Alyssa R Martin1, Alexandra M Bender2,3, Jada Hackman1, Kyungyoon J Kwon2, Briana A Lynch1,2, Daniel Bruno4, Craig Martens4, Subul Beg2, Sander S Florman5, Niraj Desai6, Dorry Segev6, Gregory M Laird7, Janet D Siliciano2, Thomas C Quinn1,2, Aaron A R Tobian8, Christine M Durand2, Robert F Siliciano2,9, Andrew D Redd1,2. 1. Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA. 2. Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 3. Department of Dermatology, University of Rochester Medical Center, Rochester, New York, USA. 4. Genomics Unit, Research Technologies Branch, Rocky Mountain Laboratories, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, USA. 5. Mount Sinai Hospital, New York City, New York, USA. 6. Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 7. Accelevir Diagnostics, Baltimore, Maryland, USA. 8. Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. 9. Howard Hughes Medical Institute, Baltimore, Maryland, USA.
Abstract
BACKGROUND: The human immunodeficiency virus (HIV)-1 latent reservoir (LR) in resting CD4+ T cells is a barrier to cure. LR measurements are commonly performed on blood samples and therefore may miss latently infected cells residing in tissues, including lymph nodes. METHODS: We determined the frequency of intact HIV-1 proviruses and proviral inducibility in matched peripheral blood (PB) and lymph node (LN) samples from 10 HIV-1-infected patients on antiretroviral therapy (ART) using the intact proviral DNA assay and a novel quantitative viral induction assay. Prominent viral sequences from induced viral RNA were characterized using a next-generation sequencing assay. RESULTS: The frequencies of CD4+ T cells with intact proviruses were not significantly different in PB versus LN (61/106 vs 104/106 CD4+ cells), and they were substantially lower than frequencies of CD4+ T cells with defective proviruses. The frequencies of CD4+ T cells induced to produce high levels of viral RNA were not significantly different in PB versus LN (4.3/106 vs 7.9/106), but they were 14-fold lower than the frequencies of cells with intact proviruses. Sequencing of HIV-1 RNA from induced proviruses revealed comparable sequences in paired PB and LN samples. CONCLUSIONS: These results further support the use of PB as an appropriate proxy for the HIV-1 LR in secondary lymphoid organs. Published by Oxford University Press for the Infectious Diseases Society of America 2020.
BACKGROUND: The human immunodeficiency virus (HIV)-1 latent reservoir (LR) in resting CD4+ T cells is a barrier to cure. LR measurements are commonly performed on blood samples and therefore may miss latently infected cells residing in tissues, including lymph nodes. METHODS: We determined the frequency of intact HIV-1 proviruses and proviral inducibility in matched peripheral blood (PB) and lymph node (LN) samples from 10 HIV-1-infected patients on antiretroviral therapy (ART) using the intact proviral DNA assay and a novel quantitative viral induction assay. Prominent viral sequences from induced viral RNA were characterized using a next-generation sequencing assay. RESULTS: The frequencies of CD4+ T cells with intact proviruses were not significantly different in PB versus LN (61/106 vs 104/106 CD4+ cells), and they were substantially lower than frequencies of CD4+ T cells with defective proviruses. The frequencies of CD4+ T cells induced to produce high levels of viral RNA were not significantly different in PB versus LN (4.3/106 vs 7.9/106), but they were 14-fold lower than the frequencies of cells with intact proviruses. Sequencing of HIV-1 RNA from induced proviruses revealed comparable sequences in paired PB and LN samples. CONCLUSIONS: These results further support the use of PB as an appropriate proxy for the HIV-1 LR in secondary lymphoid organs. Published by Oxford University Press for the Infectious Diseases Society of America 2020.
Entities:
Keywords:
HIV latency; T cell; intact provirus; latent reservoir; next-generation sequencing
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