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Association of VH4-59 Antibody Variable Gene Usage with Recognition of an Immunodominant Epitope on the HIV-1 Gag Protein.

Chukwuma VU, Hicar MD, Chen X, Nicholas KJ, Joyner A, Kalams SA, Landucci G, Forthal DN, Spearman PW, Crowe JE - PLoS ONE (2015)

Bottom Line: We found no evidence that mAb 3E4 exhibited any function in laboratory studies aimed at elucidating the immunologic activity, including assays for neutralization, Ab-dependent cell-mediated virus inhibition, or enhanced T cell reactivity caused by Gag-3E4 complexes.The findings suggest this immunodominant epitope in Gag protein, which is associated with VH4-59 germline gene usage, may induce a high level of B cells that encode binding but non-functional antibodies that occupy significant repertoire space following HIV infection.The studies define an additional specific molecular mechanism in the immune distraction activity of the HIV virion.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America.

ABSTRACT
The human antibody response against HIV-1 infection recognizes diverse antigenic subunits of the virion, and includes a high level of antibodies to the Gag protein. We report here the isolation and characterization of a subset of Gag-specific human monoclonal antibodies (mAbs) that were prevalent in the antibody repertoire of an HIV-infected individual. Several lineages of Gag-specifc mAbs were encoded by a single antibody heavy chain variable region, VH4-59, and a representative antibody from this group designated mAb 3E4 recognized a linear epitope on the globular head of the p17 subunit of Gag. We found no evidence that mAb 3E4 exhibited any function in laboratory studies aimed at elucidating the immunologic activity, including assays for neutralization, Ab-dependent cell-mediated virus inhibition, or enhanced T cell reactivity caused by Gag-3E4 complexes. The findings suggest this immunodominant epitope in Gag protein, which is associated with VH4-59 germline gene usage, may induce a high level of B cells that encode binding but non-functional antibodies that occupy significant repertoire space following HIV infection. The studies define an additional specific molecular mechanism in the immune distraction activity of the HIV virion.

No MeSH data available.


Related in: MedlinePlus

Heavy chain amino acid sequence alignment of VH4-59 encoded mAbs.The heavy chain amino acid sequence of HIV-specific VH4-59 encoded mAbs are shown aligned to the VH4-59 germline gene. Conservation with the germline gene sequence is indicated by a * symbol in the alignments.
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pone.0133509.g001: Heavy chain amino acid sequence alignment of VH4-59 encoded mAbs.The heavy chain amino acid sequence of HIV-specific VH4-59 encoded mAbs are shown aligned to the VH4-59 germline gene. Conservation with the germline gene sequence is indicated by a * symbol in the alignments.

Mentions: We performed single cell cytometric sorting of B cells from an HIV-infected individual designated as subject 10076, using fluorescently labeled VLPs displaying a stabilized form of the BaL strain HIV Env protein. Out of 448 B cells sorted, 45 B cells were shown to be secreting HIV-specific antibodies in culture. Through binding analysis of B cell supernates to HIV antigens, we identified a subset of six B cells that showed binding to HIV VLPs, but not to purified HIV Env proteins. This subset of B cells represented a dominant response to HIV infection this individual, and sequence analysis revealed that the six mAbs with this binding pattern were encoded by the same heavy chain variable germline gene, VH4-59 (Table 1). Comparison of the heavy chain amino acid sequences to the germline gene sequence and to each other showed that the mAbs grouped into two distinct lineages, designated lineages A and B. Further analysis showed that although mAbs 3E4, 4C8, 6D11 and 7F2 shared sequence homology within the framework regions, there were distinguishing mutations occurring in the complementarity determining regions particularly in the HCDR3 of 3E4 (Fig 1).


Association of VH4-59 Antibody Variable Gene Usage with Recognition of an Immunodominant Epitope on the HIV-1 Gag Protein.

Chukwuma VU, Hicar MD, Chen X, Nicholas KJ, Joyner A, Kalams SA, Landucci G, Forthal DN, Spearman PW, Crowe JE - PLoS ONE (2015)

Heavy chain amino acid sequence alignment of VH4-59 encoded mAbs.The heavy chain amino acid sequence of HIV-specific VH4-59 encoded mAbs are shown aligned to the VH4-59 germline gene. Conservation with the germline gene sequence is indicated by a * symbol in the alignments.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4520566&req=5

pone.0133509.g001: Heavy chain amino acid sequence alignment of VH4-59 encoded mAbs.The heavy chain amino acid sequence of HIV-specific VH4-59 encoded mAbs are shown aligned to the VH4-59 germline gene. Conservation with the germline gene sequence is indicated by a * symbol in the alignments.
Mentions: We performed single cell cytometric sorting of B cells from an HIV-infected individual designated as subject 10076, using fluorescently labeled VLPs displaying a stabilized form of the BaL strain HIV Env protein. Out of 448 B cells sorted, 45 B cells were shown to be secreting HIV-specific antibodies in culture. Through binding analysis of B cell supernates to HIV antigens, we identified a subset of six B cells that showed binding to HIV VLPs, but not to purified HIV Env proteins. This subset of B cells represented a dominant response to HIV infection this individual, and sequence analysis revealed that the six mAbs with this binding pattern were encoded by the same heavy chain variable germline gene, VH4-59 (Table 1). Comparison of the heavy chain amino acid sequences to the germline gene sequence and to each other showed that the mAbs grouped into two distinct lineages, designated lineages A and B. Further analysis showed that although mAbs 3E4, 4C8, 6D11 and 7F2 shared sequence homology within the framework regions, there were distinguishing mutations occurring in the complementarity determining regions particularly in the HCDR3 of 3E4 (Fig 1).

Bottom Line: We found no evidence that mAb 3E4 exhibited any function in laboratory studies aimed at elucidating the immunologic activity, including assays for neutralization, Ab-dependent cell-mediated virus inhibition, or enhanced T cell reactivity caused by Gag-3E4 complexes.The findings suggest this immunodominant epitope in Gag protein, which is associated with VH4-59 germline gene usage, may induce a high level of B cells that encode binding but non-functional antibodies that occupy significant repertoire space following HIV infection.The studies define an additional specific molecular mechanism in the immune distraction activity of the HIV virion.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, Tennessee, United States of America.

ABSTRACT
The human antibody response against HIV-1 infection recognizes diverse antigenic subunits of the virion, and includes a high level of antibodies to the Gag protein. We report here the isolation and characterization of a subset of Gag-specific human monoclonal antibodies (mAbs) that were prevalent in the antibody repertoire of an HIV-infected individual. Several lineages of Gag-specifc mAbs were encoded by a single antibody heavy chain variable region, VH4-59, and a representative antibody from this group designated mAb 3E4 recognized a linear epitope on the globular head of the p17 subunit of Gag. We found no evidence that mAb 3E4 exhibited any function in laboratory studies aimed at elucidating the immunologic activity, including assays for neutralization, Ab-dependent cell-mediated virus inhibition, or enhanced T cell reactivity caused by Gag-3E4 complexes. The findings suggest this immunodominant epitope in Gag protein, which is associated with VH4-59 germline gene usage, may induce a high level of B cells that encode binding but non-functional antibodies that occupy significant repertoire space following HIV infection. The studies define an additional specific molecular mechanism in the immune distraction activity of the HIV virion.

No MeSH data available.


Related in: MedlinePlus