Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection
| Autor: | Gustavo Reyes-Terán, Carlos Mejía-Villatoro, Simon Mallal, Zabrina L. Brumme, Philip J. R. Goulder, Guinevere Q. Lee, Guillermo Porras-Cortés, Santiago Ávila-Ríos, Masafumi Takiguchi, Hiroyuki Gatanaga, Emily Adland, Elsa Palou, Tsunefusa Hayashida, Art F. Y. Poon, Mary Carrington, Takayuki Chikata, Juan Miguel Pascale, Kinh Van Nguyen, Rita I Meza, Shinichi Oka, Jeffrey N. Martin, Marvin Manzanero, Giang Van Tran, Mina John, Humberto Valenzuela-Ponce |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
HLA-B18 Antigen Immunology Mutation Missense HIV Infections Human leukocyte antigen Drug resistance Biology Global Health Article 03 medical and health sciences chemistry.chemical_compound Pre-exposure prophylaxis 0302 clinical medicine Immune system Drug Resistance Viral Genotype Humans Immunology and Allergy Missense mutation 030212 general & internal medicine Immune Evasion Polymorphism Genetic Rilpivirine Virology HIV Reverse Transcriptase Reverse transcriptase 030104 developmental biology Infectious Diseases Anti-Retroviral Agents chemistry HIV-1 Pre-Exposure Prophylaxis |
| Zdroj: | AIDS |
| ISSN: | 0269-9370 |
| DOI: | 10.1097/qad.0000000000001575 |
| Popis: | Objective: Long-acting rilpivirine is a candidate for preexposure prophylaxis (PrEP) for prevention of HIV-1 infection. However, rilpivirine resistance mutations at reverse transcriptase codon 138 (E138X) occur naturally in a minority of HIV-1-infected persons; in particular those expressing human leukocyte antigen (HLA)-B*18 where reverse transcriptase-E138X arises as an immune escape mutation. We investigate the global prevalence, B*18-linkage and replicative cost of reverse transcriptase-E138X and its regional implications for rilpivirine PrEP. Methods: We analyzed linked reverse transcriptase-E138X/HLA data from 7772 antiretroviral-naive patients from 16 cohorts spanning five continents and five HIV-1 subtypes, alongside unlinked global reverse transcriptase-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. Results: Reverse transcriptase-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 = 3.5 × 10−20) and in all HIV-1 subtypes except A. Reverse transcriptase-E138X and B*18 frequencies correlated positively in 16 cohorts with linked HIV/HLA genotypes (Spearman's R = 0.75; P = 7.6 × 10−4) and in unlinked HIV/HLA data from 43 countries (Spearman's R = 0.34, P = 0.02). Notably, reverse transcriptase-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 reverse transcriptase-E138X variants do not confer in-vitro replicative costs, supports their persistence, and ongoing accumulation in circulation over time. Conclusions: Results illustrate the potential for a natural immune-driven HIV-1 polymorphism to compromise antiretroviral-based prevention, particularly in key epidemic regions. Regional reverse transcriptase-E138X surveillance should be undertaken before use of rilpivirine PrEP. |
| Databáze: | OpenAIRE |
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