Escape of HIV-1 from a small molecule CCR5 inhibitor is not associated with a fitness loss.
Fitness is a parameter used to quantify how well an organism adapts to its environment; in the present study, fitness is a measure of how well strains of human immunodeficiency virus type 1 (HIV-1) replicate in tissue culture. When HIV-1 develops resistance in vitro or in vivo to antiretroviral drug...
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2007-06-01
|
| Series: | PLoS Pathogens |
| Online Access: | http://europepmc.org/articles/PMC1885273?pdf=render |
| _version_ | 1818110932059947008 |
|---|---|
| author | Cleo G Anastassopoulou Andre J Marozsan Alexandre Matet Amy D Snyder Eric J Arts Shawn E Kuhmann John P Moore |
| author_facet | Cleo G Anastassopoulou Andre J Marozsan Alexandre Matet Amy D Snyder Eric J Arts Shawn E Kuhmann John P Moore |
| author_sort | Cleo G Anastassopoulou |
| collection | DOAJ |
| description | Fitness is a parameter used to quantify how well an organism adapts to its environment; in the present study, fitness is a measure of how well strains of human immunodeficiency virus type 1 (HIV-1) replicate in tissue culture. When HIV-1 develops resistance in vitro or in vivo to antiretroviral drugs such as reverse transcriptase or protease inhibitors, its fitness is often impaired. Here, we have investigated whether the development of resistance in vitro to a small molecule CCR5 inhibitor, AD101, has an associated fitness cost. To do this, we developed a growth-competition assay involving dual infections with molecularly cloned viruses that are essentially isogenic outside the env genes under study. Real-time TaqMan quantitative PCR (QPCR) was used to quantify each competing virus individually via probes specific to different, phenotypically silent target sequences engineered within their vif genes. Head-to-head competition assays of env clones derived from the AD101 escape mutant isolate, the inhibitor-sensitive parental virus, and a passage control virus showed that AD101 resistance was not associated with a fitness loss. This observation is consistent with the retention of the resistant phenotype when the escape mutant was cultured for a total of 20 passages in the absence of the selecting compound. Amino acid substitutions in the V3 region of gp120 that confer complete AD101 resistance cause a fitness loss when introduced into an AD101-sensitive, parental clone; however, in the resistant isolate, changes elsewhere in env that occurred prior to the substitutions within V3 appear to compensate for the adverse effect of the V3 changes on replicative capacity. These in vitro studies may have implications for the development and management of resistance to other CCR5 inhibitors that are being evaluated clinically for the treatment of HIV-1 infection. |
| first_indexed | 2024-12-11T02:55:00Z |
| format | Article |
| id | doaj.art-96c2514afa774e0aac42b2f29bf3eb83 |
| institution | Directory Open Access Journal |
| issn | 1553-7366 1553-7374 |
| language | English |
| last_indexed | 2024-12-11T02:55:00Z |
| publishDate | 2007-06-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj.art-96c2514afa774e0aac42b2f29bf3eb832022-12-22T01:23:11ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742007-06-0136e7910.1371/journal.ppat.0030079Escape of HIV-1 from a small molecule CCR5 inhibitor is not associated with a fitness loss.Cleo G AnastassopoulouAndre J MarozsanAlexandre MatetAmy D SnyderEric J ArtsShawn E KuhmannJohn P MooreFitness is a parameter used to quantify how well an organism adapts to its environment; in the present study, fitness is a measure of how well strains of human immunodeficiency virus type 1 (HIV-1) replicate in tissue culture. When HIV-1 develops resistance in vitro or in vivo to antiretroviral drugs such as reverse transcriptase or protease inhibitors, its fitness is often impaired. Here, we have investigated whether the development of resistance in vitro to a small molecule CCR5 inhibitor, AD101, has an associated fitness cost. To do this, we developed a growth-competition assay involving dual infections with molecularly cloned viruses that are essentially isogenic outside the env genes under study. Real-time TaqMan quantitative PCR (QPCR) was used to quantify each competing virus individually via probes specific to different, phenotypically silent target sequences engineered within their vif genes. Head-to-head competition assays of env clones derived from the AD101 escape mutant isolate, the inhibitor-sensitive parental virus, and a passage control virus showed that AD101 resistance was not associated with a fitness loss. This observation is consistent with the retention of the resistant phenotype when the escape mutant was cultured for a total of 20 passages in the absence of the selecting compound. Amino acid substitutions in the V3 region of gp120 that confer complete AD101 resistance cause a fitness loss when introduced into an AD101-sensitive, parental clone; however, in the resistant isolate, changes elsewhere in env that occurred prior to the substitutions within V3 appear to compensate for the adverse effect of the V3 changes on replicative capacity. These in vitro studies may have implications for the development and management of resistance to other CCR5 inhibitors that are being evaluated clinically for the treatment of HIV-1 infection.http://europepmc.org/articles/PMC1885273?pdf=render |
| spellingShingle | Cleo G Anastassopoulou Andre J Marozsan Alexandre Matet Amy D Snyder Eric J Arts Shawn E Kuhmann John P Moore Escape of HIV-1 from a small molecule CCR5 inhibitor is not associated with a fitness loss. PLoS Pathogens |
| title | Escape of HIV-1 from a small molecule CCR5 inhibitor is not associated with a fitness loss. |
| title_full | Escape of HIV-1 from a small molecule CCR5 inhibitor is not associated with a fitness loss. |
| title_fullStr | Escape of HIV-1 from a small molecule CCR5 inhibitor is not associated with a fitness loss. |
| title_full_unstemmed | Escape of HIV-1 from a small molecule CCR5 inhibitor is not associated with a fitness loss. |
| title_short | Escape of HIV-1 from a small molecule CCR5 inhibitor is not associated with a fitness loss. |
| title_sort | escape of hiv 1 from a small molecule ccr5 inhibitor is not associated with a fitness loss |
| url | http://europepmc.org/articles/PMC1885273?pdf=render |
| work_keys_str_mv | AT cleoganastassopoulou escapeofhiv1fromasmallmoleculeccr5inhibitorisnotassociatedwithafitnessloss AT andrejmarozsan escapeofhiv1fromasmallmoleculeccr5inhibitorisnotassociatedwithafitnessloss AT alexandrematet escapeofhiv1fromasmallmoleculeccr5inhibitorisnotassociatedwithafitnessloss AT amydsnyder escapeofhiv1fromasmallmoleculeccr5inhibitorisnotassociatedwithafitnessloss AT ericjarts escapeofhiv1fromasmallmoleculeccr5inhibitorisnotassociatedwithafitnessloss AT shawnekuhmann escapeofhiv1fromasmallmoleculeccr5inhibitorisnotassociatedwithafitnessloss AT johnpmoore escapeofhiv1fromasmallmoleculeccr5inhibitorisnotassociatedwithafitnessloss |