Journal Article

HIV-1 viremia not suppressible by antiretroviral therapy can originate from large T cell clones producing infectious virus

Sobolewski, Michele D., Bale, Michael J., Kearney, Mary F., Keele, Brandon F., Hughes, Stephen H., Brandt, Leah D., Shao, Wei, Coffin, John M., Joseph, Kevin W., Tumiotto, Camille, Wu, Xiaolin, Morse, Gene D., Mellors, John W., Bui, John K., Guo, Shuang, Jacobs, Jana L., Halvas, Elias K., Cyktor, Joshua C., Rausch, Jason W.

2020

Overview

BACKGROUNDHIV-1 viremia that is not suppressed by combination antiretroviral therapy (ART) is generally attributed to incomplete medication adherence and/or drug resistance. We evaluated individuals referred by clinicians for nonsuppressible viremia (plasma HIV-1 RNA above 40 copies/mL) despite reported adherence to ART and the absence of drug resistance to the current ART regimen.METHODSSamples were collected from at least 2 time points from 8 donors who had nonsuppressible viremia for more than 6 months. Single templates of HIV-1 RNA obtained from plasma and viral outgrowth of cultured cells and from proviral DNA were amplified by PCR and sequenced for evidence of clones of cells that produced infectious viruses. Clones were confirmed by host-proviral integration site analysis.RESULTSHIV-1 genomic RNA with identical sequences were identified in plasma samples from all 8 donors. The identical viral RNA sequences did not change over time and did not evolve resistance to the ART regimen. In 4 of the donors, viral RNA sequences obtained from plasma matched those sequences from viral outgrowth cultures, indicating that the viruses were replication competent. Integration sites for infectious proviruses from those 4 donors were mapped to the introns of the MATR3, ZNF268, ZNF721/ABCA11P, and ABCA11P genes. The sizes of the clones were estimated to be from 50 million to 350 million cells.CONCLUSIONThese findings show that clones of HIV-1-infected cells producing virus can cause failure of ART to suppress viremia. The mechanisms involved in clonal expansion and persistence need to be defined to effectively target viremia and the HIV-1 reservoir.FUNDINGNational Cancer Institute, NIH; Howard Hughes Medical Research Fellows Program, Howard Hughes Medical Institute; Bill and Melinda Gates Foundation; Office of AIDS Research; American Cancer Society; National Cancer Institute through a Leidos subcontract; National Institute for Allergy and Infectious Diseases, NIH, to the I4C Martin Delaney Collaboratory; University of Rochester Center for AIDS Research and University of Rochester HIV/AIDS Clinical Trials Unit.

• Publisher: American Society for Clinical Investigation
• Subject: Acquired immune deficiency syndrome / AIDS / Allergies / Anti-Retroviral Agents / Antigen T (large) / Antiretroviral drugs / Antiretroviral therapy / Biomedical research / Cancer / Causes of / Clinical Medicine / Clinical trials / Cloning / Deoxyribonucleic acid / DNA / Drug resistance / Drug therapy / Female / Gene therapy / Genetic aspects / Genomic analysis / Health aspects / HIV / HIV infections / HIV Infections - genetics / HIV Infections - immunology / HIV-1 - genetics / HIV-1 - immunology / Human immunodeficiency virus / Humans / Infectious diseases / Integration / Introns / Introns - immunology / Lymphocytes / Lymphocytes T / Male / Medical research / Nucleotide sequence / Patient outcomes / Phylogenetics / Plasma / Proviruses / Ribonucleic acid / RNA / RNA, Viral - genetics / RNA, Viral - immunology / T cells / T-Lymphocytes - immunology / T-Lymphocytes - virology / Viremia / Viremia - genetics / Viremia - immunology / Virus Integration / Virus replication / Viruses