Genetic determinants of HIV-1 subtype C Nef-mediated SERINC3 down-regulation
Abstract Background Nef-mediated down-regulation of the host restriction factors SERINC3 and SERINC5 significantly enhances HIV-1 infectivity. Natural Nef polymorphisms that affect SERINC3 down-regulation are not as well-characterised as those that affect SERINC5 down-regulation, particularly in HIV...
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| Format: | Article |
| Language: | English |
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BMC
2025-04-01
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| Series: | Virology Journal |
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| Online Access: | https://doi.org/10.1186/s12985-025-02705-x |
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| author | Nikeisha Samlall Tarylee Reddy Nasreen Ismail Mark A. Brockman Zabrina L. Brumme Thumbi Ndung’u Jaclyn K. Mann |
| author_facet | Nikeisha Samlall Tarylee Reddy Nasreen Ismail Mark A. Brockman Zabrina L. Brumme Thumbi Ndung’u Jaclyn K. Mann |
| author_sort | Nikeisha Samlall |
| collection | DOAJ |
| description | Abstract Background Nef-mediated down-regulation of the host restriction factors SERINC3 and SERINC5 significantly enhances HIV-1 infectivity. Natural Nef polymorphisms that affect SERINC3 down-regulation are not as well-characterised as those that affect SERINC5 down-regulation, particularly in HIV-1 subtype C infection. We therefore aimed to identify genetic determinants of SERINC3 down-regulation by subtype C Nef. In addition, we investigated the role of SERINC3 down-regulation activity in disease progression and its contribution to overall Nef function, using Nef fitness model-derived E values as a proxy for overall Nef function in vivo. Methods SERINC3 down-regulation activity of 107 participant-derived Nef clones was measured using a flow cytometry-based assay in a T cell line. The relationship between SERINC3 down-regulation activity and viral load set point or rate of CD4 + T cell decline during untreated HIV infection was analysed by linear regression. Quantile regression was used to assess the contribution of SERINC3 down-regulation activity to overall Nef function. Individual Nef amino acids associated with a significantly altered SERINC3 down-regulation activity were identified using codon-by-codon Mann Whitney U tests. Results SERINC3 down-regulation activity was not a significant predictor of viral load set point nor rate of CD4 + T cell decline. SERINC3 down-regulation activity was a significant predictor of estimated Nef fitness (E values) in univariate analysis (p < 0.0001) and remained significant in multivariate analyses adjusting for other Nef functions that were measured for the same Nef clones (p < 0.02). A total of 30 amino acids were identified to be associated with differential Nef-mediated ability to down-regulate SERINC3 (p < 0.05 and q < 0.3), with 63% of these residues being in the N-terminal domain. Conclusion Although SERINC3 down-regulation did not associate significantly with markers of HIV disease progression, our results nevertheless suggest that SERINC3 down-regulation contributes significantly to overall Nef function and fitness. The identification of Nef amino acids associated with differential SERINC3 down-regulation ability may be useful for rational design of therapeutics and vaccines targeting the Nef region. |
| format | Article |
| id | doaj-art-d70fe6f8051e4351b0717a7904d5960d |
| institution | OA Journals |
| issn | 1743-422X |
| language | English |
| publishDate | 2025-04-01 |
| publisher | BMC |
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| series | Virology Journal |
| spelling | doaj-art-d70fe6f8051e4351b0717a7904d5960d2025-08-20T02:17:04ZengBMCVirology Journal1743-422X2025-04-0122111110.1186/s12985-025-02705-xGenetic determinants of HIV-1 subtype C Nef-mediated SERINC3 down-regulationNikeisha Samlall0Tarylee Reddy1Nasreen Ismail2Mark A. Brockman3Zabrina L. Brumme4Thumbi Ndung’u5Jaclyn K. Mann6HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of Kwazulu-NatalMedical Research Council, Biostatistics UnitHIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of Kwazulu-NatalFaculty of Health Sciences, Simon Fraser UniversityFaculty of Health Sciences, Simon Fraser UniversityHIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of Kwazulu-NatalHIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of Kwazulu-NatalAbstract Background Nef-mediated down-regulation of the host restriction factors SERINC3 and SERINC5 significantly enhances HIV-1 infectivity. Natural Nef polymorphisms that affect SERINC3 down-regulation are not as well-characterised as those that affect SERINC5 down-regulation, particularly in HIV-1 subtype C infection. We therefore aimed to identify genetic determinants of SERINC3 down-regulation by subtype C Nef. In addition, we investigated the role of SERINC3 down-regulation activity in disease progression and its contribution to overall Nef function, using Nef fitness model-derived E values as a proxy for overall Nef function in vivo. Methods SERINC3 down-regulation activity of 107 participant-derived Nef clones was measured using a flow cytometry-based assay in a T cell line. The relationship between SERINC3 down-regulation activity and viral load set point or rate of CD4 + T cell decline during untreated HIV infection was analysed by linear regression. Quantile regression was used to assess the contribution of SERINC3 down-regulation activity to overall Nef function. Individual Nef amino acids associated with a significantly altered SERINC3 down-regulation activity were identified using codon-by-codon Mann Whitney U tests. Results SERINC3 down-regulation activity was not a significant predictor of viral load set point nor rate of CD4 + T cell decline. SERINC3 down-regulation activity was a significant predictor of estimated Nef fitness (E values) in univariate analysis (p < 0.0001) and remained significant in multivariate analyses adjusting for other Nef functions that were measured for the same Nef clones (p < 0.02). A total of 30 amino acids were identified to be associated with differential Nef-mediated ability to down-regulate SERINC3 (p < 0.05 and q < 0.3), with 63% of these residues being in the N-terminal domain. Conclusion Although SERINC3 down-regulation did not associate significantly with markers of HIV disease progression, our results nevertheless suggest that SERINC3 down-regulation contributes significantly to overall Nef function and fitness. The identification of Nef amino acids associated with differential SERINC3 down-regulation ability may be useful for rational design of therapeutics and vaccines targeting the Nef region.https://doi.org/10.1186/s12985-025-02705-xHIV-1NefHIV-1 subtype CSERINC3 down-regulationSERINC5 down-regulation |
| spellingShingle | Nikeisha Samlall Tarylee Reddy Nasreen Ismail Mark A. Brockman Zabrina L. Brumme Thumbi Ndung’u Jaclyn K. Mann Genetic determinants of HIV-1 subtype C Nef-mediated SERINC3 down-regulation Virology Journal HIV-1 Nef HIV-1 subtype C SERINC3 down-regulation SERINC5 down-regulation |
| title | Genetic determinants of HIV-1 subtype C Nef-mediated SERINC3 down-regulation |
| title_full | Genetic determinants of HIV-1 subtype C Nef-mediated SERINC3 down-regulation |
| title_fullStr | Genetic determinants of HIV-1 subtype C Nef-mediated SERINC3 down-regulation |
| title_full_unstemmed | Genetic determinants of HIV-1 subtype C Nef-mediated SERINC3 down-regulation |
| title_short | Genetic determinants of HIV-1 subtype C Nef-mediated SERINC3 down-regulation |
| title_sort | genetic determinants of hiv 1 subtype c nef mediated serinc3 down regulation |
| topic | HIV-1 Nef HIV-1 subtype C SERINC3 down-regulation SERINC5 down-regulation |
| url | https://doi.org/10.1186/s12985-025-02705-x |
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