Journal article
Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection
AIDS, Vol.31(14), pp.1935-1943
2017
Abstract
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.
Details
- Title
- Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection
- Authors/Creators
- H. Gatanaga (Author/Creator)Z.L. Brumme (Author/Creator)E. Adland (Author/Creator)G. Reyes-Teran (Author/Creator)S. Avila-Rios (Author/Creator)C.R. Mejía-Villatoro (Author/Creator)T. Hayashida (Author/Creator)T. Chikata (Author/Creator)G. Van Tran (Author/Creator)K. Van Nguyen (Author/Creator)R.I. Meza (Author/Creator)E.Y. Palou (Author/Creator)H. Valenzuela-Ponce (Author/Creator)J.M. Pascale (Author/Creator)G. Porras-Cortés (Author/Creator)M. Manzanero (Author/Creator)G.Q. Lee (Author/Creator)J.N. Martin (Author/Creator)M.N. Carrington (Author/Creator)M. John (Author/Creator)S. Mallal (Author/Creator)A.F.Y. Poon (Author/Creator)P. Goulder (Author/Creator)M. Takiguchi (Author/Creator)S. Oka (Author/Creator)
- Publication Details
- AIDS, Vol.31(14), pp.1935-1943
- Publisher
- Lippincott Williams & Wilkins Ltd.
- Identifiers
- 991005544284707891
- Copyright
- © 2017 Ovid Technologies, Inc.
- Murdoch Affiliation
- Institute for Immunology and Infectious Diseases
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.66 HIV
- 1.66.46 HIV Pathogenesis
- Web Of Science research areas
- Immunology
- Infectious Diseases
- Virology
- ESI research areas
- Immunology