Mechanisms of Immunoglobulin Somatic Hypermutation During Retroviral Infection

Released on by Sean Taylor Jones
preview-18

  • Mechanisms of Immunoglobulin Somatic Hypermutation During Retroviral Infection Book Detail

  • Author : Sean Taylor Jones
  • Release Date : 2019
  • Publisher :
  • Genre :
  • Pages : 146
  • ISBN 13 :
  • File Size : 62,62 MB
DOWNLOAD BOOK

Mechanisms of Immunoglobulin Somatic Hypermutation During Retroviral Infection by Sean Taylor Jones PDF Summary

Book Description: A potential HIV-1 vaccine should stimulate a broadly neutralizing antibody (bNAb) response, which overcomes HIV-1 mutational escape to typical NAb responses that develop by covering a wide variety of HIV-1 strains. bNAbs have been shown to both be highly mutated as well as contain essential mutations in framework regions (FWRs) of the immunoglobulin (Ig) variable domain. The typical mutator of Ig genes, AID, preferentially targets WRCY hotspot motifs, which are enriched in Complementary Determining Regions (CDRs) of Ig genes but underrepresented in FWRs. An evolutionarily related group of deoxycytidine deaminases, the human APOBEC3s (hA3s), however, preferentially mutate in the AID YC coldspot context, which is enriched in FWRs in both human and mouse Ig genes. The hA3s are interferon stimulated genes that have been widely studied for their restriction of retroviruses and have been implicated in several cancer types, demonstrating their ability to mutate genomic DNA. Notably, mouse Apobec3 (mA3) was shown to mutate virus-reactive antibodies in the context of retroviral infection. This dissertation aims to explore mechanisms of somatic hypermutation (SHM) during retroviral infection. In the first part, I utilized a transgenic human APOBEC3 (hA3-Tg) mouse model to study the role of the hA3s in Ig SHM. hA3s were both functional and expressed in B cells of hA3-Tg mice and negatively impacted the neutralizing antibody (NAb) response against Friend retrovirus (FV) while not interfering with IgG binding titers. Virus-reactive hybridomas as well as bulk bone marrow Ig sequences were obtained to show that the hA3+ transgenic mice (hA3-Tg) are generating higher mutation rates, especially in FWRs relative to their mA3-KO controls. Interestingly, the AID-hotspot RC motif mutation rates were significantly increased in both data sets, but not the hA3-hotspot YC motif mutation rates. In a pilot experiment, mutation rates following FV infection were explored in AID-deficient versions of the hA3-Tg mice. There was again a significant increase in hA3-Tg mouse mutation rates even in the absence of AID. The second part of this dissertation aims to tie these findings back into humans by determining if hA3 expression levels associate with SHM during HIV-1 infection. The gut during HIV-1 infection is an interesting location to explore potential effects on SHM from the hA3s, as there is rapid CD4+ T cell depletion. As AID activity is generally driven by T cell help, this may provide a good context to study alternatives to AID-driven SHM, especially the interferon inducible hA3s. Colon pinch biopsies from a clinical cohort of chronically HIV-1 infected, untreated patients and age- and sex-matched controls were analyzed using RNAseq and Illumina NGS methods to analyze alterations in hA3 levels, V-gene usage as well as mutation rates of Ig genes in these patients. In these colon pinch biopsies, expression of human APOBEC3C, DE, F, and G were significantly increased during infection. There was, however, a significant decrease in overall SHM rates in the HIV-1 infected group that was consistent across CDR and FWR as well as RC and YC hotspot motifs. Notably, I found no evidence of hA3 expression levels correlating with mutation rates. Interestingly, alterations in the Ig repertoire did correlate with alterations in the microbiome and there was a significant decrease in highly mutated IgA sequences consistent with a shift towards T-independent IgA responses. Overall, this dissertation demonstrates an increase in SHM driven by the human APOBEC3s, especially in FWRs, which is evident even in the absence of AID. This may prove to be a useful pathway to investigate for generating abnormal mutations, such as FWR mutations, in the context of a viral infection or type 1 interferon response. This pattern was not evident in chronic HIV-1 infection in the gut, which experience impaired T cell help; there was, however, evidence of alterations in the gut IgA response that correlated with dysbiosis. These alterations could help explore basic questions about interactions between IgA and the gut microbiome and provide potential targets to help ameliorate the pathogenesis in the gut that helps to drive disease progression in HIV-1 infection. By better understanding mechanisms driving somatic hypermutation during retroviral infection, potential new pathways may provide a new approach at stimulating otherwise unlikely responses such as HIV-1 broadly neutralizing antibodies.

Disclaimer: www.yourbookbest.com does not own Mechanisms of Immunoglobulin Somatic Hypermutation During Retroviral Infection books pdf, neither created or scanned. We just provide the link that is already available on the internet, public domain and in Google Drive. If any way it violates the law or has any issues, then kindly mail us via contact us page to request the removal of the link.

Molecular Biology of B Cells

Molecular Biology of B Cells

File Size : 78,78 MB
Total View : 9278 Views
DOWNLOAD

Molecular Biology of B Cells, Second Edition is a comprehensive reference to how B cells are generated, selected, activated and engaged in antibody production.

Janeway's Immunobiology

Janeway's Immunobiology

File Size : 15,15 MB
Total View : 9883 Views
DOWNLOAD

The Janeway's Immunobiology CD-ROM, Immunobiology Interactive, is included with each book, and can be purchased separately. It contains animations and videos wi

Lymphocyte Updates

Lymphocyte Updates

File Size : 86,86 MB
Total View : 9590 Views
DOWNLOAD

This book represents a synergic effort of an international team of specialists in immunology to expand the scientific achievements in the field of lymphocytes.

Somatic Genome Variation

Somatic Genome Variation

File Size : 50,50 MB
Total View : 8502 Views
DOWNLOAD

Written by an international team of experts, Somatic Genome Variation presents a timely summary of the latest understanding of somatic genome development and va