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恒河猴感染猴免疫缺陷病毒期间免疫球蛋白VH基因多样性和体细胞超突变

Immunoglobulin VH gene diversity and somatic hypermutation during SIV infection of rhesus macaques.

作者信息

Guo Kejun, Halemano Kalani, Schmitt Kimberly, Katuwal Miki, Wang Yaqiong, Harper Michael S, Heilman Karl J, Kuwata Takeo, Stephens Edward B, Santiago Mario L

机构信息

Departments of Medicine, Immunology and Microbiology, University of Colorado Denver, Aurora, CO, 80045, USA.

出版信息

Immunogenetics. 2015 Jul;67(7):355-70. doi: 10.1007/s00251-015-0844-3. Epub 2015 May 21.

DOI:10.1007/s00251-015-0844-3
PMID:25994147
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5439441/
Abstract

B cell functional defects are associated with delayed neutralizing antibody development in pathogenic lentivirus infections. However, the timeframe for alterations in the antibody repertoire and somatic hypermutation (SHM) remains unclear. Here, we utilized the SIV/rhesus macaque (RM) model to investigate the dynamics of immunoglobulin V(H) gene diversity and SHM following infection. Three RMs were infected with SIVmac239, and V(H)1, V(H)3, and V(H)4 genes were amplified from peripheral blood at 0, 2, 6, 24, and 36 weeks postinfection for next-generation sequencing. Analysis of over 3.8 million sequences against currently available RM germline V(H) genes revealed a highly biased V(H) gene repertoire in outbred RMs. SIV infection did not significantly perturb the predominant IgG1 response, but overall immunoglobulin SHM declined during the course of SIV infection. Moreover, SHM at the AID deamination hotspot, WRC, rapidly decreased and was suppressed throughout SIV infection. In contrast, a transient increase in mutations at the APOBEC3G deamination hotspot, CCC, coincided with a spike in APOBEC3G expression during acute SIV infection. The results outline a timetable for altered V(H) gene repertoire and IgG SHM in the SIV/RM model and suggest a burst of APOBEC3G-mediated antibody SHM during acute SIV infection.

摘要

B细胞功能缺陷与致病性慢病毒感染中中和抗体产生延迟有关。然而，抗体库和体细胞高频突变（SHM）发生改变的时间框架仍不清楚。在此，我们利用SIV/恒河猴（RM）模型来研究感染后免疫球蛋白V(H)基因多样性和SHM的动态变化。三只恒河猴感染了SIVmac239，并在感染后0、2、6、24和36周从外周血中扩增V(H)1、V(H)3和V(H)4基因用于下一代测序。针对目前可用的恒河猴种系V(H)基因对超过380万个序列进行分析，结果显示远交恒河猴的V(H)基因库存在高度偏差。SIV感染并未显著扰乱主要的IgG1反应，但在SIV感染过程中，总体免疫球蛋白SHM下降。此外，在AID脱氨基热点WRC处的SHM迅速下降，并在整个SIV感染过程中受到抑制。相比之下，在APOBEC3G脱氨基热点CCC处的突变短暂增加，这与急性SIV感染期间APOBEC3G表达的峰值一致。这些结果勾勒出了SIV/RM模型中V(H)基因库和IgG SHM改变的时间表，并表明在急性SIV感染期间存在APOBEC3G介导的抗体SHM爆发。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/3bb2/5439441/20fc98e4bd1d/nihms693205f8.jpg
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