Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection
| Autor: | Gatanaga, Hiroyuki, Brumme, Zabrina L, Adland, Emily, Reyes-Terán, Gustavo, Avila-Rios, Santiago, Mejía-Villatoro, Carlos R, Hayashida, Tsunefusa, Chikata, Takayuki, Van Tran, Giang, Van Nguyen, Kinh, Meza, Rita I, Palou, Elsa Y, Valenzuela-Ponce, Humberto, Pascale, Juan M, Porras-Cortés, Guillermo, Manzanero, Marvin, Lee, Guinevere Q, Martin, Jeffrey N, Carrington, Mary N, John, Mina, Mallal, Simon, Poon, Art FY, Goulder, Philip, Takiguchi, Masafumi, Oka, Shinichi, International HIV Adaptation Collaborative |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
HLA-B18 Antigen
Drug Resistance HIV Infections International HIV Adaptation Collaborative Global Health Medical and Health Sciences E138X rilpivirine Genetic Clinical Research Virology Genetics Humans Viral Polymorphism Aetiology Immune Evasion Prevention human leukocyte antigen-B*18 Psychology and Cognitive Sciences replication fitness Biological Sciences HIV Reverse Transcriptase Infectious Diseases Anti-Retroviral Agents escape mutation Mutation HIV-1 HIV/AIDS Pre-Exposure Prophylaxis Missense Infection 2.4 Surveillance and distribution |
| Zdroj: | AIDS (London, England), vol 31, iss 14 |
| Popis: | ObjectiveLong-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)-B18 where reverse transcriptase-E138X arises as an immune escape mutation. We investigate the global prevalence, B18-linkage and replicative cost of reverse transcriptase-E138X and its regional implications for rilpivirine PrEP.MethodsWe 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.ResultsReverse transcriptase-E138X variants, where the most common were rilpivirine resistance-associated mutations E138A/G/K, were significantly enriched in HLA-B18-positive individuals globally (P = 3.5 × 10) and in all HIV-1 subtypes except A. Reverse transcriptase-E138X and B18 frequencies correlated positively in 16 cohorts with linked HIV/HLA genotypes (Spearman's R = 0.75; P = 7.6 × 10) 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 B18 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.ConclusionsResults 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 |
| Externí odkaz: |
|