Blood Biomarkers of Expressed and Inducible HIV-1

Overview

Journal AIDS

Specialty Infectious Diseases

Date 2018 Jan 16

PMID 29334544

Citations 13

Authors

Anthony R Cillo

Francis Hong

Angela Tsai

Alivelu Irrinki

Jasmine Kaur

Derek D Sloan

Mattie Follen

Romas Geleziunas

Tomas Cihlar

Sandra S Win

Jeffrey P Murry

John W Mellors

Affiliations

Soon will be listed here.

Abstract

Objective: To define the relationships between molecular measures of viral persistence in blood (i.e., plasma viremia, cellular HIV-1 DNA, and mRNA) and expressed or inducible virus from resting CD4 T cells of individuals on suppressive antiretroviral therapy.

Design: We compared molecular measurements of HIV-1 in plasma and in uncultured peripheral blood mononuclear cells (PBMCs) to the levels of virions produced by either unstimulated or phorbol myristate acetate and ionomycin (PMA/iono)-stimulated PBMC or resting CD4 T cells from 21 donors on suppressive antiretroviral therapy.

Results: We found that unstimulated virion release from cultured resting CD4 T cells was positively correlated with the levels of plasma viremia in vivo (Spearman rho = 0.67, P = 0.0017). We also found that levels of both cellular HIV-1 DNA and unspliced HIV-1 mRNA per million uncultured PBMC were positively correlated with the levels of inducible virion release from both PMA/iono-stimulated PBMC (total HIV-1 DNA: rho = 0.64, P = 0.0017; unspliced HIV-1 RNA: rho = 0.77, P < 0.001) and PMA/iono-stimulated resting CD4 T cells (total HIV-1 DNA: rho = 0.75, P < 0.001; unspliced HIV-1 RNA: rho = 0.75, P < 0.001).

Conclusion: These results show for the first time that there are strong associations between in-vivo measures of HIV-1 persistence and ex-vivo measures of spontaneous and inducible virus production from cultured PBMC and resting CD4 T cells. Findings from this study provide insight into the biology of HIV-1 persistence and suggest methods to guide the evaluation of clinical strategies to reduce the size of the viral reservoir.

Citing Articles

Persistent HIV-1 transcription in CD4 T cells from ART-suppressed individuals can originate from biologically competent proviruses.

Vignoles M, Andrade V, Noguera M, Brander C, Mavian C, Salemi M J Virus Erad. 2021; 7(3):100053.

PMID: 34621530 PMC: 8479831. DOI: 10.1016/j.jve.2021.100053.

Predicting Post-treatment HIV Remission: Does Size of the Viral Reservoir Matter?.

Pasternak A, Psomas C, Berkhout B Front Microbiol. 2021; 12:648434.

PMID: 33717047 PMC: 7952863. DOI: 10.3389/fmicb.2021.648434.

Residual Proviral Reservoirs: A High Risk for HIV Persistence and Driving Forces for Viral Rebound after Analytical Treatment Interruption.

Wang X, Xu H Viruses. 2021; 13(2).

PMID: 33670027 PMC: 7926539. DOI: 10.3390/v13020335.

Immune Responses and Viral Persistence in Simian/Human Immunodeficiency Virus SHIV.C.CH848-Infected Rhesus Macaques.

Ziani W, Bauer A, Lu H, Wang X, Wu X, Bar K J Virol. 2021; 95(9).

PMID: 33568508 PMC: 8104099. DOI: 10.1128/JVI.02198-20.

Mucosal integrin α4β7 blockade fails to reduce the seeding and size of viral reservoirs in SIV-infected rhesus macaques.

Ziani W, Shao J, Fang A, Connolly P, Wang X, Veazey R FASEB J. 2021; 35(2):e21282.

PMID: 33484474 PMC: 7839271. DOI: 10.1096/fj.202002235R.

References

Chomont N, El-Far M, Ancuta P, Trautmann L, Procopio F, Yassine-Diab B . HIV reservoir size and persistence are driven by T cell survival and homeostatic proliferation. Nat Med. 2009; 15(8):893-900. PMC: 2859814. DOI: 10.1038/nm.1972. View

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

Laird G, Eisele E, Rabi S, Lai J, Chioma S, Blankson J . Rapid quantification of the latent reservoir for HIV-1 using a viral outgrowth assay. PLoS Pathog. 2013; 9(5):e1003398. PMC: 3667757. DOI: 10.1371/journal.ppat.1003398. View

Siliciano J, Kajdas J, Finzi D, Quinn T, Chadwick K, Margolick J . Long-term follow-up studies confirm the stability of the latent reservoir for HIV-1 in resting CD4+ T cells. Nat Med. 2003; 9(6):727-8. DOI: 10.1038/nm880. View

Kiselinova M, De Spiegelaere W, Buzon M, Malatinkova E, Lichterfeld M, Vandekerckhove L . Integrated and Total HIV-1 DNA Predict Ex Vivo Viral Outgrowth. PLoS Pathog. 2016; 12(3):e1005472. PMC: 4777389. DOI: 10.1371/journal.ppat.1005472. View

Rothenberger M, Keele B, Wietgrefe S, Fletcher C, Beilman G, Chipman J . Large number of rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues after treatment interruption. Proc Natl Acad Sci U S A. 2015; 112(10):E1126-34. PMC: 4364237. DOI: 10.1073/pnas.1414926112. View

Murray J, McBride K, Boesecke C, Bailey M, Amin J, Suzuki K . Integrated HIV DNA accumulates prior to treatment while episomal HIV DNA records ongoing transmission afterwards. AIDS. 2012; 26(5):543-50. DOI: 10.1097/QAD.0b013e328350fb3c. View

Besson G, Lalama C, Bosch R, Gandhi R, Bedison M, Aga E . HIV-1 DNA decay dynamics in blood during more than a decade of suppressive antiretroviral therapy. Clin Infect Dis. 2014; 59(9):1312-21. PMC: 4200019. DOI: 10.1093/cid/ciu585. View

Williams J, Hurst J, Stohr W, Robinson N, Brown H, Fisher M . HIV-1 DNA predicts disease progression and post-treatment virological control. Elife. 2014; 3:e03821. PMC: 4199415. DOI: 10.7554/eLife.03821. View

10.

Bui J, Mellors J, Cillo A . HIV-1 Virion Production from Single Inducible Proviruses following T-Cell Activation Ex Vivo. J Virol. 2015; 90(3):1673-6. PMC: 4719601. DOI: 10.1128/JVI.02520-15. View

11.

Finzi D, Blankson J, Siliciano J, Margolick J, Chadwick K, Pierson T . Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy. Nat Med. 1999; 5(5):512-7. DOI: 10.1038/8394. View

12.

Hammer S, Squires K, Hughes M, Grimes J, Demeter L, Currier J . A controlled trial of two nucleoside analogues plus indinavir in persons with human immunodeficiency virus infection and CD4 cell counts of 200 per cubic millimeter or less. AIDS Clinical Trials Group 320 Study Team. N Engl J Med. 1997; 337(11):725-33. DOI: 10.1056/NEJM199709113371101. View

13.

Gandhi R, McMahon D, Bosch R, Lalama C, Cyktor J, Macatangay B . Levels of HIV-1 persistence on antiretroviral therapy are not associated with markers of inflammation or activation. PLoS Pathog. 2017; 13(4):e1006285. PMC: 5398724. DOI: 10.1371/journal.ppat.1006285. View

14.

Crooks A, Bateson R, Cope A, Dahl N, Griggs M, Kuruc J . Precise Quantitation of the Latent HIV-1 Reservoir: Implications for Eradication Strategies. J Infect Dis. 2015; 212(9):1361-5. PMC: 4601910. DOI: 10.1093/infdis/jiv218. View

15.

Siliciano J, Siliciano R . Enhanced culture assay for detection and quantitation of latently infected, resting CD4+ T-cells carrying replication-competent virus in HIV-1-infected individuals. Methods Mol Biol. 2005; 304:3-15. DOI: 10.1385/1-59259-907-9:003. View

16.

Kearney M, Wiegand A, Shao W, Coffin J, Mellors J, Lederman M . Origin of Rebound Plasma HIV Includes Cells with Identical Proviruses That Are Transcriptionally Active before Stopping of Antiretroviral Therapy. J Virol. 2015; 90(3):1369-76. PMC: 4719635. DOI: 10.1128/JVI.02139-15. View

17.

Persaud D, Gay H, Ziemniak C, Chen Y, Piatak Jr M, Chun T . Absence of detectable HIV-1 viremia after treatment cessation in an infant. N Engl J Med. 2013; 369(19):1828-35. PMC: 3954754. DOI: 10.1056/NEJMoa1302976. View

18.

Koelsch K, Liu L, Haubrich R, May S, Havlir D, Gunthard H . Dynamics of total, linear nonintegrated, and integrated HIV-1 DNA in vivo and in vitro. J Infect Dis. 2008; 197(3):411-9. DOI: 10.1086/525283. View

19.

Perelson A, Neumann A, Markowitz M, Leonard J, Ho D . HIV-1 dynamics in vivo: virion clearance rate, infected cell life-span, and viral generation time. Science. 1996; 271(5255):1582-6. DOI: 10.1126/science.271.5255.1582. View

20.

Ho Y, Shan L, Hosmane N, Wang J, Laskey S, Rosenbloom D . Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure. Cell. 2013; 155(3):540-51. PMC: 3896327. DOI: 10.1016/j.cell.2013.09.020. View