The apparent interferon resistance of transmitted HIV-1 is possibly a consequence of enhanced replicative fitness.
HIV-1 transmission via sexual exposure is an inefficient process. When transmission does occur, newly infected individuals are colonized by the descendants of either a single virion or a very small number of establishing virions. These transmitted founder (TF) viruses are more interferon (IFN)-resis...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2022-11-01
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| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1010973&type=printable |
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| author | Elena Sugrue Arthur Wickenhagen Nardus Mollentze Muhamad Afiq Aziz Vattipally B Sreenu Sven Truxa Lily Tong Ana da Silva Filipe David L Robertson Joseph Hughes Suzannah J Rihn Sam J Wilson |
| author_facet | Elena Sugrue Arthur Wickenhagen Nardus Mollentze Muhamad Afiq Aziz Vattipally B Sreenu Sven Truxa Lily Tong Ana da Silva Filipe David L Robertson Joseph Hughes Suzannah J Rihn Sam J Wilson |
| author_sort | Elena Sugrue |
| collection | DOAJ |
| description | HIV-1 transmission via sexual exposure is an inefficient process. When transmission does occur, newly infected individuals are colonized by the descendants of either a single virion or a very small number of establishing virions. These transmitted founder (TF) viruses are more interferon (IFN)-resistant than chronic control (CC) viruses present 6 months after transmission. To identify the specific molecular defences that make CC viruses more susceptible to the IFN-induced 'antiviral state', we established a single pair of fluorescent TF and CC viruses and used arrayed interferon-stimulated gene (ISG) expression screening to identify candidate antiviral effectors. However, we observed a relatively uniform ISG resistance of transmitted HIV-1, and this directed us to investigate possible underlying mechanisms. Simple simulations, where we varied a single parameter, illustrated that reduced growth rate could possibly underly apparent interferon sensitivity. To examine this possibility, we closely monitored in vitro propagation of a model TF/CC pair (closely matched in replicative fitness) over a targeted range of IFN concentrations. Fitting standard four-parameter logistic growth models, in which experimental variables were regressed against growth rate and carrying capacity, to our in vitro growth curves, further highlighted that small differences in replicative growth rates could recapitulate our in vitro observations. We reasoned that if growth rate underlies apparent interferon resistance, transmitted HIV-1 would be similarly resistant to any growth rate inhibitor. Accordingly, we show that two transmitted founder HIV-1 viruses are relatively resistant to antiretroviral drugs, while their matched chronic control viruses were more sensitive. We propose that, when present, the apparent IFN resistance of transmitted HIV-1 could possibly be explained by enhanced replicative fitness, as opposed to specific resistance to individual IFN-induced defences. However, further work is required to establish how generalisable this mechanism of relative IFN resistance might be. |
| format | Article |
| id | doaj-art-312eb46f19e0404c960c54ff41b6efb3 |
| institution | OA Journals |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2022-11-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-312eb46f19e0404c960c54ff41b6efb32025-08-20T02:22:26ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742022-11-011811e101097310.1371/journal.ppat.1010973The apparent interferon resistance of transmitted HIV-1 is possibly a consequence of enhanced replicative fitness.Elena SugrueArthur WickenhagenNardus MollentzeMuhamad Afiq AzizVattipally B SreenuSven TruxaLily TongAna da Silva FilipeDavid L RobertsonJoseph HughesSuzannah J RihnSam J WilsonHIV-1 transmission via sexual exposure is an inefficient process. When transmission does occur, newly infected individuals are colonized by the descendants of either a single virion or a very small number of establishing virions. These transmitted founder (TF) viruses are more interferon (IFN)-resistant than chronic control (CC) viruses present 6 months after transmission. To identify the specific molecular defences that make CC viruses more susceptible to the IFN-induced 'antiviral state', we established a single pair of fluorescent TF and CC viruses and used arrayed interferon-stimulated gene (ISG) expression screening to identify candidate antiviral effectors. However, we observed a relatively uniform ISG resistance of transmitted HIV-1, and this directed us to investigate possible underlying mechanisms. Simple simulations, where we varied a single parameter, illustrated that reduced growth rate could possibly underly apparent interferon sensitivity. To examine this possibility, we closely monitored in vitro propagation of a model TF/CC pair (closely matched in replicative fitness) over a targeted range of IFN concentrations. Fitting standard four-parameter logistic growth models, in which experimental variables were regressed against growth rate and carrying capacity, to our in vitro growth curves, further highlighted that small differences in replicative growth rates could recapitulate our in vitro observations. We reasoned that if growth rate underlies apparent interferon resistance, transmitted HIV-1 would be similarly resistant to any growth rate inhibitor. Accordingly, we show that two transmitted founder HIV-1 viruses are relatively resistant to antiretroviral drugs, while their matched chronic control viruses were more sensitive. We propose that, when present, the apparent IFN resistance of transmitted HIV-1 could possibly be explained by enhanced replicative fitness, as opposed to specific resistance to individual IFN-induced defences. However, further work is required to establish how generalisable this mechanism of relative IFN resistance might be.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1010973&type=printable |
| spellingShingle | Elena Sugrue Arthur Wickenhagen Nardus Mollentze Muhamad Afiq Aziz Vattipally B Sreenu Sven Truxa Lily Tong Ana da Silva Filipe David L Robertson Joseph Hughes Suzannah J Rihn Sam J Wilson The apparent interferon resistance of transmitted HIV-1 is possibly a consequence of enhanced replicative fitness. PLoS Pathogens |
| title | The apparent interferon resistance of transmitted HIV-1 is possibly a consequence of enhanced replicative fitness. |
| title_full | The apparent interferon resistance of transmitted HIV-1 is possibly a consequence of enhanced replicative fitness. |
| title_fullStr | The apparent interferon resistance of transmitted HIV-1 is possibly a consequence of enhanced replicative fitness. |
| title_full_unstemmed | The apparent interferon resistance of transmitted HIV-1 is possibly a consequence of enhanced replicative fitness. |
| title_short | The apparent interferon resistance of transmitted HIV-1 is possibly a consequence of enhanced replicative fitness. |
| title_sort | apparent interferon resistance of transmitted hiv 1 is possibly a consequence of enhanced replicative fitness |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1010973&type=printable |
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