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Journal of Immunology Research 2015HIV/AIDS is a leading cause of mortality and morbidity worldwide. In spite of successful interventions and treatment protocols, an HIV vaccine would be the ultimate... (Review)
Review
HIV/AIDS is a leading cause of mortality and morbidity worldwide. In spite of successful interventions and treatment protocols, an HIV vaccine would be the ultimate prevention and control strategy. Ever since identification of HIV/AIDS, there have been meticulous efforts for vaccine development. The specific aim of this paper is to review recent vaccine efficacy trials and associated advancements and discuss the current challenges and future directions. Recombinant DNA technologies greatly facilitated development of many viral products which were later incorporated into vectors for effective vaccines. Over the years, a number of scientific approaches have gained popularity and include the induction of neutralizing antibodies in late 1980s, induction of CD8 T cell in early 1990s, and combination approaches currently. Scientists have hypothesized that stimulation of right sequences of somatic hypermutations could induce broadly reactive neutralizing antibodies (bnAbs) capable of effective neutralization and viral elimination. Studies have shown that a number of host and viral factors affect these processes. Similarly, eliciting specific CD8 T cells immune responses through DNA vaccines hold future promises. In summary, future studies should focus on the continuous fight between host immune responses and ever-evasive viral factors for effective vaccines.
Topics: AIDS Vaccines; Antibodies, Neutralizing; CD8-Positive T-Lymphocytes; Clinical Trials as Topic; Genetic Vectors; HIV Antibodies; HIV Infections; Humans; Vaccines, DNA
PubMed: 26579546
DOI: 10.1155/2015/560347 -
Bioconjugate Chemistry May 2022Dense glycosylation and the trimeric conformation of the human immunodeficiency virus-1 (HIV-1) envelope protein limit the accessibility of some cellular glycan...
Dense glycosylation and the trimeric conformation of the human immunodeficiency virus-1 (HIV-1) envelope protein limit the accessibility of some cellular glycan processing enzymes and end up with high-mannose-type -linked glycans on the envelope spike, among which the ManGlcNAc structure occupies a certain proportion. The ManGlcNAc glycan composes the binding sites of some potent broadly neutralizing antibodies, and some lectins that can bind ManGlcNAc show HIV-neutralizing activity. Therefore, ManGlcNAc is a potential target for HIV-1 vaccine development. Herein, a highly convergent and effective strategy was developed for the synthesis of Man and its monofluoro-modified, trifluoro-modified, and -linked analogues. We coupled these haptens to carrier protein CRM197 and evaluated the immunogenicity of the glycoconjugates in mice. The serological assays showed that the native Man conjugates failed to induce Man-specific antibodies , while the modified analogue conjugates induced stronger antibody responses. However, these antibodies could not bind the native gp120 antigen. These results demonstrated that the immune tolerance mechanism suppressed the immune responses to Man-related structures and the conformation of glycan epitopes on the synthesized glycoconjugates was distinct from that of native glycan epitopes on gp120.
Topics: Animals; Antibodies, Neutralizing; Epitopes; Glycoconjugates; HIV Antibodies; HIV Envelope Protein gp120; HIV-1; Humans; Mice; Polysaccharides; Vaccines
PubMed: 35470665
DOI: 10.1021/acs.bioconjchem.2c00079 -
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 -
AIDS Research and Human Retroviruses Aug 2017Antibodies that cross-react with multiple HIV-1 envelopes (Envs) are useful reagents for characterizing Env proteins and for soluble Env capture and purification assays....
Antibodies that cross-react with multiple HIV-1 envelopes (Envs) are useful reagents for characterizing Env proteins and for soluble Env capture and purification assays. We previously reported 10 murine monoclonal antibodies induced by group M consensus Env, CON-6 immunization. Each demonstrated broad cross-reactivity to recombinant Envs. Here we characterized the Env epitopes to which they bind. Seven mapped to linear epitopes in gp120, five at the Env N-terminus, and two at the Env C-terminus. One antibody, 13D7, bound at the gp120 N-terminus (aa 30-42), reacted with HIV-1-infected CD4 T cells, and when expressed in a human IgG1 backbone, mediated antibody-dependent cellular cytotoxicity. Antibody 18F11 bound at the gp120 C-terminus (aa 445-459) and reactivity was glycan dependent. Antibodies 13D7, 3B3, and 16H3 bound to 100 percent of HIV-1 Envs tested in ELISA and sodium dodecyl sulfate/polyacrylamide gel electrophoresis/western blot analysis. These data define the epitopes of monoclonal antibody reagents for characterization of recombinant Envs, one epitope of which is also expressed on the surface of HIV-1-infected CD4 T cells.
Topics: AIDS Vaccines; Animals; Antibodies, Monoclonal; Antibody-Dependent Cell Cytotoxicity; Consensus Sequence; Epitope Mapping; Epitopes; HIV Antibodies; HIV-1; Mice, Inbred BALB C; env Gene Products, Human Immunodeficiency Virus
PubMed: 28314374
DOI: 10.1089/AID.2016.0294 -
Current Opinion in HIV and AIDS Mar 2016The paediatric HIV epidemic is changing. Over the past decade, new infections have substantially reduced, whereas access to antiretroviral therapy (ART) has increased.... (Review)
Review
PURPOSE OF REVIEW
The paediatric HIV epidemic is changing. Over the past decade, new infections have substantially reduced, whereas access to antiretroviral therapy (ART) has increased. Overall this success means that numbers of children living with HIV are climbing. In addition, the problems observed in adult infection resulting from chronic inflammation triggered by persistent immune activation even following ART mediated suppression of viral replication are magnified in children infected from birth.
RECENT FINDINGS
Features of immune ontogeny favour low immune activation in early life, whereas specific aspects of paediatric HIV infection tend to increase it. A subset of ART-naïve nonprogressing children exists in whom normal CD4 cell counts are maintained in the setting of persistent high viremia and yet in the context of low immune activation. This sooty mangabey-like phenotype contrasts with nonprogressing adult infection which is characterized by the expression of protective HLA class I molecules and low viral load. The particular factors contributing to raised or lowered immune activation in paediatric infection, which ultimately influence disease outcome, are discussed.
SUMMARY
Novel strategies to circumvent the unwanted long-term consequences of HIV infection may be possible in children in whom natural immune ontogeny in early life militates against immune activation. Defining the mechanisms underlying low immune activation in natural HIV infection would have applications beyond paediatric HIV.
Topics: HIV Antibodies; HIV Infections; HIV-1; Host-Pathogen Interactions; Humans; Milk, Human; Treatment Outcome
PubMed: 26679413
DOI: 10.1097/COH.0000000000000231 -
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 -
Cell Jun 2016Synergistic bispecific antibodies against HIV exhibit extraordinary potency and breadth of neutralization as promising candidates for treatment and prevention.
Synergistic bispecific antibodies against HIV exhibit extraordinary potency and breadth of neutralization as promising candidates for treatment and prevention.
Topics: Antibodies, Bispecific; Antibodies, Neutralizing; HIV Antibodies; HIV Infections; HIV-1; Humans
PubMed: 27315470
DOI: 10.1016/j.cell.2016.06.004 -
Frontiers in Immunology 2021Since their discovery, antibodies capable of broad neutralisation have been at the forefront of HIV-1 research and are of particular interest due to passive transfer... (Review)
Review
Since their discovery, antibodies capable of broad neutralisation have been at the forefront of HIV-1 research and are of particular interest due to passive transfer studies demonstrating their potential to provide protection. Currently an exact definition of what is required for a monoclonal antibody to be classed as a broadly neutralising antibody (bnAb) has not yet been established. This has led to hundreds of antibodies with varying neutralisation breadth being studied and has given insight into antibody maturation pathways and epitopes targeted. However, even with this knowledge, immunisation studies and vaccination trials to date have had limited success in eliciting antibodies with neutralisation breadth. For this reason there is a growing need to identify factors specifically associated with bnAb development, yet to do this a set of criteria is necessary to distinguish bnAbs from non-bnAbs. This review aims to define what it means to be a HIV-1 bnAb by comparing neutralisation breadth, genetic features and epitopes of bnAbs, and in the process highlights the challenges of comparing the array of antibodies that have been isolated over the years.
Topics: Broadly Neutralizing Antibodies; HIV Antibodies; HIV Infections; HIV-1; Humans
PubMed: 34737737
DOI: 10.3389/fimmu.2021.708227 -
Advances in Experimental Medicine and... 2015This chapter discusses the emerging field of vector-mediated antibody gene transfer as an alternative vaccine for infectious disease, with a specific focus on HIV.... (Review)
Review
This chapter discusses the emerging field of vector-mediated antibody gene transfer as an alternative vaccine for infectious disease, with a specific focus on HIV. However, this methodology need not be confined to HIV-1; the general strategy of vector-mediated antibody gene transfer can be applied to other difficult vaccine targets like hepatitis C virus, malaria, respiratory syncytial virus, and tuberculosis. This approach is an improvement over classical passive immunization strategies that administer antibody proteins to the host to provide protection from infection. With vector-mediated gene transfer, the antibody gene is delivered to the host, via a recombinant adeno-associated virus (rAAV) vector; this in turn results in long-term endogenous antibody expression from the injected muscle that confers protective immunity. Vector-mediated antibody gene transfer can rapidly move existing, potent broadly cross-neutralizing HIV-1-specific antibodies into the clinic. The gene transfer products demonstrate a potency and breadth identical to the original product. This strategy eliminates the need for immunogen design and interaction with the adaptive immune system to generate protection, a strategy that so far has shown limited promise.
Topics: Animals; Antibodies, Monoclonal; Antibodies, Neutralizing; Communicable Diseases; Gene Transfer Techniques; Genes, Immunoglobulin; Genetic Vectors; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunization, Passive; Vaccines, DNA
PubMed: 25757620
DOI: 10.1007/978-1-4939-2432-5_8 -
The Journal of Clinical Investigation Jun 2015Several HIV envelope-targeting (Env-targeting) antibodies with broad and potent neutralizing activity have been identified and shown to have unusual features. Of these,...
Several HIV envelope-targeting (Env-targeting) antibodies with broad and potent neutralizing activity have been identified and shown to have unusual features. Of these, the PG9 antibody has a long heavy chain complementarity determining region 3 (HCDR3) and possesses unique structural elements that interact with protein and glycan features of the HIV Env glycoprotein. Here, we used the Rosetta software suite to design variants of the PG9 antibody HCDR3 loop with the goal of identifying variants with increased potency and breadth of neutralization for diverse HIV strains. One variant, designated PG9_N100(F)Y, possessed increased potency and was able to neutralize a diverse set of PG9-resistant HIV strains, including those lacking the Env N160 glycan, which is critical for PG9 binding. An atomic resolution structure of the PG9_N100(F)Y fragment antigen binding (Fab) confirmed that the mutated residue retains the paratope surface when compared with WT PG9. Differential scanning calorimetry experiments revealed that the mutation caused a modest increase in thermodynamic stability of the Fab, a feature predicted by the computational model. Our findings suggest that thermodynamic stabilization of the long HCDR3 in its active conformation is responsible for the increased potency of PG9_N100(F)Y, and strategies aimed at stabilizing this region in other HIV antibodies could become an important approach to in silico optimization of antibodies.
Topics: Complementarity Determining Regions; HIV Antibodies; HIV Envelope Protein gp160; HIV-1; Humans; Models, Molecular; Protein Structure, Tertiary; Software
PubMed: 25985274
DOI: 10.1172/JCI80693