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Biochimica Et Biophysica Acta Oct 2014The rare, broadly neutralizing antibodies, 4E10 and 2F5, that target the HIV-1 membrane proximal external region also associate with HIV-1 membrane lipids as part of a...
The rare, broadly neutralizing antibodies, 4E10 and 2F5, that target the HIV-1 membrane proximal external region also associate with HIV-1 membrane lipids as part of a required first-step in HIV-1 neutralization. HIV-1 virions have high concentration of cholesterol and sphingomyelin, which are able to organize into liquid-ordered domains (i.e., lipid rafts), and could influence the interaction of neutralizing antibodies with epitopes proximal to the membrane. The objective of this research is to understand how these lipid domains contribute to 2F5/4E10 membrane interactions and to antigen presentation in liposomal form of HIV-1 vaccines. To this end we have engineered biomimetic supported lipid bilayers and are able to use atomic force microscopy to visualize membrane domains, antigen clustering, and antibody-membrane interactions. Our results demonstrate that 2F5/4E10 do not interact with highly ordered gel and liquid-ordered domains and exclusively bind to a liquid-disordered lipid phase. This suggests that vaccine liposomes that contain key viral membrane components, such as high cholesterol content, may not be advantageous for 2F5/4E10 vaccine strategies. Rather, vaccine liposomes that primarily contain a liquid-disordered phase may be more likely to elicit production of lipid reactive, 2F5- and 4E10-like antibodies.
Topics: AIDS Vaccines; Animals; Antibodies, Monoclonal, Murine-Derived; Antigen Presentation; Biomimetic Materials; Cell Line; HIV Antibodies; HIV-1; Humans; Liposomes; Membrane Microdomains; Mice
PubMed: 25019685
DOI: 10.1016/j.bbamem.2014.07.007 -
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 -
MAbs 2021Passive transfer of broadly neutralizing antibodies is showing promise in the treatment and prevention of HIV-1. One class of antibodies, the VRC01 class, appears... (Review)
Review
Passive transfer of broadly neutralizing antibodies is showing promise in the treatment and prevention of HIV-1. One class of antibodies, the VRC01 class, appears especially promising. To improve VRC01-class antibodies, we combined structure-based design with a matrix-based approach to generate VRC01-class variants that filled an interfacial cavity, used diverse third-complementarity-determining regions, reduced potential steric clashes, or exploited extended contacts to a neighboring protomer within the envelope trimer. On a 208-strain panel, variant VRC01.23LS neutralized 90% of the panel at a geometric mean IC less than 1 μg/ml, and in transgenic mice with human neonatal-Fc receptor, the serum half-life of VRC01.23LS was indistinguishable from that of the parent VRC01LS, which has a half-life of 71 d in humans. A cryo-electron microscopy structure of VRC01.23 Fab in complex with BG505 DS-SOSIP.664 Env trimer determined at 3.4-Å resolution confirmed the structural basis for its ~10-fold improved potency relative to VRC01. Another variant, VRC07-523-F54-LS.v3, neutralized 95% of the 208-isolated panel at a geometric mean IC of less than 1 μg/ml, with a half-life comparable to that of the parental VRC07-523LS. Our matrix-based structural approach thus enables the engineering of VRC01 variants for HIV-1 therapy and prevention with improved potency, breadth, and pharmacokinetics.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Neutralizing; HIV Antibodies; HIV Infections; HIV-1; Humans; Mice, Knockout; Mice
PubMed: 34328065
DOI: 10.1080/19420862.2021.1946918 -
Advances in Immunology 2019Neutralizing antibodies against human immunodeficiency virus subtype 1 (HIV-1) bind to its envelope glycoprotein (Env). Half of the molecular mass of Env is carbohydrate... (Review)
Review
Neutralizing antibodies against human immunodeficiency virus subtype 1 (HIV-1) bind to its envelope glycoprotein (Env). Half of the molecular mass of Env is carbohydrate making it one of the most heavily glycosylated proteins known in nature. HIV-1 Env glycans are derived from the host and present a formidable challenge for host anti-glycan antibody induction. Anti-glycan antibody induction is challenging because anti-HIV-1 glycan antibodies should recognize Env antigen while not acquiring autoreactivity. Thus, the glycan network on HIV-1 Env is referred to as the glycan shield. Despite the challenges presented by immune recognition of host-derived glycans, neutralizing antibodies capable of binding the glycans on HIV-1 Env can be generated by the host immune system in the setting of HIV-1 infection. In particular, a cluster of high mannose glycans, including an N-linked glycan at position 332, form the high mannose patch and are targeted by a variety of broadly neutralizing antibodies. These high mannose patch-directed HIV-1 antibodies can be categorized into distinct categories based on their antibody paratope structure, neutralization activity, and glycan and peptide reactivity. Below we will compare and contrast each of these classes of HIV-1 glycan-dependent antibodies and describe vaccine design efforts to elicit each of these antibody types.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Neutralizing; Antibody Formation; Broadly Neutralizing Antibodies; Epitopes; Glycosylation; HIV Antibodies; HIV Envelope Protein gp120; HIV Infections; HIV-1; Humans; Immunogenicity, Vaccine; Mannose; Peptide Fragments; Polysaccharides
PubMed: 31607367
DOI: 10.1016/bs.ai.2019.08.002 -
Journal of Virology Jul 2014The RV144 ALVAC/AIDSVax HIV-1 vaccine clinical trial showed an estimated vaccine efficacy of 31.2%. Viral genetic analysis identified a vaccine-induced site of immune... (Randomized Controlled Trial)
Randomized Controlled Trial
The RV144 ALVAC/AIDSVax HIV-1 vaccine clinical trial showed an estimated vaccine efficacy of 31.2%. Viral genetic analysis identified a vaccine-induced site of immune pressure in the HIV-1 envelope (Env) variable region 2 (V2) focused on residue 169, which is included in the epitope recognized by vaccinee-derived V2 monoclonal antibodies. The ALVAC/AIDSVax vaccine induced antibody-dependent cellular cytotoxicity (ADCC) against the Env V2 and constant 1 (C1) regions. In the presence of low IgA Env antibody levels, plasma levels of ADCC activity correlated with lower risk of infection. In this study, we demonstrate that C1 and V2 monoclonal antibodies isolated from RV144 vaccinees synergized for neutralization, infectious virus capture, and ADCC. Importantly, synergy increased the HIV-1 ADCC activity of V2 monoclonal antibody CH58 at concentrations similar to that observed in plasma of RV144 vaccinees. These findings raise the hypothesis that synergy among vaccine-induced antibodies with different epitope specificities contributes to HIV-1 antiviral antibody responses and is important to induce for reduction in the risk of HIV-1 transmission. Importance: The Thai RV144 ALVAC/AIDSVax prime-boost vaccine efficacy trial represents the only example of HIV-1 vaccine efficacy in humans to date. Studies aimed at identifying immune correlates involved in the modest vaccine-mediated protection identified HIV-1 envelope (Env) variable region 2-binding antibodies as inversely correlated with infection risk, and genetic analysis identified a site of immune pressure within the region recognized by these antibodies. Despite this evidence, the antiviral mechanisms by which variable region 2-specific antibodies may have contributed to lower rates of infection remain unclear. In this study, we demonstrate that vaccine-induced HIV-1 envelope variable region 2 and constant region 1 antibodies synergize for recognition of virus-infected cells, infectious virion capture, virus neutralization, and antibody-dependent cellular cytotoxicity. This is a major step in understanding how these types of antibodies may have cooperatively contributed to reducing infection risk and should be considered in the context of prospective vaccine design.
Topics: AIDS Vaccines; Antibodies, Monoclonal; HIV Antibodies; HIV-1; Humans; env Gene Products, Human Immunodeficiency Virus
PubMed: 24807721
DOI: 10.1128/JVI.00156-14 -
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 -
Current Opinion in HIV and AIDS May 2014This review discusses progress in understanding the impact of immune tolerance on inducing broadly neutralizing antibodies (bnAbs), and how such knowledge can be... (Review)
Review
PURPOSE OF REVIEW
This review discusses progress in understanding the impact of immune tolerance on inducing broadly neutralizing antibodies (bnAbs), and how such knowledge can be incorporated into novel immunization approaches.
RECENT FINDINGS
Over 120 bnAbs have now been isolated, all of which bear unusual features associated with host tolerance controls, but paradoxically may also be required for their function. Evidence that poly/autoreactivity of membrane proximal external region bnAbs can invoke such controls has been demonstrated by knock-in technology, highlighting its potential for studying the impact of tolerance in the generation of bnAb lineages to distinct HIV-1 envelope targets. The requirement for extensive affinity maturation in developing neutralization breadth/potency during infection is being examined, and similar studies in the setting of immunization will be aided by testing novel vaccine approaches in knock-in models that either selectively express reverted V(D)J rearrangements, or unrearranged germline segments, from which bnAb lineages originate.
SUMMARY
It is increasingly apparent that immune tolerance, sometimes invoked by self-reactivity that overlaps with bnAb epitope specificity, adds to a formidable set of roadblocks impeding bnAb induction. The path to an effective HIV-1 vaccine may thus benefit from a deeper understanding of host controls, including categorizing those that are unique or common at distinct bnAb targets, and ranking those most feasible to overcome by immunization. Ultimately, such emerging information will be critical to incorporate into new vaccine approaches that can be tested in human trials.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Antibody Formation; Autoimmunity; HIV Antibodies; HIV Infections; Humans; Immune Tolerance
PubMed: 24714565
DOI: 10.1097/COH.0000000000000049 -
Molecules and Cells Sep 2012Since the discovery more than 30 years ago of human immunodeficiency virus (HIV) as the causative agent of the deadly disease, acquired immune deficiency disease (AIDS),...
Since the discovery more than 30 years ago of human immunodeficiency virus (HIV) as the causative agent of the deadly disease, acquired immune deficiency disease (AIDS), there have been no efficient vaccines against the virus. For the infection of the virus, the HIV surface glycoprotein gp120 first recognizes the CD4 receptor on the target helper T-cell, which initiates HIV fusion with the target cell and, if unchecked, leads to destruction of the patient's immune system. Despite the difficulty of developing appropriate immune responses in HIV-infected individuals, patient sera often contain antibodies that have broad neutralization activity, indicating the possibility of immunological treatment and prevention. Recently, through extensive structural studies of neutralizing antibodies of HIV in complex with gp120, the critical mechanisms of broad neutralization against HIV have been elucidated. Based on these discoveries, the structure-aided designs of antibodies and novel scaffolds were performed to create extremely potent neutralizing antibodies against HIV. These new discoveries and advances shed light on the road to development of efficient immunological therapies against AIDS.
Topics: AIDS Vaccines; Antibodies, Neutralizing; Binding Sites; CD4 Antigens; Drug Design; HIV; HIV Antibodies; HIV Envelope Protein gp120; Humans; Protein Conformation; Structure-Activity Relationship
PubMed: 22736269
DOI: 10.1007/s10059-012-0104-4 -
PLoS Pathogens Jan 2022Antibodies are principal immune components elicited by vaccines to induce protection from microbial pathogens. In the Thai RV144 HIV-1 vaccine trial, vaccine efficacy...
Antibodies are principal immune components elicited by vaccines to induce protection from microbial pathogens. In the Thai RV144 HIV-1 vaccine trial, vaccine efficacy was 31% and the sole primary correlate of reduced risk was shown to be vigorous antibody response targeting the V1V2 region of HIV-1 envelope. Antibodies against V3 also were inversely correlated with infection risk in subsets of vaccinees. Antibodies recognizing these regions, however, do not exhibit potent neutralizing activity. Therefore, we examined the antiviral potential of poorly neutralizing monoclonal antibodies (mAbs) against immunodominant V1V2 and V3 sites by passive administration of human mAbs to humanized mice engrafted with CD34+ hematopoietic stem cells, followed by mucosal challenge with an HIV-1 infectious molecular clone expressing the envelope of a tier 2 resistant HIV-1 strain. Treatment with anti-V1V2 mAb 2158 or anti-V3 mAb 2219 did not prevent infection, but V3 mAb 2219 displayed a superior potency compared to V1V2 mAb 2158 in reducing virus burden. While these mAbs had no or weak neutralizing activity and elicited undetectable levels of antibody-dependent cellular cytotoxicity (ADCC), V3 mAb 2219 displayed a greater capacity to bind virus- and cell-associated HIV-1 envelope and to mediate antibody-dependent cellular phagocytosis (ADCP) and C1q complement binding as compared to V1V2 mAb 2158. Mutations in the Fc region of 2219 diminished these effector activities in vitro and lessened virus control in humanized mice. These results demonstrate the importance of Fc functions other than ADCC for antibodies without potent neutralizing activity.
Topics: Animals; Antibodies, Monoclonal; Gene Products, env; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunization, Passive; Immunoglobulin Constant Regions; Mice; Mucous Membrane; Viral Load
PubMed: 34986207
DOI: 10.1371/journal.ppat.1010183 -
Current Opinion in HIV and AIDS Sep 2013Although a large number of novel broadly neutralizing antibodies has been recently described, the induction of such antibodies via vaccination has proven difficult. By... (Review)
Review
PURPOSE OF REVIEW
Although a large number of novel broadly neutralizing antibodies has been recently described, the induction of such antibodies via vaccination has proven difficult. By contrast, nonneutralizing antibodies arise early during infection and have been repeatedly associated with both protection from infection and disease progression.
RECENT FINDINGS
We are beginning to gain new insights into the broader landscape of antiviral mechanisms that nonneutralizing antibodies may harness to fight HIV, providing an unprecedented breadth of approaches by which HIV can be blocked and contained.
SUMMARY
In this review, we summarize the characteristics of nonneutralizing antibodies, their role in HIV infection, and new paradigm-shifting functions that may be exploited by next-generation vaccine approaches aimed at blocking HIV infection.
Topics: HIV; HIV Antibodies; HIV Infections; Humans
PubMed: 23924999
DOI: 10.1097/COH.0b013e328363d486