scholarly journals Plant-made HIV vaccines and potential candidates

2020 ◽  
Author(s):  
Jocelyne Tremouillaux-Guiller ◽  
Khaled Moustafa ◽  
Kathleen Hefferon ◽  
Goabaone Gaobotse ◽  
Abdullah Makhzoum
Keyword(s):  
Neutralizing Antibodies ◽  
Opportunistic Infections ◽  
Broadly Neutralizing Antibodies ◽  
Hiv Vaccines ◽  
Therapeutic Vaccines ◽  
Hiv Therapy ◽  
The Past ◽  
Health Burdens ◽  
Anti Hiv ◽  
Hiv 1

Millions of people around the world suffer from heavy social and health burdens related to HIV/AIDS and its associated opportunistic infections. To reduce these burdens, preventive and therapeutic vaccines are required. Effective HIV vaccines have been under investigation for several decades using different animal models. Potential plant-made HIV vaccine candidates have also gained attention in the past few years. In addition to this, broadly neutralizing antibodies produced in plants which can target conserved viral epitopes and neutralize mutating HIV strains have been identified. Numerous epitopes of glycoproteins and capsid proteins of HIV-1 are a part of HIV therapy. Here, we discuss some recent findings aiming to produce anti-HIV-1 recombinant proteins in engineered plants for AIDS prophylactics and therapeutic treatments.

scholarly journals Broad neutralization by a combination of antibodies recognizing the CD4 binding site and a new conformational epitope on the HIV-1 envelope protein

2012 ◽  
Vol 209 (8) ◽  
pp. 1469-1479 ◽  
Author(s):  
Florian Klein ◽  
Christian Gaebler ◽  
Hugo Mouquet ◽  
D. Noah Sather ◽  
Clara Lehmann ◽  
...  
Keyword(s):  
Binding Site ◽  
Envelope Protein ◽  
Neutralizing Antibodies ◽  
Conformational Epitope ◽  
Broadly Neutralizing Antibodies ◽  
Cd4 Binding Site ◽  
Capture Method ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Viral Isolates

Two to three years after infection, a fraction of HIV-1–infected individuals develop serologic activity that neutralizes most viral isolates. Broadly neutralizing antibodies that recognize the HIV-1 envelope protein have been isolated from these patients by single-cell sorting and by neutralization screens. Here, we report a new method for anti–HIV-1 antibody isolation based on capturing single B cells that recognize the HIV-1 envelope protein expressed on the surface of transfected cells. Although far less efficient than soluble protein baits, the cell-based capture method identified antibodies that bind to a new broadly neutralizing epitope in the vicinity of the V3 loop and the CD4-induced site (CD4i). The new epitope is expressed on the cell surface form of the HIV-1 spike, but not on soluble forms of the same envelope protein. Moreover, the new antibodies complement the neutralization spectrum of potent broadly neutralizing anti-CD4 binding site (CD4bs) antibodies obtained from the same individual. Thus, combinations of potent broadly neutralizing antibodies with complementary activity can account for the breadth and potency of naturally arising anti–HIV-1 serologic activity. Therefore, vaccines aimed at eliciting anti–HIV-1 serologic breadth and potency should not be limited to single epitopes.

scholarly journals Anti-V3/Glycan and Anti-MPER Neutralizing Antibodies, but Not Anti-V2/Glycan Site Antibodies, Are Strongly Associated with Greater Anti-HIV-1 Neutralization Breadth and Potency

2015 ◽  
Vol 89 (10) ◽  
pp. 5264-5275 ◽  
Author(s):  
Rajesh Abraham Jacob ◽  
Thandeka Moyo ◽  
Michael Schomaker ◽  
Fatima Abrahams ◽  
Berta Grau Pujol ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Prediction Interval ◽  
Vaccine Design ◽  
Broadly Neutralizing Antibodies ◽  
External Region ◽  
Membrane Proximal External Region ◽  
Site Recognition ◽  
Anti Hiv ◽  
Glycan Site ◽  
Hiv 1

ABSTRACTThe membrane-proximal external region (MPER), the V2/glycan site (initially defined by PG9 and PG16 antibodies), and the V3/glycans (initially defined by PGT121–128 antibodies) are targets of broadly neutralizing antibodies and potential targets for anti-HIV-1 antibody-based vaccines. Recent evidence shows that antibodies with moderate neutralization breadth are frequently attainable, with 50% of sera from chronically infected individuals neutralizing ≥50% of a large, diverse set of viruses. Nonetheless, there is little systematic information addressing which specificities are preferentially targeted among such commonly found, moderately broadly neutralizing sera. We explored associations between neutralization breadth and potency and the presence of neutralizing antibodies targeting the MPER, V2/glycan site, and V3/glycans in sera from 177 antiretroviral-naive HIV-1-infected (>1 year) individuals. Recognition of both MPER and V3/glycans was associated with increased breadth and potency. MPER-recognizing sera neutralized 4.62 more panel viruses than MPER-negative sera (95% prediction interval [95% PI], 4.41 to 5.20), and V3/glycan-recognizing sera neutralized 3.24 more panel viruses than V3/glycan-negative sera (95% PI, 3.15 to 3.52). In contrast, V2/glycan site-recognizing sera neutralized only 0.38 more panel viruses (95% PI, 0.20 to 0.45) than V2/glycan site-negative sera and no association between V2/glycan site recognition and breadth or potency was observed. Despite autoreactivity of many neutralizing antibodies recognizing MPER and V3/glycans, antibodies to these sites are major contributors to neutralization breadth and potency in this cohort. It may therefore be appropriate to focus on developing immunogens based upon the MPER and V3/glycans.IMPORTANCEPrevious candidate HIV vaccines have failed either to induce wide-coverage neutralizing antibodies or to substantially protect vaccinees. Therefore, current efforts focus on novel approaches never before successfully used in vaccine design, including modeling epitopes. Candidate immunogen models identified by broadly neutralizing antibodies include the membrane-proximal external region (MPER), V3/glycans, and the V2/glycan site. Autoreactivity and polyreactivity of anti-MPER and anti-V3/glycan antibodies are thought to pose both direct and indirect barriers to achieving neutralization breadth. We found that antibodies to the MPER and the V3/glycans contribute substantially to neutralization breadth and potency. In contrast, antibodies to the V2/glycan site were not associated with neutralization breadth/potency. This suggests that the autoreactivity effect is not critical and that the MPER and the V3/glycans should remain high-priority vaccine candidates. The V2/glycan site result is surprising because broadly neutralizing antibodies to this site have been repeatedly observed. Vaccine design priorities should shift toward the MPER and V3/glycans.

scholarly journals Employing Broadly Neutralizing Antibodies as a Human Immunodeficiency Virus Prophylactic & Therapeutic Application

2021 ◽  
Vol 12 ◽  
Author(s):  
Chengchao Ding ◽  
Darshit Patel ◽  
Yunjing Ma ◽  
Jamie F. S. Mann ◽  
Jianjun Wu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Neutralizing Antibodies ◽  
Broadly Neutralizing Antibodies ◽  
Genome Sequences ◽  
Therapeutic Application ◽  
Immunodeficiency Virus ◽  
Acquired Immunodeficiency ◽  
Immunodeficiency Syndrome ◽  
Anti Hiv ◽  
Hiv 1

Despite the discovery that the human immunodeficiency virus 1 (HIV-1) is the pathogen of acquired immunodeficiency syndrome (AIDS) in 1983, there is still no effective anti-HIV-1 vaccine. The major obstacle to the development of HIV-1 vaccine is the extreme diversity of viral genome sequences. Nonetheless, a number of broadly neutralizing antibodies (bNAbs) against HIV-1 have been made and identified in this area. Novel strategies based on using these bNAbs as an efficacious preventive and/or therapeutic intervention have been applied in clinical. In this review, we summarize the recent development of bNAbs and its application in HIV-1 acquisition prevention as well as discuss the innovative approaches being used to try to convey protection within individuals at risk and being treated for HIV-1 infection.

scholarly journals Anti-HIV-1 B cell responses are dependent on B cell precursor frequency and antigen binding affinity

2018 ◽  
Author(s):  
Pia Dosenovic ◽  
Ervin E. Kara ◽  
Anna-Klara Pettersson ◽  
Andrew McGuire ◽  
Matthew Gray ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Neutralizing Antibodies ◽  
Cell Receptor ◽  
Broadly Neutralizing Antibodies ◽  
Precursor Frequency ◽  
The Relationship ◽  
Anti Hiv ◽  
Hiv 1

AbstractThe discovery that humans can produce potent broadly neutralizing antibodies (bNAbs) to several different epitopes on the HIV-1 spike has reinvigorated efforts to develop an antibody based HIV-1 vaccine. Antibody cloning from single cells revealed that nearly all bNAbs show unusual features that could help explain why it has not been possible to elicit them by traditional vaccination, and instead that it would require a sequence of different immunogens. This idea is supported by experiments with genetically modified immunoglobulin knock-in mice. Sequential immunization with a series of specifically designed immunogens was required to shepherd the development of bNAbs. However, knock-in mice contain super-physiologic numbers of bNAb precursor expressing B cells and therefore how these results can be translated to a more physiologic setting remains to be determined. Here we make use of adoptive transfer experiments using knock-in B cells that carry a synthetic intermediate in the pathway to anti-HIV-1 bNAb development to examine how the relationship between B cell receptor affinity and precursor frequency affects germinal center B cell recrutiment and clonal expansion. Immunization with soluble HIV-1 antigens can recruit bNAb precursor B cells to the germinal center when there are as few as 10 such cells per mouse. However, at low precursor frequencies the extent of clonal expansion is directly proportional to the affinity of the antigen for the B cell receptor, and recruitment to germinal centers is variable and dependent on re-circulation.Significance statementAn essential requirement for an HIV-vaccine is to elicit antibodies to conserved regions of the spike protein (Env) becasue these antibodies can protect against infection. Although broadly neutralizing antibodies develop naturally in rare individuals after prolongued HIV infection, eliciting them by vaccination has only been possible in artificial knock-in mouse models wherein the number of B cells expressing the antibody precursor is super-physiologic. To understand the relationship between precursor frequency, antigen affinity and germinal center recruitment we have performed adoptive transfer experiments in which fixed numbers of precursor cells are engrafted in wild type mice. Our results provide a framework for understanding how precursor frequency and antigen affinity shape humoral immunity to HIV.

scholarly journals Enhancement of antibody-dependent cellular cytotoxicity and phagocytosis in anti‐HIV‐1 bovine chimeric broadly-neutralizing antibodies.

2021 ◽  
Author(s):  
Jack M Edwards ◽  
Behnaz Heydarchi ◽  
Georges Khoury ◽  
Natalia A Salazar-Quiroz ◽  
Christopher A Gonelli ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Variable Region ◽  
Cellular Cytotoxicity ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Broadly Neutralizing Antibodies ◽  
Effector Functions ◽  
Human Igg1 ◽  
Topical Microbicides ◽  
Anti Hiv ◽  
Hiv 1

No prophylactic vaccine has provided robust protection against HIV-1. Vaccine-induced broadly neutralizing antibodies (bnAbs) have not been achieved in humans and most animals, however cows vaccinated with HIV-1 envelope trimers produce bnAbs with unusually long third heavy complementarity determining regions (CDRH3). Alongside neutralization, Fc-mediated effector functions including antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis (ADP) may be critical for in vivo bnAb antiviral activity. Here, we aimed to augment the Fc-dependent effector functions of a chimeric human-bovine bnAb, NC-Cow1, which binds the CD4 binding site (CD4bs) and exhibits broader and more potent neutralization than most human CD4bs bnAbs by using an exceptionally long 60aa CDRH3. The bovine variable region of NC-Cow1 was paired with a human IgG1 Fc region mutated to create three variants: G236R/L328R (GRLR) that abrogates Fc-gamma receptor (FcγR) binding, and two variants that enhance binding: G236A/S239D/I332E (GASDIE) and G236A/S239D/A330L/I332E (GASDALIE). Both GASDIE and GASDALIE improved binding to human FcγRIIA and FcγRIIIA, enhanced human NK cell activation and mediated higher levels of ADCC and ADP activity compared to the wild-type human IgG1 Fc. GASDALIE mediated higher phagocytic activity compared to GASDIE. As expected, GRLR eliminated binding to FcγRs and did not mediate ADCC or ADP. We demonstrated that mutations in the human Fc region of bovine chimeric antibodies with ultra-long CDRH3 regions could enhance antibody effector functions while maintaining envelope binding and neutralization. This study will have significant implications in the development of multifunctional anti-HIV antibodies, which may be important to prevent HIV-1 transmission in an antibody-based topical microbicide. IMPORTANCE Despite successful antiviral chemotherapy, HIV is still a lifelong persistent virus and no vaccine yet prevents HIV transmission. Topical microbicides offer an important alternative method to prevent sexual transmission of HIV-1. With the production of highly potent anti-HIV-1 bnAbs and multifunctional antibodies, monoclonal antibodies are now important prophylactic agents. Recently discovered anti-HIV-1 bovine bnAbs (with higher potency and breadth than most human bnAbs) could be novel candidates as potent topical microbicides. Our study is significant as it demonstrates the compatibility of combining bovine-derived neutralization with human-derived antibody-effector functions. This study is a new approach to antibody engineering that strengthens the feasibility of using high potency bovine variable region bnAbs with augmented Fc function and promotes them as a strong candidate for antibody-mediated therapies.

scholarly journals Trimeric Glycosylphosphatidylinositol-Anchored HCDR3 of Broadly Neutralizing Antibody PG16 Is a Potent HIV-1 Entry Inhibitor

2012 ◽  
Vol 87 (3) ◽  
pp. 1899-1905 ◽  
Author(s):  
Lihong Liu ◽  
Weiming Wang ◽  
Lifei Yang ◽  
Huanhuan Ren ◽  
Jason T. Kimata ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Lipid Rafts ◽  
Neutralizing Antibodies ◽  
Quaternary Structure ◽  
Neutralizing Antibody ◽  
Entry Inhibitor ◽  
Broadly Neutralizing Antibodies ◽  
Broadly Neutralizing Antibody ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACTPG9 and PG16 are two quaternary-structure-specific broadly neutralizing antibodies with unique HCDR3 subdomains. Previously, we showed that glycosylphosphatidylinositol (GPI)-anchored HCDR3 subdomains (GPI-HCDR3) can be targeted to lipid rafts of the plasma membrane, bind to the epitope recognized by HCDR3 of PG16, and neutralize diverse HIV-1 isolates. In this study, we further developed trimeric GPI-HCDR3s and demonstrated that trimeric GPI-HCDR3 (PG16) dramatically improves anti-HIV-1 neutralization, suggesting that a stoichiometry of recognition of 3 or 2 HCDR3 molecules (PG16) to 1 viral spike is possible.

scholarly journals Can Broadly Neutralizing HIV-1 Antibodies Help Achieve an ART-Free Remission?

2021 ◽  
Vol 12 ◽  
Author(s):  
Denise C. Hsu ◽  
John W. Mellors ◽  
Sandhya Vasan
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Functions ◽  
Design Strategies ◽  
Broadly Neutralizing Antibodies ◽  
Therapeutic Vaccines ◽  
Infected Cells ◽  
Key Topics ◽  
Antibody Design ◽  
Cellular Immune ◽  
Hiv 1

Many broadly neutralizing antibodies (bnAbs) targeting the HIV-1 envelope glycoprotein are being assessed in clinical trials as strategies for HIV-1 prevention, treatment, and antiretroviral-free remission. BnAbs can neutralize HIV-1 and target infected cells for elimination. Concerns about HIV-1 resistance to single bnAbs have led to studies of bnAb combinations with non-overlapping resistance profiles. This review focuses on the potential for bnAbs to induce HIV-1 remission, either alone or in combination with latency reversing agents, therapeutic vaccines or other novel therapeutics. Key topics include preliminary activity of bnAbs in preclinical models and in human studies of HIV-1 remission, clinical trial designs, and antibody design strategies to optimize pharmacokinetics, coverage of rebound-competent virus, and enhancement of cellular immune functions.

scholarly journals An antigenic atlas of HIV-1 escape from broadly neutralizing antibodies

2018 ◽  
Author(s):  
Adam S. Dingens ◽  
Dana Arenz ◽  
Haidyn Weight ◽  
Julie Overbaugh ◽  
Jesse D. Bloom
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Single Amino Acid ◽  
Structural Studies ◽  
Broadly Neutralizing Antibodies ◽  
Functional Studies ◽  
Amino Acid Mutations ◽  
Env Protein ◽  
Anti Hiv ◽  
Hiv 1

SummaryAnti-HIV broadly neutralizing antibodies (bnAbs) have revealed vaccine targets on the virus’s Env protein and are themselves promising immunotherapeutics. The efficacy of bnAb-based therapies and vaccines depends in part on how readily the virus can escape neutralization. While structural studies can define contacts between bnAbs and Env, only functional studies can define mutations that confer escape. Here we map how all single amino-acid mutations to Env affect neutralization of HIV by nine bnAbs targeting five epitopes. For most bnAbs, mutations at only a small fraction of structurally defined contact sites mediated escape, and most escape occurred at sites that are near but do not directly contact the antibody. The mutations selected by two pooled bnAbs were similar to those expected from the combination of the bnAbs’ independent action. Overall, our mutation-level antigenic atlas provides a comprehensive dataset for understanding viral immune escape and refining therapies and vaccines.

scholarly journals Lack of ADCC Breadth of Human Nonneutralizing Anti-HIV-1 Antibodies

2017 ◽  
Vol 91 (8) ◽  
Author(s):  
Timothée Bruel ◽  
Florence Guivel-Benhassine ◽  
Valérie Lorin ◽  
Hugues Lortat-Jacob ◽  
Françoise Baleux ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Hiv Positive ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Broadly Neutralizing Antibodies ◽  
Efficacy Trial ◽  
Immunodeficiency Virus ◽  
Infected Cells ◽  
Anti Hiv ◽  
Hiv 1 ◽  
Rv144 Vaccine

ABSTRACT Anti-human immunodeficiency virus type 1 (HIV-1) nonneutralizing antibodies (nnAbs) capable of antibody-dependent cellular cytotoxicity (ADCC) have been identified as a protective immune correlate in the RV144 vaccine efficacy trial. Broadly neutralizing antibodies (bNAbs) also mediate ADCC in cell culture and rely on their Fc region for optimal efficacy in animal models. Here, we selected 9 monoclonal nnAbs and 5 potent bNAbs targeting various epitopes and conformations of the gp120/41 complex and analyzed the potency of the two types of antibodies to bind and eliminate HIV-1-infected cells in culture. Regardless of their neutralizing activity, most of the selected antibodies recognized and killed cells infected with two laboratory-adapted HIV-1 strains. Some nnAbs also bound bystander cells that may have captured viral proteins. However, in contrast to the bNAbs, the nnAbs bound poorly to reactivated infected cells from 8 HIV-positive individuals and did not mediate effective ADCC against these cells. The nnAbs also inefficiently recognize cells infected with 8 different transmitted-founder (T/F) isolates. The addition of a synthetic CD4 mimetic enhanced the binding and killing efficacy of some of the nnAbs in an epitope-dependent manner without reaching the levels achieved by the most potent bNAbs. Overall, our data reveal important qualitative and quantitative differences between nnAbs and bNAbs in their ADCC capacity and strongly suggest that the breadth of recognition of HIV-1 by nnAbs is narrow. IMPORTANCE Most of the anti-HIV antibodies generated by infected individuals do not display potent neutralizing activities. These nonneutralizing antibodies (nnAbs) with antibody-dependent cellular cytotoxicity (ADCC) have been identified as a protective immune correlate in the RV144 vaccine efficacy trial. However, in primate models, the nnAbs do not protect against simian-human immunodeficiency virus (SHIV) acquisition. Thus, the role of nnAbs with ADCC activity in protection from infection remains debatable. In contrast, broadly neutralizing antibodies (bNAbs) neutralize a large array of viral strains and mediate ADCC in cell culture. We analyzed the capacities of 9 nnAbs and 5 bNAbs to eliminate infected cells. We selected 18 HIV-1 strains, including virus reactivated from the reservoir of HIV-positive individuals and transmitted-founder isolates. We report that the nnAbs bind poorly to cells infected with primary HIV-1 strains and do not mediate potent ADCC. Overall, our data show that the breadth of recognition of HIV-1 by nnAbs is narrow.

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