Similar Frequency and Inducibility of Intact Human Immunodeficiency Virus-1 Proviruses in Blood and Lymph Nodes

Overview

Journal J Infect Dis

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2020 Dec 3

PMID 33269401

Citations 16

Authors

Alyssa R Martin

Alexandra M Bender

Jada Hackman

Kyungyoon J Kwon

Briana A Lynch

Daniel Bruno

Craig Martens

Subul Beg

Sander S Florman

Niraj Desai

Dorry Segev

Gregory M Laird

Janet D Siliciano

Thomas C Quinn

Aaron A R Tobian

Christine M Durand

Robert F Siliciano

Andrew D Redd

Affiliations

Soon will be listed here.

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.

Citing Articles

Blood and tissue HIV-1 reservoirs display plasticity and lack of compartmentalization in virally suppressed people.

Pardons M, Lambrechts L, Noppe Y, Termote L, De Braekeleer S, Vega J Nat Commun. 2025; 16(1):2173.

PMID: 40038305 PMC: 11880387. DOI: 10.1038/s41467-025-57332-5.

Rapid biphasic decay of intact and defective HIV DNA reservoir during acute treated HIV disease.

Barbehenn A, Shi L, Shao J, Hoh R, Hartig H, Pae V Nat Commun. 2024; 15(1):9966.

PMID: 39557853 PMC: 11574060. DOI: 10.1038/s41467-024-54116-1.

Longitudinal analysis of viral dynamics in HIV+-to-HIV+ HOPE Act kidney-transplant recipients.

Travieso T, Stadtler H, Alavian N, Gao F, Klotman M, Wolfe C J Clin Invest. 2024; 134(20).

PMID: 39255037 PMC: 11473162. DOI: 10.1172/JCI181560.

Spatial technologies to evaluate the HIV-1 reservoir and its microenvironment in the lymph node.

Zaman F, Smith M, Balagopal A, Durand C, Redd A, Tobian A mBio. 2024; 15(8):e0190924.

PMID: 39058091 PMC: 11324018. DOI: 10.1128/mbio.01909-24.

Rapid Biphasic Decay of Intact and Defective HIV DNA Reservoir During Acute Treated HIV Disease.

Barbehenn A, Shi L, Shao J, Hoh R, Hartig H, Pae V medRxiv. 2024; .

PMID: 38585951 PMC: 10996734. DOI: 10.1101/2024.03.27.24304867.

References

Bullen C, Laird G, Durand C, Siliciano J, Siliciano R . New ex vivo approaches distinguish effective and ineffective single agents for reversing HIV-1 latency in vivo. Nat Med. 2014; 20(4):425-9. PMC: 3981911. DOI: 10.1038/nm.3489. View

Laskey S, Pohlmeyer C, Bruner K, Siliciano R . Evaluating Clonal Expansion of HIV-Infected Cells: Optimization of PCR Strategies to Predict Clonality. PLoS Pathog. 2016; 12(8):e1005689. PMC: 4975415. DOI: 10.1371/journal.ppat.1005689. View

Rosenbloom D, Hill A, Laskey S, Siliciano R . Re-evaluating evolution in the HIV reservoir. Nature. 2017; 551(7681):E6-E9. PMC: 6103791. DOI: 10.1038/nature24634. View

Deeks S, Lewin S, Ross A, Ananworanich J, Benkirane M, Cannon P . International AIDS Society global scientific strategy: towards an HIV cure 2016. Nat Med. 2016; 22(8):839-50. PMC: 5322797. DOI: 10.1038/nm.4108. View

Lorenzi J, Cohen Y, Cohn L, Kreider E, Barton J, Learn G . Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA. Proc Natl Acad Sci U S A. 2016; 113(49):E7908-E7916. PMC: 5150408. DOI: 10.1073/pnas.1617789113. View

Wang Z, Gurule E, Brennan T, Gerold J, Kwon K, Hosmane N . Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane. Proc Natl Acad Sci U S A. 2018; 115(11):E2575-E2584. PMC: 5856552. DOI: 10.1073/pnas.1720665115. View

Lee M, Mandl J, Germain R, Yates A . The race for the prize: T-cell trafficking strategies for optimal surveillance. Blood. 2012; 120(7):1432-8. PMC: 3423781. DOI: 10.1182/blood-2012-04-424655. View

Bozzi G, Simonetti F, Watters S, Anderson E, Gouzoulis M, Kearney M . No evidence of ongoing HIV replication or compartmentalization in tissues during combination antiretroviral therapy: Implications for HIV eradication. Sci Adv. 2019; 5(9):eaav2045. PMC: 6760922. DOI: 10.1126/sciadv.aav2045. View

Pantaleo G, Graziosi C, Demarest J, Butini L, Montroni M, Fox C . HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature. 1993; 362(6418):355-8. DOI: 10.1038/362355a0. View

10.

Wong J, Hezareh M, Gunthard H, Havlir D, Ignacio C, Spina C . Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science. 1997; 278(5341):1291-5. DOI: 10.1126/science.278.5341.1291. View

11.

Imamichi H, Dewar R, Adelsberger J, Rehm C, ODoherty U, Paxinos E . Defective HIV-1 proviruses produce novel protein-coding RNA species in HIV-infected patients on combination antiretroviral therapy. Proc Natl Acad Sci U S A. 2016; 113(31):8783-8. PMC: 4978246. DOI: 10.1073/pnas.1609057113. View

12.

Chun T, Stuyver L, Mizell S, Ehler L, Mican J, Baseler M . Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 1997; 94(24):13193-7. PMC: 24285. DOI: 10.1073/pnas.94.24.13193. View

13.

Lee G, Orlova-Fink N, Einkauf K, Chowdhury F, Sun X, Harrington S . Clonal expansion of genome-intact HIV-1 in functionally polarized Th1 CD4+ T cells. J Clin Invest. 2017; 127(7):2689-2696. PMC: 5490740. DOI: 10.1172/JCI93289. View

14.

Hiener B, Horsburgh B, Eden J, Barton K, Schlub T, Lee E . Identification of Genetically Intact HIV-1 Proviruses in Specific CD4 T Cells from Effectively Treated Participants. Cell Rep. 2017; 21(3):813-822. PMC: 5960642. DOI: 10.1016/j.celrep.2017.09.081. View

15.

Banga R, Procopio F, Noto A, Pollakis G, Cavassini M, Ohmiti K . PD-1(+) and follicular helper T cells are responsible for persistent HIV-1 transcription in treated aviremic individuals. Nat Med. 2016; 22(7):754-61. DOI: 10.1038/nm.4113. View

16.

Vibholm L, Lorenzi J, Pai J, Cohen Y, Oliveira T, Barton J . Characterization of Intact Proviruses in Blood and Lymph Node from HIV-Infected Individuals Undergoing Analytical Treatment Interruption. J Virol. 2019; 93(8). PMC: 6450127. DOI: 10.1128/JVI.01920-18. View

17.

Hosmane N, Kwon K, Bruner K, Capoferri A, Beg S, Rosenbloom D . Proliferation of latently infected CD4 T cells carrying replication-competent HIV-1: Potential role in latent reservoir dynamics. J Exp Med. 2017; 214(4):959-972. PMC: 5379987. DOI: 10.1084/jem.20170193. View

18.

von Stockenstrom S, Odevall L, Lee E, Sinclair E, Bacchetti P, Killian M . Longitudinal Genetic Characterization Reveals That Cell Proliferation Maintains a Persistent HIV Type 1 DNA Pool During Effective HIV Therapy. J Infect Dis. 2015; 212(4):596-607. PMC: 4539896. DOI: 10.1093/infdis/jiv092. View

19.

Simonetti F, White J, Tumiotto C, Ritter K, Cai M, Gandhi R . Intact proviral DNA assay analysis of large cohorts of people with HIV provides a benchmark for the frequency and composition of persistent proviral DNA. Proc Natl Acad Sci U S A. 2020; 117(31):18692-18700. PMC: 7414172. DOI: 10.1073/pnas.2006816117. View

20.

Deleage C, Wietgrefe S, Del Prete G, Morcock D, Hao X, Piatak Jr M . Defining HIV and SIV Reservoirs in Lymphoid Tissues. Pathog Immun. 2016; 1(1):68-106. PMC: 4943335. DOI: 10.20411/pai.v1i1.100. View