Article thumbnail

Induction of HIV Neutralizing Antibodies against the MPER of the HIV Envelope Protein by HA/gp41 Chimeric Protein-Based DNA and VLP Vaccines

By Ling Ye, Zhiyuan Wen, Ke Dong, Xi Wang, Zhigao Bu, Huizhong Zhang, Richard W. Compans and Chinglai Yang

Abstract

Several conserved neutralizing epitopes have been identified in the HIV Env protein and among these, the MPER of gp41 has received great attention and is widely recognized as a promising target. However, little success has been achieved in eliciting MPER-specific HIV neutralizing antibodies by a number of different vaccine strategies. We investigated the ability of HA/gp41 chimeric protein-based vaccines, which were designed to enhance the exposure of the MPER in its native conformation, to induce MPER-specific HIV neutralizing antibodies. In characterization of the HA/gp41 chimeric protein, we found that by mutating an unpaired Cys residue (Cys-14) in its HA1 subunit to a Ser residue, the modified chimeric protein HA-C14S/gp41 showed increased reactivity to a conformation-sensitive monoclonal antibody against HA and formed more stable trimers in VLPs. On the other hand, HA-C14S/gp41 and HA/gp41 chimeric proteins expressed on the cell surfaces exhibited similar reactivity to monoclonal antibodies 2F5 and 4E10. Immunization of guinea pigs using the HA-C14S/gp41 DNA or VLP vaccines induced antibodies against the HIV gp41 as well as to a peptide corresponding to a segment of MPER at higher levels than immunization by standard HIV VLPs. Further, sera from vaccinated guinea pigs were found to exhibit HIV neutralizing activities. Moreover, sera from guinea pigs vaccinated by HA-C14S/gp41 DNA and VLP vaccines but not the standard HIV VLPs, were found to neutralize HIV pseudovirions containing a SIV-4E10 chimeric Env protein. The virus neutralization could be blocked by a MPER-specific peptide, thus demonstrating induction of MPER-specific HIV neutralizing antibodies by this novel vaccine strategy. These results show that induction of MPER-specific HIV neutralizing antibodies can be achieved through a rationally designed vaccine strategy

Topics: Research Article
Publisher: Public Library of Science
OAI identifier: oai:pubmedcentral.nih.gov:3098228
Provided by: PubMed Central

To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.

Suggested articles

Citations

  1. (2008). 4E10-resistant variants in a human immunodeficiency virus type 1 subtype C-infected individual with an anti-membrane-proximal external region-neutralizing antibody response.
  2. (2008). A brief history of HIV vaccine research: stepping back to the drawing board?
  3. (1998). A conserved HIV gp120 glycoprotein structure involved in chemokine receptor binding.
  4. (1993). A conserved neutralizing epitope on gp41 of human immunodeficiency virus type 1.
  5. (1999). A conserved tryptophan-rich motif in the membrane-proximal region of the human immunodeficiency virus type 1 gp41 ectodomain is important for Env-mediated fusion and virus infectivity.
  6. (2001). A potent cross-clade neutralizing human monoclonal antibody against a novel epitope on gp41 of human immunodeficiency virus type 1.
  7. (2003). Access of antibody molecules to the conserved coreceptor binding site on glycoprotein gp120 is sterically restricted on primary human immunodeficiency virus type 1.
  8. (1983). Analyses of the antigenicity of influenza haemagglutinin at the pH optimum for virus-mediated membrane fusion.
  9. (1998). Analysis of intercurrent human immunodeficiency virus type 1 infections in phase I and II trials of candidate AIDS vaccines.
  10. (2009). Analysis of neutralization specificities in polyclonal sera derived from human immunodeficiency virus type 1-infected individuals.
  11. (2008). Analysis of the human immunodeficiency virus type 1 gp41 membrane proximal external region arrayed on hepatitis B surface antigen particles.
  12. (2005). Anti-human immunodeficiency virus type 1 (HIV-1) antibodies 2F5 and 4E10 require surprisingly few crucial residues in the membrane-proximal external region of glycoprotein gp41 to neutralize HIV-1.
  13. (2007). Antigenic and immunogenic study of membrane-proximal external region-grafted gp120 antigens by a DNA prime-protein boost immunization strategy.
  14. (2006). Antigenic properties of a transport-competent influenza HA/HIV Env chimeric protein.
  15. (2000). Antigenicity and immunogenicity of the HIV-1 gp41 epitope ELDKWA inserted into permissive sites of the MalE protein.
  16. (1996). Assembly and release of SIV env proteins with full-length or truncated cytoplasmic domains.
  17. (1995). Assembly of SIV virus-like particles containing envelope proteins using a baculovirus expression system.
  18. (2001). Broadly neutralizing antibodies targeted to the membrane-proximal external region of human immunodeficiency virus type 1 glycoprotein gp41.
  19. (2008). Challenges in the development of an HIV-1 vaccine.
  20. (2009). Characterization of a trimeric MPER containing HIV-1 gp41 antigen.
  21. (2003). Clinical research. A setback and an advance on the AIDS vaccine front.
  22. (2010). Computational design of epitope-scaffolds allows induction of antibodies specific for a poorly immunogenic HIV vaccine epitope.
  23. (2005). Conformational constraints imposed on a pan-neutralizing HIV-1 antibody epitope result in increased antigenicity but not neutralizing response.
  24. (1999). Cross-subtype neutralizing antibodies induced in baboons by a subtype E gp120 immunogen based on an R5 primary human immunodeficiency virus type 1 envelope.
  25. (2000). Current evidence and future directions for targeting HIV entry: therapeutic and prophylactic strategies.
  26. (2007). Dissecting the neutralizing antibody specificities of broadly neutralizing sera from human immunodeficiency virus type 1-infected donors.
  27. (2000). Effect of the cytoplasmic domain of the simian immunodeficiency virus envelope protein on incorporation of heterologous envelope proteisns and sensitivity to neutralization.
  28. (2010). Elicitation of structure-specific antibodies by epitope scaffolds.
  29. (2004). Enhancement of immunogenicity of an HIV Env DNA vaccine by mutation of the Tyr-based endocytosis motif in the cytoplasmic domain.
  30. (1999). Epitope insertion into variable loops of HIV-1 gp120 as a potential means to improve immunogenicity of viral envelope protein.
  31. (2008). HIV vaccine research: the way forward.
  32. (2008). HIV-1 broadly neutralizing antibody extracts its epitope from a kinked gp41 ectodomain region on the viral membrane.
  33. (2005). Human immunodeficiency virus type 1 env clones from acute and early subtype B infections for standardized assessments of vaccine-elicited neutralizing antibodies.
  34. (2009). Immunization by influenza virus-like particles protects aged mice against lethal influenza virus challenge.
  35. (1996). Immunogenic presentation of a conserved gp41 epitope of human immunodeficiency virus type 1 on recombinant surface antigen of hepatitis B virus.
  36. (2001). Immunogenicity and protective efficacy of oligomeric human immunodeficiency virus type 1 gp140.
  37. (2007). Immunogenicity of recombinant human immunodeficiency virus type 1-like particles expressing gp41 derivatives in a pre-fusion state.
  38. (1998). Immunological and virological analyses of persons infected by human immunodeficiency virus type 1 while participating in trials of recombinant gp120 subunit vaccines.
  39. (2008). Importance of the membrane-perturbing properties of the membrane-proximal external region of human immunodeficiency virus type 1 gp41 to viral fusion.
  40. (1998). Induction of immune responses to HIV-1 by canarypox virus (ALVAC) HIV-1 and gp120 SF-2 recombinant vaccines in uninfected volunteers.
  41. (2006). Induction of neutralizing antibody against human immunodeficiency virus type 1 (HIV-1) by immunization with gp41 membrane-proximal external region (MPER) fused with porcine endogenous retrovirus (PERV) p15E fragment.
  42. (1983). Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS).
  43. (1983). Isolation of human T-cell leukemia virus in acquired immune deficiency syndrome (AIDS).
  44. (1995). Mucosal model of immunization against human immunodeficiency virus type 1 with a chimeric influenza virus.
  45. (2007). Neutralizing antibody responses in acute human immunodeficiency virus type 1 subtype C infection.
  46. (2000). Production and characterization of simian–human immunodeficiency virus-like particles.
  47. (2006). Randomized, double-blind, placebo-controlled efficacy trial of a bivalent recombinant glycoprotein 120 HIV-1 vaccine among injection drug users in Bangkok, Thailand.
  48. (2010). Rational antibody-based HIV-1 vaccine design: current approaches and future directions.
  49. (2006). Simian immunodeficiency virus engrafted with human immunodeficiency virus type 1 (HIV-1)-specific epitopes: replication, neutralization, and survey of HIV-1-positive plasma.
  50. (2004). Structure and mechanistic analysis of the anti-human immunodeficiency virus type 1 antibody 2F5 in complex with its gp41 epitope.
  51. (1998). Structure of an HIV gp120 envelope glycoprotein in complex with the CD4 receptor and a neutralizing human antibody.
  52. (2004). Surface stability and immunogenicity of the human immunodeficiency virus envelope glycoprotein: role of the cytoplasmic domain.
  53. (2008). The challenges of eliciting neutralizing antibodies to HIV-1 and to influenza virus.
  54. (1998). The HIV-1 envelope glycoproteins: fusogens, antigens, and immunogens.
  55. (2008). The membraneproximal external region of the human immunodeficiency virus type 1 envelope: dominant site of antibody neutralization and target for vaccine design.
  56. (2008). Toward an AIDS vaccine.