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Retrovirology Sep 2018An effective HIV-1 vaccine probably will need to be able to induce broadly neutralizing HIV-1 antibodies (bNAbs) in order to be efficacious. The many bNAbs that have... (Review)
Review
An effective HIV-1 vaccine probably will need to be able to induce broadly neutralizing HIV-1 antibodies (bNAbs) in order to be efficacious. The many bNAbs that have been isolated from HIV-1 infected patients illustrate that the human immune system is able to elicit this type of antibodies. The elucidation of the structure of the HIV-1 envelope glycoprotein (Env) trimer has further fueled the search for Env immunogens that induce bNAbs, but while native Env trimer mimetics are often capable of inducing strain-specific neutralizing antibodies (NAbs) against the parental virus, they have not yet induced potent bNAb responses. To improve the performance of Env trimer immunogens, researchers have studied the immune responses that Env trimers have induced in animals; they have evaluated how to best use Env trimers in various immunization regimens; and they have engineered increasingly stabilized Env trimer variants. Here, we review the different approaches that have been used to increase the stability of HIV-1 Env trimer immunogens with the aim of improving the induction of NAbs. In particular, we draw parallels between the various approaches to stabilize Env trimers and ones that have been used by nature in extremophile microorganisms in order to survive in extreme environmental conditions.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Epitopes; HIV Antibodies; HIV-1; Humans; Immunization; Models, Molecular; Protein Multimerization; env Gene Products, Human Immunodeficiency Virus
PubMed: 30208933
DOI: 10.1186/s12977-018-0445-y -
Cells Dec 2021Since its discovery 35 years ago, there have been no therapeutic interventions shown to enable full HIV-1 remission. Combined antiretroviral therapy (cART) has achieved... (Review)
Review
Since its discovery 35 years ago, there have been no therapeutic interventions shown to enable full HIV-1 remission. Combined antiretroviral therapy (cART) has achieved the sustained control of HIV-1 replication, however, the life-long treatment does not eradicate long-lived latently infected reservoirs and can result in multiple side effects including the development of multidrug-resistant escape mutants. Antibody-based treatments have emerged as alternative approaches for a HIV-1 cure. Here, we will review clinical advances in coreceptor-targeting antibodies, with respect to anti-CCR5 antibodies in particular, which are currently being generated to target the early stages of infection. Among the Env-specific antibodies widely accepted as relevant in cure strategies, the potential role of those targeting CD4-induced (CD4i) epitopes of the CD4-binding site (CD4bs) in eliminating HIV-1 infected cells has gained increasing interest and will be presented. Together, with approaches targeting the HIV-1 replication cycle, we will discuss the strategies aimed at boosting and modulating specific HIV-1 immune responses, highlighting the harnessing of TLR agonists for their dual role as latency reverting agents (LRAs) and immune-modulatory compounds. The synergistic combinations of different approaches have shown promising results to ultimately enable a HIV-1 cure.
Topics: Antibodies, Bispecific; Biological Products; HIV Antibodies; HIV Infections; Humans; Immunotherapy; Toll-Like Receptors
PubMed: 35011639
DOI: 10.3390/cells11010077 -
AIDS Research and Therapy Sep 2017The extreme HIV diversity posts a great challenge on development of an effective anti-HIV vaccine. To solve this problem, it is crucial to discover an appropriate... (Review)
Review
The extreme HIV diversity posts a great challenge on development of an effective anti-HIV vaccine. To solve this problem, it is crucial to discover an appropriate immunogens and strategies that are able to prevent the transmission of the diverse viruses that are circulating in the world. Even though there have been a number of broadly neutralizing anti-HIV antibodies (bNAbs) been discovered in recent years, induction of such antibodies to date has only been observed in HIV-1 infection. Here, in this mini review, we review the progress in development of HIV vaccine in eliciting broad immune response, especially production of bNAbs, discuss possible strategies, such as polyvalent sequential vaccination, that facilitates B cell maturation leading to bNAb response.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; B-Lymphocytes; Drug Design; Genetic Variation; HIV Antibodies; HIV Infections; HIV-1; Humans; Mice; env Gene Products, Human Immunodeficiency Virus
PubMed: 28893278
DOI: 10.1186/s12981-017-0178-3 -
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 -
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 -
Immunity Jul 2018The HIV-1 fusion peptide is a target for broadly neutralizing antibodies. In a recent issue of Nature Medicine, Xu et al. (2018) provide proof-of-concept that...
The HIV-1 fusion peptide is a target for broadly neutralizing antibodies. In a recent issue of Nature Medicine, Xu et al. (2018) provide proof-of-concept that vaccination with fusion peptide followed by vaccination with an envelope glycoprotein trimer can induce antibodies in animal models that neutralize diverse HIV-1 viruses.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Epitopes; HIV Antibodies; HIV Infections; HIV-1; Peptides
PubMed: 30021141
DOI: 10.1016/j.immuni.2018.07.003 -
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 -
Human Vaccines & Immunotherapeutics Jan 2017So far, the development of a human immunodeficiency virus (HIV) vaccine has been unsuccessful. However, recent progress in the field of broadly neutralizing antibodies... (Review)
Review
So far, the development of a human immunodeficiency virus (HIV) vaccine has been unsuccessful. However, recent progress in the field of broadly neutralizing antibodies (bNAbs) has reinvigorated the search for an HIV vaccine. bNAbs develop in a minority of HIV infected individuals and passive transfer of these bNAbs to non-human primates provides protection from HIV infection. Studies in a number of HIV infected individuals on bNAb maturation alongside viral evolution and escape have shed light on the features important for bNAb elicitation. Here we review the observations from these studies, and how they influence the rational design of HIV vaccines.
Topics: AIDS Vaccines; Animals; Antibodies, Neutralizing; Drug Discovery; HIV Antibodies; HIV Infections; Humans; Primates
PubMed: 27649455
DOI: 10.1080/21645515.2016.1232785 -
Advanced Drug Delivery Reviews Aug 2016A combination of advances spanning from isolation to delivery of potent HIV-specific antibodies has begun to revolutionize understandings of antibody-mediated antiviral... (Review)
Review
A combination of advances spanning from isolation to delivery of potent HIV-specific antibodies has begun to revolutionize understandings of antibody-mediated antiviral activity. As a result, the set of broadly neutralizing and highly protective antibodies has grown in number, diversity, potency, and breadth of viral recognition and neutralization. These antibodies are now being further enhanced by rational engineering of their anti-HIV activities and coupled to cutting edge gene delivery and strategies to optimize their pharmacokinetics and biodistribution. As a result, the prospects for clinical use of HIV-specific antibodies to treat, clear, and prevent HIV infection are gaining momentum. Here we discuss the diverse methods whereby antibodies are being optimized for neutralization potency and breadth, biodistribution, pharmacokinetics, and effector function with the aim of revolutionizing HIV treatment and prevention options.
Topics: Antibodies, Neutralizing; HIV Antibodies; HIV Infections; HIV-1; Humans
PubMed: 26827912
DOI: 10.1016/j.addr.2016.01.013 -
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