The Persistence of HIV Diversity, Transcription, and Nef Protein in Kaposi's Sarcoma Tumors during Antiretroviral Therapy

Authors

David J. Nolan, Bioinfoexperts, LLC, Thibodaux, LA 70301, USA.
Rebecca Rose, Bioinfoexperts, LLC, Thibodaux, LA 70301, USA.
Rongzhen Zhang, Departments of Laboratory Medicine, Pathology and Medicine, The University of California at San Francisco, San Francisco, CA 94110, USA.
Alan Leong, Departments of Laboratory Medicine, Pathology and Medicine, The University of California at San Francisco, San Francisco, CA 94110, USA.
Gary B. Fogel, Natural Selection, Inc., San Diego, CA 92127, USA.
Larissa L. Scholte, Department of Microbiology, Immunology and Tropical Medicine, The George Washington University, Washington, DC 20037, USA.
Jeffrey M. Bethony, Department of Microbiology, Immunology and Tropical Medicine, The George Washington University, Washington, DC 20037, USA.
Paige Bracci, The AIDS and Cancer Specimen Resource, San Francisco, CA 94110, USA.
Susanna L. Lamers, Bioinfoexperts, LLC, Thibodaux, LA 70301, USA.
Michael S. McGrath, Departments of Laboratory Medicine, Pathology and Medicine, The University of California at San Francisco, San Francisco, CA 94110, USA.

Document Type

Journal Article

Publication Date

12-13-2022

Journal

Viruses

Volume

14

Issue

12

DOI

10.3390/v14122774

Keywords

HIV Nef; HIV transcription; Kaposi’s sarcoma; viral reservoirs

Abstract

Epidemic Kaposi's sarcoma (KS), defined by co-infection with Human Herpes Virus 8 (HHV-8) and the Human Immunodeficiency Virus (HIV), is a major cause of mortality in sub-Saharan Africa. Antiretroviral therapy (ART) significantly reduces the risk of developing KS, and for those with KS, tumors frequently resolve with ART alone. However, for unknown reasons, a significant number of KS cases do not resolve and can progress to death. To explore how HIV responds to ART in the KS tumor microenvironment, we sequenced HIV found in DNA and RNA isolated from plasma, peripheral blood mononuclear cells, and tumor biopsies, before and after ART, in four Ugandan study participants who had unresponsive or progressive KS after 180-250 days of ART. We performed immunohistochemistry experiments to detect viral proteins in matched formalin-fixed tumor biopsies. Our sequencing results showed that HIV diversity and RNA expression in KS tumors are maintained after ART, despite undetectable plasma viral loads. The presence of spliced HIV transcripts in KS tumors after ART was consistent with a transcriptionally active viral reservoir. Immunohistochemistry staining found colocalization of HIV Nef protein and tissue-resident macrophages in the KS tumors. Overall, our results demonstrated that even after ART reduced plasma HIV viral load to undetectable levels and restored immune function, HIV in KS tumors continues to be transcriptionally and translationally active, which could influence tumor maintenance and progression.

APA Citation

Nolan, David J.; Rose, Rebecca; Zhang, Rongzhen; Leong, Alan; Fogel, Gary B.; Scholte, Larissa L.; Bethony, Jeffrey M.; Bracci, Paige; Lamers, Susanna L.; and McGrath, Michael S., "The Persistence of HIV Diversity, Transcription, and Nef Protein in Kaposi's Sarcoma Tumors during Antiretroviral Therapy" (2022). GW Authored Works. Paper 2105.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/2105

Department

Microbiology, Immunology, and Tropical Medicine