A Potent anti-Simian Immunodeficiency Virus Neutralizing Antibody Induction Associated with a Germline Immunoglobulin Gene Polymorphism in Rhesus Macaques

Virus infection induces B cells with a wide variety of B cell receptor (BCR) repertoires. Patterns of induced BCR repertoires are different in individuals, while the underlying mechanism causing this difference remains largely unclear. In particular, the impact of germ line BCR immunoglobulin (Ig) gene polymorphism on B cell/antibody induction has not fully been determined. In the present study, we found a potent antibody induction associated with a germ line BCR Ig gene polymorphism. B404-class antibodies, which were previously reported as potent anti-simian immunodeficiency virus (SIV) neutralizing antibodies using the germ line VH3.33 gene-derived Ig heavy chain, were induced in five of 10 rhesus macaques after SIVsmH635FC infection. Investigation of VH3.33 genes in B404-class antibody inducers (n = 5) and non-inducers (n = 5) revealed association of B404-class antibody induction with a germ line VH3.33 polymorphism. Analysis of reconstructed antibodies indicated that the VH3.33 residue 38 is the determinant for B404-class antibody induction. B404-class antibodies were induced in all the macaques possessing the B404-associated VH3.33 allele, even under undetectable viremia. Our results show that a single nucleotide polymorphism in germ line VH genes could be a determinant for induction of potent antibodies against virus infection, implying that germ line VH-gene polymorphisms can be a factor restricting effective antibody induction or responsiveness to vaccination. IMPORTANCE Vaccines against a wide variety of infectious diseases have been developed mostly to induce antibodies targeting pathogens. However, small but significant percentage of people fail to mount potent antibody responses after vaccination, while the underlying mechanism of host failure in antibody induction remains largely unclear. In particular, the impact of germ line B cell receptor (BCR)/antibody immunoglobulin (Ig) gene polymorphism on B cell/antibody induction has not fully been determined. In the present study, we found a potent anti-simian immunodeficiency virus neutralizing antibody induction associated with a germ line BCR/antibody Ig gene polymorphism in rhesus macaques. Our results demonstrate that a single nucleotide polymorphism in germ line Ig genes could be a determinant for induction of potent antibodies against virus infection, implying that germ line BCR/antibody Ig gene polymorphisms can be a factor restricting effective antibody induction or responsiveness to vaccination.

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Simian immunodeficiency virus infection in rhesus macaques induces selective tissue specific B cell defects in double positive CD21+CD27+ memory B cells

Clinical Immunology ◽

10.1016/j.clim.2011.04.018 ◽

2011 ◽

Vol 140 (3) ◽

pp. 223-228 ◽

Cited By ~ 17

Author(s):

Arpita Das ◽

Ronald S. Veazey ◽

Xiaolei Wang ◽

Andrew A. Lackner ◽

Huanbin Xu ◽

...

Keyword(s):

B Cells ◽

Virus Infection ◽

B Cell ◽

Simian Immunodeficiency Virus ◽

Rhesus Macaques ◽

Memory B Cells ◽

Simian Immunodeficiency Virus Infection ◽

Double Positive ◽

Tissue Specific ◽

Immunodeficiency Virus

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Faculty Opinions recommendation of Evidence of early B-cell dysregulation in simian immunodeficiency virus infection: rapid depletion of naïve and memory B-cell subsets with delayed reconstitution of the naïve B-cell population.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.3317956.3004055 ◽

2010 ◽

Author(s):

Willy Bogers

Keyword(s):

Virus Infection ◽

B Cell ◽

Simian Immunodeficiency Virus ◽

Cell Population ◽

Simian Immunodeficiency Virus Infection ◽

Memory B Cell ◽

Immunodeficiency Virus ◽

B Cell Subsets

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Induction of Th2 Cytokine Expression for p27‐Specific IgA B Cell Responses after Targeted Lymph Node Immunization with Simian Immunodeficiency Virus Antigens in Rhesus Macaques

The Journal of Infectious Diseases ◽

10.1086/513811 ◽

1998 ◽

Vol 177 (1) ◽

pp. 26-33 ◽

Cited By ~ 20

Author(s):

Shigetada Kawabata ◽

Christopher J. Miller ◽

Thomas Lehner ◽

Kohtaro Fujihashi ◽

Mitsuru Kubota ◽

...

Keyword(s):

Lymph Node ◽

B Cell ◽

Simian Immunodeficiency Virus ◽

Rhesus Macaques ◽

Cytokine Expression ◽

Cell Responses ◽

Th2 Cytokine ◽

Immunodeficiency Virus ◽

Virus Antigens ◽

Node Immunization

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B cell follicle sanctuary permits persistent productive simian immunodeficiency virus infection in elite controllers

Nature Medicine ◽

10.1038/nm.3781 ◽

2015 ◽

Vol 21 (2) ◽

pp. 132-139 ◽

Cited By ~ 305

Author(s):

Yoshinori Fukazawa ◽

Richard Lum ◽

Afam A Okoye ◽

Haesun Park ◽

Kenta Matsuda ◽

...

Keyword(s):

Virus Infection ◽

B Cell ◽

Simian Immunodeficiency Virus ◽

Simian Immunodeficiency Virus Infection ◽

Elite Controllers ◽

Immunodeficiency Virus ◽

Cell Follicle

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Induction of B Cell Hyperplasia in Simian Immunodeficiency Virus–Infected Rhesus Macaques with the Simian Homologue of Kaposi's Sarcoma–Associated Herpesvirus

Journal of Experimental Medicine ◽

10.1084/jem.190.6.827 ◽

1999 ◽

Vol 190 (6) ◽

pp. 827-840 ◽

Cited By ~ 96

Author(s):

Scott W. Wong ◽

Eric P. Bergquam ◽

Ryan M. Swanson ◽

Felix W. Lee ◽

Stanley M. Shiigi ◽

...

Keyword(s):

Antibody Response ◽

B Cell ◽

Simian Immunodeficiency Virus ◽

Kaposi's Sarcoma ◽

Rhesus Macaques ◽

Kaposi’S Sarcoma ◽

Lymphoid Tissues ◽

Immunodeficiency Virus ◽

Kaposi's Sarcoma Associated Herpesvirus ◽

Kaposi’S Sarcoma Associated Herpesvirus

A simian homologue of Kaposi's sarcoma–associated herpesvirus (KSHV), the eighth human herpesvirus (HHV8), was isolated from a simian immunodeficiency virus (SIV)-infected rhesus macaque (Macaca mulatta) that developed a multicentric lymphoproliferative disorder (LPD). This simian rhadinovirus is genetically similar to a recently described rhesus rhadinovirus (RRV) (Desrosiers, R.C., V.G. Sasseville, S.C. Czajak, X. Zhang, K.G. Mansfield, A. Kaur, R.P. Johnson, A.A. Lackner, and J.U. Jung. 1997. J. Virol. 71:9764–9769) and is designated RRV 17577. RRV 17577 was experimentally inoculated into rhesus macaques with and without SIVmac239 infection to determine if RRV played a role in development of the LPD observed in the index case. In contrast to control animals inoculated with SIVmac239 or RRV alone, two animals coinfected with SIVmac239 and RRV 17577 developed hyperplastic LPD resembling the multicentric plasma cell variant of Castleman's disease, characterized by persistent angiofollicular lymphadenopathy, hepatomegaly, splenomegaly, and hypergammaglobulinemia. Hypergammaglobulinemia was associated with severe immune-mediated hemolytic anemia in one RRV/SIV-infected macaque. Both RRV/SIV-infected macaques exhibited persistent RRV viremia with little or no RRV-specific antibody response. The macaques inoculated with RRV alone displayed transient viremia followed by a vigorous anti-RRV antibody response and lacked evidence of LPD in peripheral blood and lymph nodes. Infectious RRV and RRV DNA were present in hyperplastic lymphoid tissues of the RRV/SIV-infected macaques, suggesting that lymphoid hyperplasia is associated with the high levels of replication. Thus, experimental RRV 17577 infection of SIV-infected rhesus macaques induces some of the hyperplastic B cell LPDs manifested in AIDS patients coinfected with KSHV.

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Roles of Target Cells and Virus-Specific Cellular Immunity in Primary Simian Immunodeficiency Virus Infection

Journal of Virology ◽

10.1128/jvi.78.9.4866-4875.2004 ◽

2004 ◽

Vol 78 (9) ◽

pp. 4866-4875 ◽

Cited By ~ 42

Author(s):

Roland R. Regoes ◽

Rustom Antia ◽

David A. Garber ◽

Guido Silvestri ◽

Mark B. Feinberg ◽

...

Keyword(s):

Virus Infection ◽

Simian Immunodeficiency Virus ◽

Cellular Immunity ◽

Target Cell ◽

Rhesus Macaques ◽

Target Cells ◽

Ongoing Debate ◽

Data Set ◽

Infection Period ◽

Immunodeficiency Virus

ABSTRACT There is an ongoing debate on whether acute human immunodeficiency virus infection is controlled by target cell limitation or by virus-specific cellular immunity. To resolve this question, we developed a novel mathematical modeling scheme which allows us to incorporate measurements of virus load, target cells, and virus-specific immunity and applied it to a comprehensive data set generated in an experiment involving rhesus macaques infected with simian immunodeficiency virus. Half of the macaques studied were treated during the primary infection period with reagents which block T-cell costimulation and as a result displayed severely impaired virus-specific immune responses. Our results show that early viral replication in normal infection is controlled to a large extent by virus-specific CD8+ T cells and not by target cell limitation.

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