Generation and properties of a human immunodeficiency virus type 1 isolate resistant to the small molecule CCR5 inhibitor, SCH-417690 (SCH-D)
| Autor: | Tom Morgan, Carolina Herrera, Enid Rivera-Troche, Andre J. Marozsan, Bahige M. Baroudy, Shawn E. Kuhmann, John P. Moore, Serena Xu, Julie M. Strizki |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
CD4-Positive T-Lymphocytes
viruses Mutant Gene Expression HIV Envelope Protein gp120 medicine.disease_cause Virus Replication Piperazines Escape mutants SCH-D CCR5 inhibitors Peptide sequence Chemokine CCL5 0303 health sciences Mutation biology Antibodies Monoclonal 3. Good health Phenotype CCR5 Receptor Antagonists Antibody Receptors CCR5 Anti-HIV Agents Molecular Sequence Data CCR5 receptor antagonist In Vitro Techniques Genes env Cell Line 03 medical and health sciences Viral entry Virology Drug Resistance Viral medicine Humans Amino Acid Sequence Gene Alleles 030304 developmental biology Base Sequence 030306 microbiology Gene Products env Peptide Fragments Pyrimidines Cell culture Drug resistance DNA Viral biology.protein HIV-1 CCR5 |
| Zdroj: | Virology. 338(1) |
| ISSN: | 0042-6822 |
| Popis: | We describe the generation of two genetically related human immunodeficiency virus type 1 (HIV-1) isolates highly (>20,000-fold) resistant to the small molecule CCR5 inhibitor, SCH-417690 (formerly SCH-D). Both viruses were cross-resistant to other small molecules targeting entry via CCR5, but they were inhibited by some MAbs against the same coreceptor on primary CD4+ T-cells. The resistant isolates remained sensitive to inhibitors of other stages of virus entry, and to replication inhibitors acting post-entry. Neither escape mutant could replicate detectably in peripheral blood mononuclear cells (PBMC) from two donors homozygous for the CCR5-Δ32 allele and both were insensitive to the CXCR4-specific inhibitor, AMD3100. Hence, the SCH-D escape mutants retained the R5 phenotype. One of the resistant isolates was, however, capable of replication in U87.CD4.CXCR4 cells and, after expansion in those cells, was sensitive to AMD3100 in primary CD4+ T-cells. Hence, some X4 variants may be present in this escape mutant swarm. A notable observation was that the SCH-D escape mutants were also cross-resistant to PSC-RANTES and AOP-RANTES, chemokine derivatives that are reported to down-regulate cell surface CCR5 almost completely. However, the extent to which CCR5 is down-regulated was dependent upon the detection MAb. Hence, the escape mutants may be using a CCR5 configuration that is only detected by some anti-CCR5 MAbs. Finally, two SCH-D-resistant clonal viruses revealed no amino acid changes in the gp120 V3 region relative to the parental viruses, in marked contrast to clones resistant to the AD101 small molecule CCR5 inhibitor that possess 4 such sequence changes. Several sequence changes elsewhere in gp120 (V2, C3 and V4) were present in the SCH-D-resistant clones. Their influence on the resistant phenotype remains to be determined. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Full Text from ScienceDirect