Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection
<h4>Objective</h4> <p>Long-acting rilpivirine is a candidate for pre-exposure prophylaxis (PrEP) for prevention of HIV-1 infection. However, rilpivirine resistance mutations at reverse transcriptase codon 138 (RT-E138X) occur naturally in a minority of HIV-1-infected persons; in p...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
| Published: |
Lippincott, Williams & Wilkins
2017
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| _version_ | 1797083320988729344 |
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| author | Gatanaga, H Brumme, Z Adland, E Reyes-Terán, G Avila-Rios, S Mejía-Villatoro, C Hayashida, T Chikata, T Van Tran, G Van Nguyen, K Meza, R Palou, E Valenzuela-Ponce, H Pascale, J Porras-Cortés, G Manzanero, M Lee, G Martin, J Carrington, M John, M Mallal, S Poon, A Goulder, P Takiguchi, M Oka, S |
| author_facet | Gatanaga, H Brumme, Z Adland, E Reyes-Terán, G Avila-Rios, S Mejía-Villatoro, C Hayashida, T Chikata, T Van Tran, G Van Nguyen, K Meza, R Palou, E Valenzuela-Ponce, H Pascale, J Porras-Cortés, G Manzanero, M Lee, G Martin, J Carrington, M John, M Mallal, S Poon, A Goulder, P Takiguchi, M Oka, S |
| author_sort | Gatanaga, H |
| collection | OXFORD |
| description | <h4>Objective</h4> <p>Long-acting rilpivirine is a candidate for pre-exposure prophylaxis (PrEP) for prevention of HIV-1 infection. However, rilpivirine resistance mutations at reverse transcriptase codon 138 (RT-E138X) occur naturally in a minority of HIV-1-infected persons; in particular those expressing Human Leukocyte Antigen (HLA)-B*18 where RT-E138X arises as an immune escape mutation. We investigate the global prevalence, B*18-linkage and replicative cost of RT-E138X and its regional implications for rilpivirine PrEP.</p> <h4>Methods</h4> <p>We analysed linked RT-E138X/HLA data from 7772 patients from 16 cohorts spanning five continents and five HIV-1 subtypes, alongside unlinked global RT-E138X and HLA frequencies from public databases. E138X-containing HIV-1 variants were assessed for in vitro replication as a surrogate of mutation stability following transmission.</p> <h4>Results</h4> <p>RT-E138X variants, where the most common were rilpivirine resistance-associated mutations E138A/G/K, were significantly enriched in HLA-B*18-positive individuals globally (p=3.5x10-20) and in all HIV-1 subtypes except A. RT-E138X and B*18 frequencies correlated positively in 16 cohorts with linked HIV/HLA genotypes (Spearman’s R=0.75; p=7.6x10-4) and in unlinked HIV/HLA data from 43 countries (Spearman's R=0.34, p=0.02). Notably, RT-E138X frequencies approached (or exceeded) 10% in key epidemic regions (e.g. Sub-Saharan Africa, Southeastern Europe) where B*18 is more common. This, along with the observation that RT-E138X variants do not confer in vitro replicative costs, supports their persistence and ongoing accumulation in circulation over time.</p> <h4>Conclusions</h4> <p>Results illustrate the potential for a natural immune-driven HIV-1 polymorphism to compromise antiretroviral-based prevention, particularly in key epidemic regions. Regional RT-E138X surveillance should be undertaken before use of rilpivirine PrEP.</p> |
| first_indexed | 2024-03-07T01:40:05Z |
| format | Journal article |
| id | oxford-uuid:968e6b2a-b351-4981-adc4-b073e3bf22a1 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-07T01:40:05Z |
| publishDate | 2017 |
| publisher | Lippincott, Williams & Wilkins |
| record_format | dspace |
| spelling | oxford-uuid:968e6b2a-b351-4981-adc4-b073e3bf22a12022-03-26T23:53:51ZPotential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infectionJournal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:968e6b2a-b351-4981-adc4-b073e3bf22a1EnglishSymplectic Elements at OxfordLippincott, Williams & Wilkins2017Gatanaga, HBrumme, ZAdland, EReyes-Terán, GAvila-Rios, SMejía-Villatoro, CHayashida, TChikata, TVan Tran, GVan Nguyen, KMeza, RPalou, EValenzuela-Ponce, HPascale, JPorras-Cortés, GManzanero, MLee, GMartin, JCarrington, MJohn, MMallal, SPoon, AGoulder, PTakiguchi, MOka, S <h4>Objective</h4> <p>Long-acting rilpivirine is a candidate for pre-exposure prophylaxis (PrEP) for prevention of HIV-1 infection. However, rilpivirine resistance mutations at reverse transcriptase codon 138 (RT-E138X) occur naturally in a minority of HIV-1-infected persons; in particular those expressing Human Leukocyte Antigen (HLA)-B*18 where RT-E138X arises as an immune escape mutation. We investigate the global prevalence, B*18-linkage and replicative cost of RT-E138X and its regional implications for rilpivirine PrEP.</p> <h4>Methods</h4> <p>We analysed linked RT-E138X/HLA data from 7772 patients from 16 cohorts spanning five continents and five HIV-1 subtypes, alongside unlinked global RT-E138X and HLA frequencies from public databases. E138X-containing HIV-1 variants were assessed for in vitro replication as a surrogate of mutation stability following transmission.</p> <h4>Results</h4> <p>RT-E138X variants, where the most common were rilpivirine resistance-associated mutations E138A/G/K, were significantly enriched in HLA-B*18-positive individuals globally (p=3.5x10-20) and in all HIV-1 subtypes except A. RT-E138X and B*18 frequencies correlated positively in 16 cohorts with linked HIV/HLA genotypes (Spearman’s R=0.75; p=7.6x10-4) and in unlinked HIV/HLA data from 43 countries (Spearman's R=0.34, p=0.02). Notably, RT-E138X frequencies approached (or exceeded) 10% in key epidemic regions (e.g. Sub-Saharan Africa, Southeastern Europe) where B*18 is more common. This, along with the observation that RT-E138X variants do not confer in vitro replicative costs, supports their persistence and ongoing accumulation in circulation over time.</p> <h4>Conclusions</h4> <p>Results illustrate the potential for a natural immune-driven HIV-1 polymorphism to compromise antiretroviral-based prevention, particularly in key epidemic regions. Regional RT-E138X surveillance should be undertaken before use of rilpivirine PrEP.</p> |
| spellingShingle | Gatanaga, H Brumme, Z Adland, E Reyes-Terán, G Avila-Rios, S Mejía-Villatoro, C Hayashida, T Chikata, T Van Tran, G Van Nguyen, K Meza, R Palou, E Valenzuela-Ponce, H Pascale, J Porras-Cortés, G Manzanero, M Lee, G Martin, J Carrington, M John, M Mallal, S Poon, A Goulder, P Takiguchi, M Oka, S Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection |
| title | Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection |
| title_full | Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection |
| title_fullStr | Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection |
| title_full_unstemmed | Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection |
| title_short | Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection |
| title_sort | potential for immune driven viral polymorphisms to compromise antiretroviral based preexposure prophylaxis for prevention of hiv 1 infection |
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