Identification of Novel UGT1A1 Variants Including UGT1A1 454C>A through the Genotyping of Healthy Participants of the HPTN 077 Study

The Johns Hopkins University School of Medicine. Division of Clinical Pharmacology. Department of Medicine. Baltimore, Maryland, United States.
The Johns Hopkins University School of Medicine. Division of Clinical Pharmacology. Department of Medicine. Baltimore, Maryland, United States.
Fred Hutchinson Cancer Research Center. Statistical Center for HIV/AIDS Research and Prevention. Seattle, Washington, United States.
Fundação Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laboratório de Pesquisa Clínica em DST/AIDS. Rio de Janeiro, RJ, Brasil.
University of KwaZulu Natal. Centre for the AIDS Programme of Research in South Africa. Durban, South Africa.
San Francisco Department of Health. Population Health Division. Bridge HIV. San Francisco, California, United States.
George Washington University. Milken Institute School of Public Health. Department of Epidemiology and Biostatistics. Washington, District of Columbia, United States.
UNC Project-Malawi. Lilongwe, Malawi.
Chris Hani Baragwanath Hospital. Perinatal HIV Research Unit. Soweto, South Africa.
Fred Hutchinson Cancer Research Center. Statistical Center for HIV/AIDS Research and Prevention. Seattle, Washington, United States.
Fred Hutchinson Cancer Research Center. Statistical Center for HIV/AIDS Research and Prevention. Seattle, Washington, United States.
National Institutes of Health. National Institute of Allergy and Infectious Diseases. Division of AIDS. Rockville, Maryland, United States.
ViiV Healthcare. Durham, North Carolina, United States.
FHI360. Durham, North Carolina, United States.
University of North Carolina at Chapel Hill. Chapel Hill, North Carolina, United States.
University of North Carolina at Chapel Hill. Chapel Hill, North Carolina, United States.
UCLA Center for Clinical AIDS Research and Education. Los Angeles, California, United States.
The Johns Hopkins University School of Medicine. Division of Clinical Pharmacology. Department of Medicine. Baltimore, Maryland, United States.
The Johns Hopkins University School of Medicine. Department of Pharmacology and Molecular Sciences. Baltimore, Maryland, United States.

Abstract

Cabotegravir (CAB) is an integrase strand-transfer inhibitor of HIV that has proven effective for HIV treatment and prevention in a long-acting injectable formulation, typically preceded by an oral formulation lead-in phase. Previous in vitro studies have demonstrated that CAB is primarily metabolized via glucuronidation by uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A9. In this study, we performed next-generation sequencing of genomic DNA isolated from the HPTN 077 participants to explore the variants within UGT1A1 and UGT1A9. Additionally, to enable correlation of UGT1A1 and UGT1A9 genotypes with plasma CAB-glucuronide levels, we quantified glucuronidated CAB following both oral administration of CAB and intramuscular injection of long-acting CAB. From these studies, 48 previously unreported variants of UGT1A1 and UGT1A9 were detected. Notably, 5/68 individuals carried a UGT1A1 454C>A variant that resulted in amino acid substitution P152T, and the use of in silico tools predicted a deleterious effect of the P152T substitution. Thus, the impact of this mutant on a range of UGT1A1 substrates was tested using a COS-7 cell-based assay. The glucuronide conjugates of CAB, dolutegravir, and raltegravir, were not formed in the COS-7 cells expressing the UGT1A1 P152T mutant. Further, formation of glucuronides of raloxifene and 7-ethyl-10-hydroxycamptothecin were reduced in the cells expressing the UGT1A1 P152T mutant. Using the same approach, we tested the activities of two UGT1A9 mutants, UGT1A9 H217Y and UGT1A9 R464G, and found that these mutations were tolerated and decreased function, respectively. These data provide insight into previously unreported genetic variants of UGT1A1 and UGT1A9.

Keywords

Cabotegravir
Long-acting
Human immunodeficiency virus
Pre-exposure prophylaxis
Uridine diphosphate glucuronosyltransferase
Cabotegravir-glucuronide

Publisher

ACS Publications

Citation

SENEVIRATNE, Herana Kamal et al. Identification of Novel UGT1A1 Variants Including UGT1A1 454C>A through the Genotyping of Healthy Participants of the HPTN 077 Study. ACS pharmacology & translational science, v. 4, n. 1, p. 226-239, 2021

DOI

10.1021/acsptsci.0c00181

ISSN

2575-9108

Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/46163

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Copyright

Restricted access

Embargo date

2023-02-28

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