Epigenetic Regulation of BST-2 Expression Levels and the Effect on HIV-1 Pathogenesis

Author:

Singh, Ravesh

Ramsuran, Veron

Naranbhai, Vivek

Yende-Zuma, Nonhlanhla

Garrett, Nigel

Mlisana, Koleka

Dong, Krista L

Walker, Bruce D

Abdool Karim, Salim S

Carrington, Mary

Ndung'u, Thumbi
Author Address

HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa., Africa Health Research Institute (AHRI), Durban, South Africa., Department of Microbiology, National Health Laboratory Services, KZN Academic Complex, Inkosi Albert Luthuli Central Hospital, Durban, South Africa., School of Laboratory Medicine and Medical Sciences, College of Health Sciences, University of KwaZulu-Natal, Durban, South Africa., The Ragon Institute of MGH, MIT and Harvard University, Cambridge, MA, United States., Basic Science Program, Frederick National Laboratory for Cancer Research in the Laboratory of Integrative Cancer Immunology, Bethesda, MD, United States., Centre for the AIDS Programme of Research in South Africa (CAPRISA), University of KwaZulu-Natal, Durban, South Africa., Max Planck Institute for Infection Biology, Chariteplatz, Berlin, Germany., Division of Infection and Immunity, University College London, London, United Kingdom.,

Abstract:

HIV-1 must overcome host antiviral restriction factors for efficient replication. We hypothesized that elevated levels of bone marrow stromal cell antigen 2 (BST-2), a potent host restriction factor that interferes with HIV-1 particle release in some human cells and is antagonized by the viral protein Vpu, may associate with viral control. Using cryopreserved samples, from HIV-1 seronegative and seropositive Black women, we measured in vitro expression levels of BST-2 mRNA using a real-time PCR assay and protein levels were validated by Western blotting. The expression level of BST-2 showed an association with viral control within two independent cohorts of Black HIV infected females (r=-0.53, p=0.015, [n =21]; and r=-0.62, p=0.0006, [n=28]). DNA methylation was identified as a mechanism regulating BST-2 levels, where increased BST-2 methylation results in lower expression levels and associates with worse HIV disease outcome. We further demonstrate the ability to regulate BST-2 levels using a DNA hypomethylation drug. Our results suggest BST-2 as a factor for potential therapeutic intervention against HIV and other diseases known to involve BST-2. Copyright © 2021 Singh, Ramsuran, Naranbhai, Yende-Zuma, Garrett, Mlisana, Dong, Walker, Abdool Karim, Carrington and Ndung’u.

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