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 A VH1-69 antibody lineage from an infected Chinese donor potently neutralizes HIV-1 by targeting the V3 glycan supersite

2020 ◽  
Vol 6 (38) ◽  
pp. eabb1328 ◽  
Author(s):  
Sonu Kumar ◽  
Bin Ju ◽  
Benjamin Shapero ◽  
Xiaohe Lin ◽  
Li Ren ◽  
...  
Keyword(s):  
Cell Sorting ◽  
Neutralizing Antibodies ◽  
Critical Role ◽  
Viral Escape ◽  
Germline Gene ◽  
Broadly Neutralizing Antibodies ◽  
Functional Studies ◽  
Single Genome ◽  
Hiv 1

An oligomannose patch around the V3 base of HIV-1 envelope glycoprotein (Env) is recognized by multiple classes of broadly neutralizing antibodies (bNAbs). Here, we investigated the bNAb response to the V3 glycan supersite in an HIV-1–infected Chinese donor by Env-specific single B cell sorting, structural and functional studies, and longitudinal analysis of antibody and virus repertoires. Monoclonal antibodies 438-B11 and 438-D5 were isolated that potently neutralize HIV-1 with moderate breadth, are encoded by the VH1-69 germline gene, and have a disulfide-linked long HCDR3 loop. Crystal structures of Env-bound and unbound antibodies revealed heavy chain–mediated recognition of the glycan supersite with a unique angle of approach and a critical role of the intra-HCDR3 disulfide. The mechanism of viral escape was examined via single-genome amplification/sequencing and glycan mutations around the N332 supersite. Our findings further emphasize the V3 glycan supersite as a prominent target for Env-based vaccine design.

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 HIV-1 Envelope Glycosylation and the Signal Peptide

2021 ◽  
Author(s):  
Gregory S. Lambert ◽  
Chitra Upadhyay
Keyword(s):  
Signal Peptide ◽  
Neutralizing Antibodies ◽  
Vaccine Trial ◽  
Vaccine Design ◽  
Antibody Responses ◽  
Broadly Neutralizing Antibodies ◽  
Structural Determinants ◽  
Humoral Immune ◽  
Env Protein ◽  
Hiv 1

The RV144 trial represents the only vaccine trial to demonstrate any protective effect against HIV-1 infection. While the reason(s) for this protection are still being evaluated, it serves as justification for widespread efforts aimed at developing new, more effective HIV-1 vaccines. Advances in our knowledge of HIV-1 immunogens and host antibody responses to these immunogens are crucial to informing vaccine design. While the envelope (Env) protein is the only viral protein present on the surface of virions, it exists in a complex trimeric conformation and is decorated with an array of variable N-linked glycans, making it an important but difficult target for vaccine design. Thus far, efforts to elicit a protective humoral immune response using structural mimics of native Env trimers have been unsuccessful. Notably, the aforementioned N-linked glycans serve as a component of many of the epitopes crucial for the induction of potentially protective broadly neutralizing antibodies (bnAbs). Thus, a greater understanding of Env structural determinants, most critically Env glycosylation, will no doubt be of importance in generating effective immunogens. Recent studies have identified the HIV-1 Env signal peptide (SP) as an important contributor to Env glycosylation. Further investigation into the mechanisms by which the SP directs glycosylation will be important, both in the context of understanding HIV-1 biology and in order to inform HIV-1 vaccine design.

scholarly journals The Neutralizing Antibody Response to the HIV-1 Env Protein

2018 ◽  
Vol 16 (1) ◽  
pp. 21-28 ◽  
Author(s):  
Penny L. Moore
Keyword(s):  
Neutralizing Antibodies ◽  
Passive Immunization ◽  
Neutralizing Antibody ◽  
Developmental Pathways ◽  
Broadly Neutralizing Antibodies ◽  
Infected People ◽  
B Cell Maturation ◽  
Public Health Challenge ◽  
Env Protein ◽  
Hiv 1

Background: A vaccine able to elicit broadly neutralizing antibodies capable of blocking infection by global viruses has not been achieved, and remains a key public health challenge.Objective: During infection, a robust strain-specific neutralizing response develops in most people, but only a subset of infected people develop broadly neutralizing antibodies. Understanding how and why these broadly neutralizing antibodies develop has been a focus of the HIV-1 vaccine field for many years, and has generated extraordinary insights into the neutralizing response to HIV-1 infection.Results: This review describes the features, targets and developmental pathways of early strainspecific antibodies and later broadly neutralizing antibodies, and explores the reasons such broad antibodies are not more commonly elicited during infection.Conclusion: The insights from these studies have been harnessed for the development of pioneering new vaccine approaches that seek to drive B cell maturation towards breadth. Overall, this review describes how findings from infected donors have impacted on active and passive immunization approaches that seek to prevent 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 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.

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