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VARIATIONS IN THE V3 CROWN OF HIV-1 ENVELOPE IMPACT AFFINITY FOR CCR5 AND AFFECT ENTRY AND REPLICATIVE FITNESS

Lobritz, Michael Andrew
http://rave.ohiolink.edu/etdc/view?acc_num=case1180728110

Abstract Details

2007, Doctor of Philosophy, Case Western Reserve University, Molecular Biology and Microbiology.
Entry inhibitors represent a new class of antiretroviral agents for the treatment of infection with HIV-1. The viral envelope glycoprotein, which mediates interaction with host cell receptors and membrane fusion, is an extremely heterogeneous protein. Consequently, diverse HIV-1 isolates exhibit a broad range of susceptibility to inhibition by agents that target envelope glycoprotein function. The V3 loop is an important functional domain of the envelope glycoprotein which mediates interaction with the HIV-1 coreceptor, either CCR5 or CXCR4. Amino acid variation within this region has important consequences for the efficiency of the host cell entry process. Polymorphisms at two positions in the V3 crown which negatively impact viral entry efficiency and replication capacity also result in increased susceptibility to entry inhibitors. Conversely, polymorphisms that decrease susceptibility to drugs also confer higher overall replicative fitness. A major mechanism involved in sensitivity to one coreceptor inhibitor, PSC-RANTES, is competitive binding between the drug and the HIV-1 envelope glycoprotein for CCR5. Correlation between entry inhibitor sensitivity and replicative fitness was most consistent for competitive inhibitors of coreceptor usage. Polymorphisms in the V3 crown appear to alter both entry inhibitor sensitivity and entry efficiency by modulating the affinity relationship between the viral envelope glycoprotein and the host cell coreceptor, specifically affecting the interaction between the V3 crown and the second extracellular loop of CCR5. Higher affinity for coreceptor resulted in faster fusion kinetics and decreased entry inhibitor sensitivity. Increases in coreceptor affinity may be a general adaptive mechanism for all viruses in response to entry inhibitor therapy.
Eric Arts (Advisor)
257 p.
HIV-1; Entry; Replicative Fitness; Entry Inhibitors

Recommended Citations

Citations

  • Lobritz, M. A. (2007). VARIATIONS IN THE V3 CROWN OF HIV-1 ENVELOPE IMPACT AFFINITY FOR CCR5 AND AFFECT ENTRY AND REPLICATIVE FITNESS [Doctoral dissertation, Case Western Reserve University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=case1180728110

    APA Style (7th edition)

  • Lobritz, Michael. VARIATIONS IN THE V3 CROWN OF HIV-1 ENVELOPE IMPACT AFFINITY FOR CCR5 AND AFFECT ENTRY AND REPLICATIVE FITNESS. 2007. Case Western Reserve University, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=case1180728110.

    MLA Style (8th edition)

  • Lobritz, Michael. "VARIATIONS IN THE V3 CROWN OF HIV-1 ENVELOPE IMPACT AFFINITY FOR CCR5 AND AFFECT ENTRY AND REPLICATIVE FITNESS." Doctoral dissertation, Case Western Reserve University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=case1180728110

    Chicago Manual of Style (17th edition)

case1180728110
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© 2007, all rights reserved.
This open access ETD is published by Case Western Reserve University School of Graduate Studies and OhioLINK.