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Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection

Gatanaga, H., Brumme, Z.L., Adland, E., Reyes-Teran, G., Avila-Rios, S., Mejía-Villatoro, C.R., Hayashida, T., Chikata, T., Van Tran, G., Van Nguyen, K., Meza, R.I., Palou, E.Y., Valenzuela-Ponce, H., Pascale, J.M., Porras-Cortés, G., Manzanero, M., Lee, G.Q., Martin, J.N., Carrington, M.N., John, M., Mallal, S., Poon, A.F.Y., Goulder, P., Takiguchi, M. and Oka, S. (2017) Potential for immune-driven viral polymorphisms to compromise antiretroviral-based preexposure prophylaxis for prevention of HIV-1 infection. AIDS, 31 (14). pp. 1935-1943.

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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.

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.

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.

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.

Item Type: Journal Article
Murdoch Affiliation: Institute for Immunology and Infectious Diseases
Journal or Publication Title: AIDS
Page Range: pp. 1935-1943
Publisher: Lippincott Williams & Wilkins Ltd.
Copyright: © 2017 Ovid Technologies, Inc.
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