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Vaccine Mar 2015Antibody-inducing vaccines are a major focus in the preventive HIV vaccine field. Because the most common tests for HIV infection rely on detecting antibodies to HIV,... (Review)
Review
Antibody-inducing vaccines are a major focus in the preventive HIV vaccine field. Because the most common tests for HIV infection rely on detecting antibodies to HIV, they may also detect antibodies induced by a candidate HIV vaccine. The detection of vaccine-induced antibodies to HIV by serological tests is most commonly referred to as vaccine-induced sero-reactivity (VISR). VISR can be misinterpreted as a sign of HIV infection in a healthy study participant. In a participant who has developed vaccine-induced antibodies, accurate diagnosis of HIV infection (or lack thereof) may require specialized tests and algorithms (differential testing) that are usually not available in community settings. Organizations sponsoring clinical testing of preventive HIV vaccine candidates have an ethical obligation not only to inform healthy volunteers about the potential problems associated with participating in a clinical trial but also to help manage any resulting issues. This article explores the scope of VISR-related issues that become increasingly prevalent as the search for an effective HIV vaccine continues and will be paramount once a preventive vaccine is deployed. We also describe ways in which organizations conducting HIV vaccine trials have addressed these issues and outline areas where more work is needed.
Topics: AIDS Vaccines; Acquired Immunodeficiency Syndrome; Clinical Trials as Topic; HIV Antibodies; HIV Seropositivity; HIV-1; Humans; Informed Consent; Seroconversion
PubMed: 25649349
DOI: 10.1016/j.vaccine.2014.10.040 -
Trends in Microbiology Sep 2022Glycans are repeating carbohydrate structures added as post-translational modifications (PTMs) to proteins, forming glycoproteins. Self-glycans found on human cells, and... (Review)
Review
Glycans are repeating carbohydrate structures added as post-translational modifications (PTMs) to proteins, forming glycoproteins. Self-glycans found on human cells, and viral glycoproteins produced in host cells, are generally weakly immunogenic, which is necessary to avoid autoimmunity. This feature is exploited by many pathogenic viruses, which glycosylate surface proteins to evade or reduce immune recognition. The HIV type-1 (HIV-1) envelope glycoprotein (Env) is heavily glycosylated, which broadly acts to shield neutralisation-relevant protein surfaces with immunorecessive self-glycans to hinder B cell recognition. However, a small subset of HIV-1-infected individuals develops potent broadly neutralising antibodies (bnAbs), many of which directly engage the glycan shield. This provides hope that such antibodies could be elicited via vaccination and help to provide protective immunity. However, HIV-1 vaccine candidates have thus far failed to fully recapitulate such glycan-specific neutralising responses. In this review we consider the fundamental glycoimmunology and structural biology that underpin glycans in antibody evasion and as antibody targets and discuss potential approaches to harness glycan targeting for HIV-1 vaccine design.
Topics: Antibodies, Neutralizing; Glycoproteins; HIV Antibodies; HIV Infections; HIV-1; Humans; Polysaccharides; env Gene Products, Human Immunodeficiency Virus
PubMed: 35279348
DOI: 10.1016/j.tim.2022.02.004 -
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 -
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 Oct 2018Vectored gene delivery of HIV-1 broadly neutralizing antibodies (bNAbs) using recombinant adeno-associated virus (rAAV) is a promising alternative to conventional... (Review)
Review
Vectored gene delivery of HIV-1 broadly neutralizing antibodies (bNAbs) using recombinant adeno-associated virus (rAAV) is a promising alternative to conventional vaccines for preventing new HIV-1 infections and for therapeutically suppressing established HIV-1 infections. Passive infusion of single bNAbs has already shown promise in initial clinical trials to temporarily decrease HIV-1 load in viremic patients, and to delay viral rebound from latent reservoirs in suppressed patients during analytical treatment interruptions of antiretroviral therapy. Long-term, continuous, systemic expression of such bNAbs could be achieved with a single injection of rAAV encoding antibody genes into muscle tissue, which would bypass the challenges of eliciting such bNAbs through traditional vaccination in naïve patients, and of life-long repeated passive transfers of such biologics for therapy. rAAV delivery of single bNAbs has already demonstrated protection from repeated HIV-1 vaginal challenge in humanized mouse models, and phase I clinical trials of this approach are underway. Selection of which individual, or combination of, bNAbs to deliver to counter pre-existing resistance and the rise of escape mutations in the virus remains a challenge, and such choices may differ depending on use of this technology for prevention versus therapy.
Topics: Animals; Antibodies, Neutralizing; Clinical Trials as Topic; Dependovirus; Disease Models, Animal; Genetic Therapy; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunization, Passive
PubMed: 30285769
DOI: 10.1186/s12977-018-0449-7 -
Chembiochem : a European Journal of... Apr 2022Oligomannose-type glycans on the spike protein of HIV-1 constitute relevant epitopes to elicit broadly neutralizing antibodies (bnAbs). Herein we describe an improved...
Oligomannose-type glycans on the spike protein of HIV-1 constitute relevant epitopes to elicit broadly neutralizing antibodies (bnAbs). Herein we describe an improved synthesis of α- and β-linked hepta- and nonamannosyl ligands that were subsequently converted into BSA and CRM neoglycoconjugates. We assembled the ligands from anomeric 3-azidopropyl spacer glycosides from select 3-O-protected thiocresyl mannoside donors. Chain extensions were achieved using [4+3] or [4+5] block synthesis of thiocresyl and trichloroacetimidate glycosyl donors. Subsequent global deprotection generated the 3-aminopropyl oligosaccharide ligands. ELISA binding data obtained with the β-anomeric hepta- and nonamannosyl conjugates with a selection of HIV-1 bnAbs showed comparable binding of both mannosyl ligands by Fab fragments yet lesser binding of the nonasaccharide conjugate by the corresponding IgG antibodies. These results support previous observations that a complete Man structure might not be the preferred antigenic binding motif for some oligomannose-specific antibodies, and have implications for glycoside designs to elicit oligomannose-targeted HIV-1-neutralizing antibodies.
Topics: Antibodies, Neutralizing; Epitopes; HIV Antibodies; HIV-1; Humans; Ligands; Male
PubMed: 35104013
DOI: 10.1002/cbic.202200061 -
Trends in Immunology Nov 2014In rare cases, B cells can supply HIV-1-infected individuals with unconventional antibodies equipped to neutralize the wide diversity of viral variants. Innovations in... (Review)
Review
In rare cases, B cells can supply HIV-1-infected individuals with unconventional antibodies equipped to neutralize the wide diversity of viral variants. Innovations in single-cell cloning, high-throughput sequencing, and structural biology methods have enabled the capture and thorough characterization of these exceptionally potent broadly neutralizing antibodies (bNAbs). Here, I review the recent findings in humoral responses to HIV-1, focusing on the interplay between naturally occurring bNAbs and the virus both at systemic and mucosal levels. In this context, I discuss how an improved understanding of bNAb generation may provide invaluable insight into the fundamental mechanisms governing adaptive B cell responses to viruses, and how this knowledge is currently contributing to the development of vaccine and therapeutic strategies against HIV-1.
Topics: Antibodies, Neutralizing; B-Lymphocytes; HIV Antibodies; HIV Infections; HIV-1; Host-Pathogen Interactions; Humans; Immune Evasion; Immune System; Immunity, Mucosal; Immunoglobulin A, Secretory
PubMed: 25240985
DOI: 10.1016/j.it.2014.08.007 -
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 -
The Journal of Infectious Diseases Jun 2024Current serologic tests for HIV screening and confirmation of infection present challenges to the adoption of HIV vaccines. The detection of vaccine-induced HIV-1... (Review)
Review
Current serologic tests for HIV screening and confirmation of infection present challenges to the adoption of HIV vaccines. The detection of vaccine-induced HIV-1 antibodies in the absence of HIV-1 infection, referred to as vaccine-induced seropositivity/seroreactivity, confounds the interpretation of test results, causing misclassification of HIV-1 status with potential affiliated stigmatization. For HIV vaccines to be widely adopted with high community confidence and uptake, tests are needed that are agnostic to the vaccination status of tested individuals (ie, positive only for true HIV-1 infection). Successful development and deployment of such tests will require HIV vaccine developers to work in concert with diagnostic developers. Such tests will need to match today's high-performance standards (accuracy, cost-effectiveness, simplicity) for use in vaccinated and unvaccinated populations, especially in low- and middle-income countries with high HIV burden. Herein, we discuss the challenges and strategies for developing modified serologic HIV tests for concurrent deployment with HIV vaccines.
Topics: Humans; HIV Infections; AIDS Vaccines; HIV-1; HIV Antibodies; Serologic Tests
PubMed: 38451247
DOI: 10.1093/infdis/jiae113