VARIATIONS IN THE V3 CROWN OF HIV-1 ENVELOPE IMPACT AFFINITY FOR CCR5 AND AFFECT ENTRY AND REPLICATIVE FITNESS
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| Language: | English |
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Case Western Reserve University School of Graduate Studies / OhioLINK
2007
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| Online Access: | http://rave.ohiolink.edu/etdc/view?acc_num=case1180728110 |
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ndltd-OhioLink-oai-etd.ohiolink.edu-case11807281102021-08-03T05:32:18Z VARIATIONS IN THE V3 CROWN OF HIV-1 ENVELOPE IMPACT AFFINITY FOR CCR5 AND AFFECT ENTRY AND REPLICATIVE FITNESS Lobritz, Michael Andrew HIV-1 Entry Replicative Fitness Entry Inhibitors 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. 2007-06-08 English text Case Western Reserve University School of Graduate Studies / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=case1180728110 http://rave.ohiolink.edu/etdc/view?acc_num=case1180728110 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
HIV-1 Entry Replicative Fitness Entry Inhibitors |
| spellingShingle |
HIV-1 Entry Replicative Fitness Entry Inhibitors Lobritz, Michael Andrew VARIATIONS IN THE V3 CROWN OF HIV-1 ENVELOPE IMPACT AFFINITY FOR CCR5 AND AFFECT ENTRY AND REPLICATIVE FITNESS |
| author |
Lobritz, Michael Andrew |
| author_facet |
Lobritz, Michael Andrew |
| author_sort |
Lobritz, Michael Andrew |
| title |
VARIATIONS IN THE V3 CROWN OF HIV-1 ENVELOPE IMPACT AFFINITY FOR CCR5 AND AFFECT ENTRY AND REPLICATIVE FITNESS |
| title_short |
VARIATIONS IN THE V3 CROWN OF HIV-1 ENVELOPE IMPACT AFFINITY FOR CCR5 AND AFFECT ENTRY AND REPLICATIVE FITNESS |
| title_full |
VARIATIONS IN THE V3 CROWN OF HIV-1 ENVELOPE IMPACT AFFINITY FOR CCR5 AND AFFECT ENTRY AND REPLICATIVE FITNESS |
| title_fullStr |
VARIATIONS IN THE V3 CROWN OF HIV-1 ENVELOPE IMPACT AFFINITY FOR CCR5 AND AFFECT ENTRY AND REPLICATIVE FITNESS |
| title_full_unstemmed |
VARIATIONS IN THE V3 CROWN OF HIV-1 ENVELOPE IMPACT AFFINITY FOR CCR5 AND AFFECT ENTRY AND REPLICATIVE FITNESS |
| title_sort |
variations in the v3 crown of hiv-1 envelope impact affinity for ccr5 and affect entry and replicative fitness |
| publisher |
Case Western Reserve University School of Graduate Studies / OhioLINK |
| publishDate |
2007 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=case1180728110 |
| work_keys_str_mv |
AT lobritzmichaelandrew variationsinthev3crownofhiv1envelopeimpactaffinityforccr5andaffectentryandreplicativefitness |
| _version_ |
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