virus
PubMed: 28422793
DOI: 10.1097/COH.0000000000000367 -
Cell Host & Microbe Apr 2020Broadly neutralizing antibodies (bnAbs) against HIV-1 provide critical insights into co-evolution between the virus and human B cell responses. In this issue of Cell...
Broadly neutralizing antibodies (bnAbs) against HIV-1 provide critical insights into co-evolution between the virus and human B cell responses. In this issue of Cell Host & Microbe, Shen et al. (2020) describe a rare mutation in an antibody lineage targeting the fusion peptide of HIV-1 envelope creating a critical bifurcation, with only one path leading to bnAb development.
Topics: Antibodies, Neutralizing; Broadly Neutralizing Antibodies; HIV Antibodies; HIV Infections; HIV-1; Humans; Mutation
PubMed: 32272069
DOI: 10.1016/j.chom.2020.03.017 -
Frontiers in Immunology 2021Understanding the interplay between systemic and mucosal anti-HIV antibodies can provide important insights to develop new prevention strategies. We used passive...
Cooperation Between Systemic IgG1 and Mucosal Dimeric IgA2 Monoclonal Anti-HIV Env Antibodies: Passive Immunization Protects Indian Rhesus Macaques Against Mucosal SHIV Challenges.
Understanding the interplay between systemic and mucosal anti-HIV antibodies can provide important insights to develop new prevention strategies. We used passive immunization systemic and/or mucosal routes to establish cause-and-effect between well-characterized monoclonal antibodies and protection against intrarectal (i.r.) SHIV challenge. In a pilot study, for which we re-used animals previously exposed to SHIV but completely protected from viremia by different classes of anti-HIV neutralizing monoclonal antibodies (mAbs), we made a surprise finding: low-dose intravenous (i.v.) HGN194-IgG1, a human neutralizing mAb against the conserved V3-loop crown, was ineffective when given alone but protected 100% of animals when combined with i.r. applied HGN194-dIgA2 that by itself had only protected 17% of the animals. Here we sought to confirm the unexpected synergy between systemically administered IgG1 and mucosally applied dIgA HGN194 forms using six groups of naïve macaques (n=6/group). Animals received i.v. HGN194-IgG1 alone or combined with i.r.-administered dIgA forms; controls remained untreated. HGN194-IgG1 i.v. doses were given 24 hours before - and all i.r. dIgA doses 30 min before - i.r. exposure to a single high-dose of SHIV-1157ipEL-p. All controls became viremic. Among passively immunized animals, the combination of IgG1+dIgA2 again protected 100% of the animals. In contrast, single-agent i.v. IgG1 protected only one of six animals (17%) - consistent with our pilot data. IgG1 combined with dIgA1 or dIgA1+dIgA2 protected 83% (5/6) of the animals. The dIgA1+dIgA2 combination without the systemically administered dose of IgG1 protected 67% (4/6) of the macaques. We conclude that combining suboptimal antibody defenses at systemic and mucosal levels can yield synergy and completely prevent virus acquisition.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Neutralizing; HIV Antibodies; HIV-1; Immunity, Mucosal; Immunization, Passive; Macaca mulatta; Pilot Projects; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus
PubMed: 34413855
DOI: 10.3389/fimmu.2021.705592 -
PLoS Computational Biology Apr 2019HIV is a highly mutable virus for which all attempts to develop a vaccine have been unsuccessful. Nevertheless, few long-infected patients develop antibodies, called...
HIV is a highly mutable virus for which all attempts to develop a vaccine have been unsuccessful. Nevertheless, few long-infected patients develop antibodies, called broadly neutralizing antibodies (bnAbs), that have a high breadth and can neutralize multiple variants of the virus. This suggests that a universal HIV vaccine should be possible. A measure of the efficacy of a HIV vaccine is the neutralization breadth of the antibodies it generates. The breadth is defined as the fraction of viruses in the Seaman panel that are neutralized by the antibody. Experimentally the neutralization ability is measured as the half maximal inhibitory concentration of the antibody (IC50). To avoid such time-consuming experimental measurements, we developed a computational approach to estimate the IC50 and use it to determine the antibody breadth. Given that no direct method exists for calculating IC50 values, we resort to a combination of atomistic modeling and machine learning. For each antibody/virus complex, an all-atoms model is built using the amino acid sequence and a known structure of a related complex. Then a series of descriptors are derived from the atomistic models, and these are used to train a Multi-Layer Perceptron (an Artificial Neural Network) to predict the value of the IC50 (by regression), or if the antibody binds or not to the virus (by classification). The neural networks are trained by use of experimental IC50 values collected in the CATNAP database. The computed breadths obtained by regression and classification are reported and the importance of having some related information in the data set for obtaining accurate predictions is analyzed. This approach is expected to prove useful for the design of HIV bnAbs, where the computation of the potency must be accompanied by a computation of the breadth, and for evaluating the efficiency of potential vaccination schemes developed through modeling and simulation.
Topics: AIDS Vaccines; Amino Acid Sequence; Antibodies, Neutralizing; CD4 Antigens; CD4 Lymphocyte Count; Computational Biology; Epitopes; HIV Antibodies; HIV Infections; HIV-1; Humans; Inhibitory Concentration 50; Machine Learning
PubMed: 30970017
DOI: 10.1371/journal.pcbi.1006954