Date of Award
Doctor of Philosophy (PhD)
Antibodies to conserved epitopes on the HIV surface protein gp140 can protect against infection in non-human primates, suggesting that vaccines that elicit such antibodies would be protective. Some HIV infected individuals develop high titers of broadly neutralizing IgG antibodies in their serum, but until recently very little was known about the specificity and activity of these antibodies. To characterize the broadly neutralizing memory antibody responses to HIV we cloned 1078 antibodies from HIV envelope binding memory B cells from eight HIV infected patients with broadly neutralizing antibodies. We found that in these patients, the B cell memory response to gp140 is composed of up to 50 independent clones expressing high affinity antibodies to the gp120 variable loops, the CD4 binding site, the co-receptor binding site, to a new neutralizing epitope that is in the same region of gp120 as the CD4 binding site and to gp41. In four patients highly potent broadly neutralizing antibody clones directed to the CD4 binding site were isolated. Despite extensive hypermutation, these broadly neutralizing CD4bs antibodies shared a consensus sequence of 68 IgH chain amino acids and arose independently from two related IgH genes. Thus, the IgG memory B cell compartment in the selected group of patients with broad serum activity to HIV is comprised of multiple clonal responses. Neutralizing activity is directed against several epitopes on gp120 with some closely related CD4 binding site directed antibody clones showing highly potent neutralizing activity. For the first time, this study has attempted to systematically describe on a monoclonal level the composition of broadly neutralizing serum activity against HIV. The techniques and antibodies presented in this work are transforming our understanding of possible targets and routes for HIV vaccine strategies and provide powerful tools for possible HIV treatment approaches.
Scheid, Johannes F., "HIV Specific B Cell Response in Patients With Broadly Neutralizing Serum Activity" (2014). Student Theses and Dissertations. 223.