scholarly journals Effects of gp120 Inner Domain (ID2) Immunogen Doses on Elicitation of Anti-HIV-1 Functional Fc-Effector Response to C1/C2 (Cluster A) Epitopes in Mice

2020 ◽  
Vol 8 (10) ◽  
pp. 1490
Author(s):  
Rebekah Sherburn ◽  
William D. Tolbert ◽  
Suneetha Gottumukkala ◽  
Guillaume Beaudoin-Bussières ◽  
Andrés Finzi ◽  
...  
Keyword(s):  
Passive Immunization ◽  
Neutralizing Antibody ◽  
Antibody Repertoire ◽  
Effector Functions ◽  
Dosing Strategies ◽  
Cluster A ◽  
Effector Response ◽  
Anti Hiv ◽  
Hiv 1

Fc-mediated effector functions of antibodies, including antibody-dependent cytotoxicity (ADCC), have been shown to contribute to vaccine-induced protection from HIV-1 infection, especially those directed against non-neutralizing, CD4 inducible (CD4i) epitopes within the gp120 constant 1 and 2 regions (C1/C2 or Cluster A epitopes). However, recent passive immunization studies have not been able to definitively confirm roles for these antibodies in HIV-1 prevention mostly due to the complications of cross-species Fc–FcR interactions and suboptimal dosing strategies. Here, we use our stabilized gp120 Inner domain (ID2) immunogen that displays the Cluster A epitopes within a minimal structural unit of HIV-1 Env to investigate an immunization protocol that induces a fine-tuned antibody repertoire capable of an effective Fc-effector response. This includes the generation of isotypes and the enhanced antibody specificity known to be vital for maximal Fc-effector activities, while minimizing the induction of isotypes know to be detrimental for these functions. Although our studies were done in in BALB/c mice we conclude that when optimally titrated for the species of interest, ID2 with GLA-SE adjuvant will elicit high titers of antibodies targeting the Cluster A region with potent Fc-mediated effector functions, making it a valuable immunogen candidate for testing an exclusive role of non-neutralizing antibody response in HIV-1 protection in vaccine settings.

scholarly journals Cocrystal Structures of Antibody N60-i3 and Antibody JR4 in Complex with gp120 Define More Cluster A Epitopes Involved in Effective Antibody-Dependent Effector Function against HIV-1

2015 ◽  
Vol 89 (17) ◽  
pp. 8840-8854 ◽  
Author(s):  
Neelakshi Gohain ◽  
William D. Tolbert ◽  
Priyamvada Acharya ◽  
Lei Yu ◽  
Tongyun Liu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Human Monoclonal Antibody ◽  
Antiretroviral Drugs ◽  
Effector Function ◽  
Effector Functions ◽  
Immunodeficiency Virus ◽  
Cluster A ◽  
Definition Of ◽  
Anti Hiv ◽  
Hiv 1

ABSTRACTAccumulating evidence indicates a role for Fc receptor (FcR)-mediated effector functions of antibodies, including antibody-dependent cell-mediated cytotoxicity (ADCC), in prevention of human immunodeficiency virus type 1 (HIV-1) acquisition and in postinfection control of viremia. Consequently, an understanding of the molecular basis for Env epitopes that constitute effective ADCC targets is of fundamental interest for humoral anti-HIV-1 immunity and for HIV-1 vaccine design. A substantial portion of FcR effector function of potentially protective anti-HIV-1 antibodies is directed toward nonneutralizing, transitional, CD4-inducible (CD4i) epitopes associated with the gp41-reactive region of gp120 (cluster A epitopes). Our previous studies defined the A32-like epitope within the cluster A region and mapped it to the highly conserved and mobile layers 1 and 2 of the gp120 inner domain within the C1-C2 regions of gp120. Here, we elucidate additional cluster A epitope structures, including an A32-like epitope, recognized by human monoclonal antibody (MAb) N60-i3, and a hybrid A32-C11-like epitope, recognized by rhesus macaque MAb JR4. These studies define for the first time a hybrid A32-C11-like epitope and map it to elements of both the A32-like subregion and the seven-layered β-sheet of the gp41-interactive region of gp120. These studies provide additional evidence that effective antibody-dependent effector function in the cluster A region depends on precise epitope targeting—a combination of epitope footprint and mode of antibody attachment. All together these findings help further an understanding of how cluster A epitopes are targeted by humoral responses.IMPORTANCEHIV/AIDS has claimed the lives of over 30 million people. Although antiretroviral drugs can control viral replication, no vaccine has yet been developed to prevent the spread of the disease. Studies of natural HIV-1 infection, simian immunodeficiency virus (SIV)- or simian-human immunodeficiency virus (SHIV)-infected nonhuman primates (NHPs), and HIV-1-infected humanized mouse models, passive transfer studies in infants born to HIV-infected mothers, and the RV144 clinical trial have linked FcR-mediated effector functions of anti-HIV-1 antibodies with postinfection control of viremia and/or blocking viral acquisition. With this report we provide additional definition of the molecular determinants for Env antigen engagement which lead to effective antibody-dependent effector function directed to the nonneutralizing CD4-dependent epitopes in the gp41-reactive region of gp120. These findings have important implications for the development of an effective HIV-1 vaccine.

scholarly journals Incorporating the Cluster A and V1V2 Targets into a Minimal Structural Unit of the HIV-1 Envelope to Elicit a Cross-Clade Response with Potent Fc-Effector Functions

Vaccines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 975
Author(s):  
Rebekah Sherburn ◽  
William D. Tolbert ◽  
Suneetha Gottumukkala ◽  
Andrew P. Hederman ◽  
Guillaume Beaudoin-Bussières ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Structural Unit ◽  
Vaccine Trial ◽  
Neutralizing Antibody ◽  
Specific Antibodies ◽  
Effector Functions ◽  
Cluster A ◽  
And Control ◽  
Antibody Epitopes ◽  
Hiv 1

The generation of a potent vaccine for the prevention and/or control of HIV-1 has been unsuccessful to date, despite decades of research. Existing evidence from both infected individuals and clinical trials support a role for non-neutralizing or weakly neutralizing antibodies with potent Fc-effector functions in the prevention and control of HIV-1 infection. Vaccination strategies that induce such antibodies have proven partially successful in preventing HIV-1 infection. This is largely thought to be due to the polyclonal response that is induced in a vaccine setting, as opposed to the infusion of a single therapeutic antibody, which is capable of diverse Fc-effector functions and targets multiple but highly conserved epitopes. Here, we build on the success of our inner domain antigen, ID2, which incorporates conformational CD4-inducible (CD4i) epitopes of constant region 1 and 2 (C1C2 or Cluster A), in the absence of neutralizing antibody epitopes, into a minimal structural unit of gp120. ID2 has been shown to induce Cluster A-specific antibodies in a BALB/c mouse model with Fc-effector functions against CD4i targets. In order to generate an immunogen that incorporates both epitope targets implicated in the protective Fc-effector functions of antibodies from the only partially successful human vaccine trial, RV144, we incorporated the V1V2 domain into our ID2 antigen generating ID2-V1V2, which we used to immunize in combination with ID2. Immunized BALB/c mice generated both Cluster A- and V1V2-specific antibodies, which synergized to significantly improve the Fc-mediated effector functions compared to mice immunized with ID2 alone. The sera were able to mediate both antibody-dependent cellular cytotoxicity (ADCC) and antibody-dependent cellular phagocytosis (ADCP). We therefore conclude that ID2-V1V2 + ID2 represents a promising vaccine immunogen candidate for the induction of antibodies with optimal Fc-mediated effector functions against HIV-1.

scholarly journals Removal of a Single N-Linked Glycan in Human Immunodeficiency Virus Type 1 gp120 Results in an Enhanced Ability To Induce Neutralizing Antibody Responses

2007 ◽  
Vol 82 (2) ◽  
pp. 638-651 ◽  
Author(s):  
Yun Li ◽  
Bradley Cleveland ◽  
Igor Klots ◽  
Bruce Travis ◽  
Barbra A. Richardson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Pronounced Increase ◽  
Enhanced Sensitivity ◽  
Subtype B ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Glycans on human immunodeficiency virus (HIV) envelope protein play an important role in infection and evasion from host immune responses. To examine the role of specific glycans, we introduced single or multiple mutations into potential N-linked glycosylation sites in hypervariable regions (V1 to V3) of the env gene of HIV type 1 (HIV-1) 89.6. Three mutants tested showed enhanced sensitivity to soluble CD4. Mutant N7 (N197Q) in the carboxy-terminal stem of the V2 loop showed the most pronounced increase in sensitivity to broadly neutralizing antibodies (NtAbs), including those targeting the CD4-binding site (IgG1b12) and the V3 loop (447-52D). This mutant is also sensitive to CD4-induced NtAb 17b in the absence of CD4. Unlike the wild-type (WT) Env, mutant N7 mediates CD4-independent infection in U87-CXCR4 cells. To study the immunogenicity of mutant Env, we immunized pig-tailed macaques with recombinant vaccinia viruses, one expressing SIVmac239 Gag-Pol and the other expressing HIV-1 89.6 Env gp160 in WT or mutant forms. Animals were boosted 14 to 16 months later with simian immunodeficiency virus gag DNA and the cognate gp140 protein before intrarectal challenge with SHIV89.6P-MN. Day-of-challenge sera from animals immunized with mutant N7 Env had significantly higher and broader neutralizing activities than sera from WT Env-immunized animals. Neutralizing activity was observed against SHIV89.6, SHIV89.6P-MN, HIV-1 SF162, and a panel of subtype B primary isolates. Compared to control animals, immunized animals showed significant reduction of plasma viral load and increased survival after challenge, which correlated with prechallenge NtAb titers. These results indicate the potential advantages for glycan modification in vaccine design, although the role of specific glycans requires further examination.

scholarly journals Role of Complement Receptors (CRs) on DCs in Anti-HIV-1 Immunity

2020 ◽  
Vol 11 ◽  
Author(s):  
Wilfried Posch ◽  
Marta Bermejo-Jambrina ◽  
Cornelia Lass-Flörl ◽  
Doris Wilflingseder
Keyword(s):  
Complement Receptors ◽  
Anti Hiv ◽  
Hiv 1

scholarly journals Vaccines and Broadly Neutralizing Antibodies for HIV-1 Prevention

2020 ◽  
Vol 38 (1) ◽  
pp. 673-703 ◽  
Author(s):  
Kathryn E. Stephenson ◽  
Kshitij Wagh ◽  
Bette Korber ◽  
Dan H. Barouch
Keyword(s):  
Clinical Trials ◽  
Neutralizing Antibodies ◽  
Passive Immunization ◽  
Neutralizing Antibody ◽  
Broadly Neutralizing Antibodies ◽  
Aids Pandemic ◽  
Broadly Neutralizing Antibody ◽  
Early Phase Clinical Trials ◽  
Hiv 1 ◽  
Review Current

Development of improved approaches for HIV-1 prevention will likely be required for a durable end to the global AIDS pandemic. Recent advances in preclinical studies and early phase clinical trials offer renewed promise for immunologic strategies for blocking acquisition of HIV-1 infection. Clinical trials are currently underway to evaluate the efficacy of two vaccine candidates and a broadly neutralizing antibody (bNAb) to prevent HIV-1 infection in humans. However, the vast diversity of HIV-1 is a major challenge for both active and passive immunization. Here we review current immunologic strategies for HIV-1 prevention, with a focus on current and next-generation vaccines and bNAbs.

scholarly journals The critical role of human transcriptional repressor CTCF mRNA up-regulation in the induction of anti-HIV-1 responses in CD4+ T cells

2008 ◽  
Vol 117 (1) ◽  
pp. 35-44 ◽  
Author(s):  
Yuchang Li ◽  
Guanhua Li ◽  
Anna Ivanova ◽  
Sagiv Aaron ◽  
Malgorzata Simm
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Critical Role ◽  
Transcriptional Repressor ◽  
Anti Hiv ◽  
Hiv 1

scholarly journals Characterization of Co-Formulated High-Concentration Broadly Neutralizing Anti-HIV-1 Monoclonal Antibodies for Subcutaneous Administration

Antibodies ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 36
Author(s):  
Vaneet K. Sharma ◽  
Bijay Misra ◽  
Kevin T. McManus ◽  
Sreenivas Avula ◽  
Kaliappanadar Nellaiappan ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Clinical Investigation ◽  
Total Concentration ◽  
Subcutaneous Administration ◽  
Analytical Techniques ◽  
Neutralizing Antibody ◽  
High Concentration ◽  
Anti Hiv ◽  
Hiv 1

The discovery of numerous potent and broad neutralizing antibodies (bNAbs) against Human Immunodeficiency Virus type 1 (HIV-1) envelope glycoprotein has invigorated the potential of using them as an effective preventative and therapeutic agent. The majority of the anti-HIV-1 antibodies, currently under clinical investigation, are formulated singly for intra-venous (IV) infusion. However, due to the high degree of genetic variability in the case of HIV-1, a single broad neutralizing antibody will likely not be sufficient to protect against the broad range of viral isolates. To that end, delivery of two or more co-formulated bnAbs against HIV-1 in a single subcutaneous (SC) injection is highly desired. We, therefore, co-formulated two anti-HIV bnAbs, 3BNC117-LS and 10-1074-LS, to a total concentration of 150 mg/mL for SC administration and analyzed them using a panel of analytical techniques. Chromatographic based methods, such as RP-HPLC, CEX-HPLC, SEC-HPLC, were developed to ensure separation and detection of each antibody in the co-formulated sample. In addition, we used a panel of diverse pseudoviruses to detect the functionality of individual antibodies in the co-formulation. We also used these methods to test the stability of the co-formulated antibodies and believe that such an approach can support future efforts towards the formulation and characterization of multiple high-concentration antibodies for SC delivery.

scholarly journals Ablation of the Complementarity-Determining Region H3 Apex of the Anti-HIV-1 Broadly Neutralizing Antibody 2F5 Abrogates Neutralizing Capacity without Affecting Core Epitope Binding

2010 ◽  
Vol 84 (9) ◽  
pp. 4136-4147 ◽  
Author(s):  
Jean-Philippe Julien ◽  
Nerea Huarte ◽  
Rubén Maeso ◽  
Stefka G. Taneva ◽  
Annie Cunningham ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Hydrophobic Interactions ◽  
Neutralizing Antibody ◽  
Titration Calorimetry ◽  
Peptide Epitope ◽  
Neutralizing Capacity ◽  
Epitope Binding ◽  
Hiv 1 ◽  
Complementarity Determining Region

ABSTRACT The identification and characterization of broadly neutralizing antibodies (bnAbs) against HIV-1 has formed a major research focus, with the ultimate goal to help in the design of an effective AIDS vaccine. One of these bnAbs, 2F5, has been extensively characterized, and residues at the apex of its unusually long complementarity-determining region (CDR) H3 loop have been shown to be crucial for neutralization. Structural studies, however, have revealed that the 100TLFGVPI100F apex residues of the CDR H3 loop do not interact directly with residues of its core gp41 epitope. In an attempt to gain better insight into the functional role of this element, we have recombinantly expressed native 2F5 Fab and two mutants in which either the apical Phe100B(H) residue was changed to an alanine or the CDR H3 residues 100TLFGVPI100F were replaced by a Ser-Gly dipeptide linker. Isothermal titration calorimetry (ITC) and competitive-binding enzyme-linked immunosorbent assays (ELISAs) rendered strikingly similar affinity constants (Kd [dissociation constant] of ∼20 nM) for linear peptide epitope binding by 2F5 Fabs, independent of the presence or absence of the apex residues. Ablation of the CDR H3 apex residues, however, abolished the cell-cell fusion inhibition and pseudovirus neutralization capacities of 2F5 Fab. We report competitive ELISA data that suggest a role of 2F5 CDR H3 apex residues in mediating weak hydrophobic interactions with residues located at the C terminus of the gp41 membrane proximal external region and/or membrane components in the context of core epitope binding. The present data therefore imply an extended 2F5 paratope that includes weak secondary interactions that are crucial for neutralization of Env-mediated fusion.

REVIEW OF HIV MODELS: THE ROLE OF THE NATURAL IMMUNE RESPONSE AND IMPLICATIONS FOR TREATMENT

2004 ◽  
Vol 12 (02) ◽  
pp. 123-135 ◽  
Author(s):  
REBECCA V. CULSHAW
Keyword(s):  
Immune Response ◽  
Optimal Treatment ◽  
Minimal Cost ◽  
Treatment Scenario ◽  
Forcing Function ◽  
Drug Regimens ◽  
Differential Equations Models ◽  
Anti Hiv ◽  
Hiv 1

We present a review and comparison of several recent differential equations models of treatment of HIV-1 infection. We seek to clarify the role of the natural anti-HIV immune response and determine its effect upon optimal treatment schemes. In this paper, we consider systems in which treatment is expressed as a forcing function, as well as those in which we determine optimal treatment via control theoretic techniques. The primary goal of this study is to compare treatment schemes for systems in which a natural nonconstant immune response of the patient is considered explicitly with those that consider implicitly a constant non-specific immune response. We find that when the natural immune response can be boosted sufficiently, drug levels may not need to be as high as previously supposed. This implies that a treatment scenario in which intervals of drug treatment are alternated with some form of immune-boosting therapy may be highly beneficial in terms of reducing toxicity to the patient. Additionally, in developing countries where HIV infection is widespread and sufficient funds are not available to supply rigourous drug regimens, the implications of these models are profound, as they suggest methods of treating HIV at a minimal cost.

scholarly journals The role of the glycosyl moiety of myricetin derivatives in anti-HIV-1 activity in vitro

2017 ◽  
Vol 14 (1) ◽  
Author(s):  
Joseph T. Ortega ◽  
Alirica I. Suárez ◽  
Maria L. Serrano ◽  
Jani Baptista ◽  
Flor H. Pujol ◽  
...  
Keyword(s):  
Anti Hiv ◽  
Hiv 1
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