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Role of human T-lymphotropic virus type 1 p30(II) and surface envelope as determinants of in vivo pathogenesis

Silverman, Lee
http://rave.ohiolink.edu/etdc/view?acc_num=osu1108502317

Abstract Details

2005, Doctor of Philosophy, Ohio State University, Veterinary Biosciences.
Human T-cell leukemia virus type 1 (HTVL-1) is the first identified human retrovirus. In addition to gag, pol, and env genes, HTLV-1 contains four open reading frames (ORF) within its pX region. ORF II encodes p30II and p13II. Herein, we determine the in vivo significance of p30II by inoculating rabbits with cell lines expressing either a wild-type clone of HTLV-1 (ACH.1) or a p30II mutant clone (ACH.30.1). Compared to ACH.1 rabbits, ACH.30.1 rabbits had lower antibody titers, a smaller percentage of seropositive animals, a smaller percentage of animals with provirus in peripheral blood mononuclear cells (PBMC), and lower proviral loads. Sequencing revealed that provirus in ACH.30.1 provirus positive rabbits had reverted to wild-type sequence. We conclude that there is strong selective pressure for expression of p30II in vivo. We next sought to determine if p30II modulates cellular apoptosis. A greater percentage of ACH.30.1 cells were induced into apoptosis compared to ACH.1 cells following treatment with camptothecin (specific for S-phase of cell cycle). There was no difference in apoptosis induction between ACH.30.1 and ACH.1 cells following treatment with etoposide (intrinsic pathway) or TRAIL (extrinsic pathway). p30II did not modulate susceptibility to apoptosis when expressed in 293T cells or in Jurkat T cells. Expression of p30II in Jurkat T cells reduced cell proliferation by delaying onset of division. Although p30II does not modulate susceptibility to apoptosis, it does reduce cell proliferation. HTLV-1 Env Ser75Ile, Asn95Asp, and Asn195Asp mutants are able to immortalize lymphocytes in vitro. Herein, we examine the effects of these mutations in rabbits via inoculations with ACH.75, ACH.95, ACH.195, and ACH.1 cell lines. All mutations were maintained in vivo. ACH.75 and ACH.95 rabbits had decreased antibody responses to Gag and Env. One ACH.195 rabbit had an antibody response to HTLV-1 proteins and HTLV-2 Env. Another ACH.195 rabbit had provirus in PBMC but no serologic response. ACH.195 rabbits had a diminished antibody response to Env surface (SU) protein. PBMC proviral loads did not correlate with antibody response to SU. These mutations in HTLV-1 Env SU alter proviral loads and antibody responses against Env but do not prevent virus replication in vivo.
Michael Lairmore (Advisor)
216 p.
Biology, Molecular
HTLV-1; Retrovirus; p30(II); Envelope; Rabbit model

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Citations

  • Silverman, L. (2005). Role of human T-lymphotropic virus type 1 p30(II) and surface envelope as determinants of in vivo pathogenesis [Doctoral dissertation, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1108502317

    APA Style (7th edition)

  • Silverman, Lee. Role of human T-lymphotropic virus type 1 p30(II) and surface envelope as determinants of in vivo pathogenesis. 2005. Ohio State University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1108502317.

    MLA Style (8th edition)

  • Silverman, Lee. "Role of human T-lymphotropic virus type 1 p30(II) and surface envelope as determinants of in vivo pathogenesis." Doctoral dissertation, Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc_num=osu1108502317

    Chicago Manual of Style (17th edition)

osu1108502317
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© 2005, all rights reserved.
This open access ETD is published by The Ohio State University and OhioLINK.