Tissue memory B cell repertoire analysis after ALVAC/AIDSVAX B/E gp120 immunization of rhesus macaques
Kan Luo, et al.
Kan Luo, et al.
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Research Article AIDS/HIV Vaccines

Tissue memory B cell repertoire analysis after ALVAC/AIDSVAX B/E gp120 immunization of rhesus macaques

Abstract

The ALVAC prime/ALVAC + AIDSVAX B/E boost RV144 vaccine trial induced an estimated 31% efficacy in a low-risk cohort where HIV‑1 exposures were likely at mucosal surfaces. An immune correlates study demonstrated that antibodies targeting the V2 region and in a secondary analysis antibody-dependent cellular cytotoxicity (ADCC), in the presence of low envelope-specific (Env-specific) IgA, correlated with decreased risk of infection. Thus, understanding the B cell repertoires induced by this vaccine in systemic and mucosal compartments are key to understanding the potential protective mechanisms of this vaccine regimen. We immunized rhesus macaques with the ALVAC/AIDSVAX B/E gp120 vaccine regimen given in RV144, and then gave a boost 6 months later, after which the animals were necropsied. We isolated systemic and intestinal vaccine Env-specific memory B cells. Whereas Env-specific B cell clonal lineages were shared between spleen, draining inguinal, anterior pelvic, posterior pelvic, and periaortic lymph nodes, members of Env‑specific B cell clonal lineages were absent in the terminal ileum. Env‑specific antibodies were detectable in rectal fluids, suggesting that IgG antibodies present at mucosal sites were likely systemically produced and transported to intestinal mucosal sites.

Authors

Kan Luo, Hua-Xin Liao, Ruijun Zhang, David Easterhoff, Kevin Wiehe, Thaddeus C. Gurley, Lawrence C. Armand, Ashley A. Allen, Tarra A. Von Holle, Dawn J. Marshall, John F. Whitesides, Jamie Pritchett, Andrew Foulger, Giovanna Hernandez, Robert Parks, Krissey E. Lloyd, Christina Stolarchuk, Sheetal Sawant, Jessica Peel, Nicole L. Yates, Erika Dunford, Sabrina Arora, Amy Wang, Cindy M. Bowman, Laura L. Sutherland, Richard M. Scearce, Shi-Mao Xia, Mattia Bonsignori, Justin Pollara, R. Whitney Edwards, Sampa Santra, Norman L. Letvin, James Tartaglia, Donald Francis, Faruk Sinangil, Carter Lee, Jaranit Kaewkungwal, Sorachai Nitayaphan, Punnee Pitisuttithum, Supachai Rerks-ngarm, Nelson L. Michael, Jerome H. Kim, S. Munir Alam, Nathan A. Vandergrift, Guido Ferrari, David C. Montefiori, Georgia D. Tomaras, Barton F. Haynes, M. Anthony Moody

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Figure 8

Clonal lineages of isolated mAbs.

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Clonal lineages of isolated mAbs. Phylograms of clonal lineages isolated...
Phylograms of clonal lineages isolated from rhesus macaques (RMs) are shown with antibody data on each line to the right of the mAb name. (A) Mature lineage DH614 potently bound to gp120 proteins and V1V2 targets with the exception of RV144 breakthrough strain gp120AE.703357; the lineage members also neutralized AE.92TH023.6 and the mature antibodies bound to the surface of AE.CM235-infected target cells. Lineage characteristics: VH3~SC11/JH4, heavy chain (HC) complementarity-determining region 3 (HCDR3) length 13, mean HC mutation frequency 10.4%; Vλ3~17/Vλ2 CDR3 length 10, mean light chain (LC) mutation frequency 5.9%. (B) Mature lineage DH612 mAbs bound to gp120M.ConS and neutralized B.MN.3 but did not bind or neutralize clade AE targets. The mature mAbs bound to the surface of AE.CM235-infected target cells. Lineage characteristics: VH4~82/JH6, HCDR3 length 24, mean HC mutation frequency 8.4%; Vκ1-LC1c/Jκ2, CDR3 length 9, mean LC mutation frequency 9.2%. (C) Mature lineage DH613 mAbs potently bound gp120 proteins from clade AE and group M consensus but did not bind V1V2-specific targets. The mature antibodies potently neutralized both AE.92TH023.6 and B.MN.3; the mature antibodies weakly bound to AE.CM235-infected target cells. Lineage characteristics: VH3~SC11/JH4, HCDR3 length 18, mean HC mutation frequency 11.1%; Vκ1~23/Jκ1, CDR3 length 9, mean LC mutation frequency 4.4%. The anatomic site of origin appears after the mAb name: BL, peripheral blood; SP, spleen; IN, inguinal lymph node (LN); AP, anterior pelvic LN; PP, posterior pelvic LN; PA, periaortic LN; MT, mesenteric LN. Data are in μg/ml, color coded as shown in the legend for ELISA half maximal effective concentration (EC50) and neutralization inhibitory dilution 50% (ID50), or as % cell binding. MFI, mean fluorescence intensity; UCA, unmutated common ancestor.