Variable region genes of anti-HIV human monoclonal antibodies: Non-restricted use of the V gene repertoire and extensive somatic mutation

Michael J. Moran, Jennifer S. Andris, Yoh ichi Matsumato, J. Donald Capra, Evan M. Hersh

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Abstract

The extent of the expressed human V gene repertoire for the most part has been derived from fetal cDNA libraries, autoantibodies, and myeloma proteins. In order to continue to explore the utilization of the VH and VL gene repertoire in response to exogenous viral antigens, the heavy and light chain cDNAs from four human anti-HIV monoclonal antibodies were PCR amplified from human-mouse heterohybridomas, cloned, and nucleotide sequence analysis performed. Of the monoclonals analyzed, three were directed against gp120 and one reacted with gp41. Three of the antibodies were of the IgG1 λ isotype and one was an IgG1 κ. Three of the four heavy chains were derived from VHI gene segments and one VHII was observed. D segments showed evidence of D-D joining and three JH4 and one JH5 gene were utilized. Two VλII lambda chains and one from the VλIII gene family were observed and the single kappa chain sequenced was from the VκIII family. DNA sequence comparison with known germline gene segments identified putative precursor V gene segments for one of the heavy chains and two light chains. Comparison of the expressed amino acid sequences with the predicted germline sequences indicated that changes were clustered in the CDRs and FR3 regions of the V gene segments. We reported previously the nucleotide sequences of five human monoclonal antibodies from HIV-infected individuals, three of which utilized VHIV, one VHV and one a VHI gene segment and also found extensive evidence of somatic mutation. Collectively, our results indicate that an antigen driven response is functioning following HIV infection and, surprisingly, to date we have not encountered a VHIII gene segment. Since VHIII is the largest human VH gene family, it may well be that this under-representation has both functional and clinical implications.

Original languageEnglish (US)
Pages (from-to)1543-1551
Number of pages9
JournalMolecular Immunology
Volume30
Issue number16
DOIs
StatePublished - Nov 1993

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ASJC Scopus subject areas

  • Immunology
  • Molecular Biology

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