Determining the Resistance Profile of Conocurvone, an Early-Stage Inhibitor of HIV-1 Replication
| dc.contributor.author | Kearney, Mary | |
| dc.contributor.department | Hood College Biology | |
| dc.contributor.program | Biomedical and Environmental Science | |
| dc.date.accessioned | 2024-01-11T19:54:12Z | |
| dc.date.available | 2024-01-11T19:54:12Z | |
| dc.date.issued | 2001-03 | |
| dc.description.abstract | A unique inhibitor of HIV-1, conocurvone, was isolated from extracts of the Australian shrub Conospermum incurvum. This compound, a trimeric napthoquinone, is a potent inhibitor of HIV-1-induced cell killing (EC50 < 20uM) that is relatively strain specific (HIV-1 RF > HIV-1 NL4-3 >>> HIV-1 111B). In vitro mechanism of action studies revealed that conocurvone may possess dual inhibitory activity against both HIV-1 integrase and HIV cell-mediated fusion. To determine whether either of these mechanisms is a biologically relevant viral target for conocurvone, a drug-resistant HIV-1 RF virus was generated by passaging under drug selection in H9 cells. This virus, denoted cono-R, was used as a template to identify conocurvone resistance-engendering mutations and to determine the mechanism of action of conocurvone. Genotypic analysis of this cono-R virus revealed four amino acid changes in gp120, four in gp41, and none in integrase, suggesting that conocurvone targets the HIV-1 envelope protein. One of the gp41 mutations introduces a premature stop codon at position W766 and, as a result, truncated more than 100 amino acids from the cytoplasmic tail of the HIV envelope protein, similar to some CD4-independent viruses. Interestingly, when an analogous proviral clone (HIV-1pNL4-3 W766*) was constructed, the resultant virus was replication-defective yet able to fully induce syncitia formation in CEM-SS cells. Three of the cono-R gp120 mutations, V64A, G145E, and N315K conferred conocurvone-resistance to NL4- 3 when introduced into the pNL4-3 provirus. The G145E and N315K mutations are located within the V1/V2 and the V3 loop respectively. These variable loops have been implicated in determining viral coreceptor usage. These resistance selection data indicate that conocurvone targets gp120 of HIV-1 and inhibits HIV fusion in T cells. This study suggests that HIV-1 may escape the activity of fusion inhibitors by introducing specific mutations that alter envelope conformation and receptor usage. | |
| dc.format.extent | 112 pages | |
| dc.genre | Thesis | |
| dc.identifier.uri | http://hdl.handle.net/11603/31266 | |
| dc.language.iso | en_US | |
| dc.title | Determining the Resistance Profile of Conocurvone, an Early-Stage Inhibitor of HIV-1 Replication | |
| dc.type | Text |