Rapid Turnover of 2-LTR HIV-1 DNA During Early Stage of Highly Active Antiretroviral Therapy

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2011 Jun 21

PMID 21687638

Citations 23

Authors

Weijun Zhu

Yanmei Jiao

Rongyue Lei

Wei Hua

Rui Wang

Yunxia Ji

Zhiying Liu

Feili Wei

Tong Zhang

Xuanlin Shi

Hao Wu

Linqi Zhang

Affiliations

Soon will be listed here.

Abstract

Background: Despite prolonged treatment with highly active antiretroviral therapy (HAART), the infectious HIV-1 continues to replicate and resides latently in the resting memory CD4+ T lymphocytes, which blocks the eradication of HIV-1. The viral persistence of HIV-1 is mainly caused by its proviral DNA being either linear nonintegrated, circular nonintegrated, or integrated. Previous reports have largely focused on the dynamics of HIV-1 DNA from the samples collected with relatively long time intervals during the process of disease and HAART treatment, which may have missed the intricate changes during the intervals in early treatment.

Methodology/principal Findings: In this study, we investigated the dynamics of HIV-1 DNA in patients during the early phase of HARRT treatment. Using optimized real time PCR, we observed significant changes in 2-LTR during the first 12-week of treatment, while total and integrated HIV-1 DNA remained stable. The doubling time and half-life of 2-LTR were not correlated with the baseline and the rate of changes in plasma viral load and various CD4+ T-cell populations. Longitudinal analyses on 2-LTR sequences and plasma lipopolysaccharide (LPS) levels did not reveal any significant changes in the same treatment period.

Conclusions/significance: Our study revealed the rapid changes in 2-LTR concentration in a relatively large number of patients during the early HAART treatment. The rapid changes indicate the rapid infusion and clearance of cells bearing 2-LTR in the peripheral blood. Those changes are not expected to be caused by the blocking of viral integration, as our study did not include the integrase inhibitor raltegravir. Our study helps better understand the dynamics of HIV-DNA and its potential role as a biomarker for the diseases and for the treatment efficacy of HAART.

Citing Articles

Validation of digital droplet PCR assays for cell-associated HIV-1 DNA, HIV-1 2-LTR circle, and HIV-1 unspliced RNA for clinical studies in HIV-1 cure research.

Reed J, Kwak G, Piliper E, Degli-Angeli E, Goecker E, Greninger A J Clin Virol. 2023; 170:105632.

PMID: 38113685 PMC: 10842696. DOI: 10.1016/j.jcv.2023.105632.

Different Pathways Conferring Integrase Strand-Transfer Inhibitors Resistance.

Richetta C, Tu N, Delelis O Viruses. 2022; 14(12).

PMID: 36560595 PMC: 9785060. DOI: 10.3390/v14122591.

Antiretroviral (ARV) Drug Resistance and HIV-1 Subtypes among Injecting Drug Users in the Coastal Region of Kenya.

Ngonga G, Ayodo G, Kawaka F, Knight V, Ngayo M, Lwembe R Adv Virol. 2022; 2022:3217749.

PMID: 35186083 PMC: 8853818. DOI: 10.1155/2022/3217749.

A comparative analysis of unintegrated HIV-1 DNA measurement as a potential biomarker of the cellular reservoir in the blood of patients controlling and non-controlling viral replication.

Orlandi C, Canovari B, Bozzano F, Marras F, Pasquini Z, Barchiesi F J Transl Med. 2020; 18(1):204.

PMID: 32429953 PMC: 7236182. DOI: 10.1186/s12967-020-02368-y.

Impact of Antiretroviral Therapy Duration on HIV-1 Infection of T Cells within Anatomic Sites.

Lee E, von Stockenstrom S, Morcilla V, Odevall L, Hiener B, Shao W J Virol. 2019; 94(3).

PMID: 31723024 PMC: 7000983. DOI: 10.1128/JVI.01270-19.

References

Ibanez A, Puig T, Elias J, Clotet B, Ruiz L, Martinez M . Quantification of integrated and total HIV-1 DNA after long-term highly active antiretroviral therapy in HIV-1-infected patients. AIDS. 1999; 13(9):1045-9. DOI: 10.1097/00002030-199906180-00007. 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

Cavert W, Notermans D, Staskus K, Wietgrefe S, Zupancic M, GEBHARD K . Kinetics of response in lymphoid tissues to antiretroviral therapy of HIV-1 infection. Science. 1997; 276(5314):960-4. DOI: 10.1126/science.276.5314.960. View

Furtado M, Callaway D, Phair J, Kunstman K, Stanton J, Macken C . Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. N Engl J Med. 1999; 340(21):1614-22. DOI: 10.1056/NEJM199905273402102. View

Gillim-Ross L, Cara A, Klotman M . HIV-1 extrachromosomal 2-LTR circular DNA is long-lived in human macrophages. Viral Immunol. 2005; 18(1):190-6. DOI: 10.1089/vim.2005.18.190. View

Delaugerre C, Charreau I, Braun J, Nere M, de Castro N, Yeni P . Time course of total HIV-1 DNA and 2-long-terminal repeat circles in patients with controlled plasma viremia switching to a raltegravir-containing regimen. AIDS. 2010; 24(15):2391-5. DOI: 10.1097/QAD.0b013e32833d214c. View

Chun T, Carruth L, Finzi D, Shen X, DiGiuseppe J, Taylor H . Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature. 1997; 387(6629):183-8. DOI: 10.1038/387183a0. View

Andreoni M, Parisi S, Sarmati L, Nicastri E, Ercoli L, Mancino G . Cellular proviral HIV-DNA decline and viral isolation in naïve subjects with <5000 copies/ml of HIV-RNA and >500 x 10(6)/l CD4 cells treated with highly active antiretroviral therapy. AIDS. 2000; 14(1):23-9. DOI: 10.1097/00002030-200001070-00003. View

Thompson J, Gibson T, Plewniak F, Jeanmougin F, Higgins D . The CLUSTAL_X windows interface: flexible strategies for multiple sequence alignment aided by quality analysis tools. Nucleic Acids Res. 1998; 25(24):4876-82. PMC: 147148. DOI: 10.1093/nar/25.24.4876. View

10.

Brenchley J, Price D, Schacker T, Asher T, Silvestri G, Rao S . Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med. 2006; 12(12):1365-71. DOI: 10.1038/nm1511. View

11.

Strain M, Gunthard H, Havlir D, Ignacio C, Smith D, Leigh-Brown A . Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: intrinsic stability predicts lifelong persistence. Proc Natl Acad Sci U S A. 2003; 100(8):4819-24. PMC: 153639. DOI: 10.1073/pnas.0736332100. View

12.

Viard J, Burgard M, Hubert J, Aaron L, Rabian C, Pertuiset N . Impact of 5 years of maximally successful highly active antiretroviral therapy on CD4 cell count and HIV-1 DNA level. AIDS. 2004; 18(1):45-9. DOI: 10.1097/00002030-200401020-00005. View

13.

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

14.

Zack J, Arrigo S, Weitsman S, Go A, Haislip A, Chen I . HIV-1 entry into quiescent primary lymphocytes: molecular analysis reveals a labile, latent viral structure. Cell. 1990; 61(2):213-22. DOI: 10.1016/0092-8674(90)90802-l. View

15.

Ho D, Neumann A, Perelson A, Chen W, Leonard J, Markowitz M . Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature. 1995; 373(6510):123-6. DOI: 10.1038/373123a0. View

16.

Huang Y, Paxton W, Wolinsky S, Neumann A, Zhang L, He T . The role of a mutant CCR5 allele in HIV-1 transmission and disease progression. Nat Med. 1996; 2(11):1240-3. DOI: 10.1038/nm1196-1240. View

17.

Fischer M, Trkola A, Joos B, Hafner R, Joller H, Muesing M . Shifts in cell-associated HIV-1 RNA but not in episomal HIV-1 DNA correlate with new cycles of HIV-1 infection in vivo. Antivir Ther. 2003; 8(2):97-104. View

18.

Yerly S, Perneger T, Vora S, Hirschel B, Perrin L . Decay of cell-associated HIV-1 DNA correlates with residual replication in patients treated during acute HIV-1 infection. AIDS. 2001; 14(18):2805-12. DOI: 10.1097/00002030-200012220-00001. View

19.

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

20.

Lai J, Yang J, Douglas S, Wang X, Riedel E, Ho W . Quantification of CCR5 mRNA in human lymphocytes and macrophages by real-time reverse transcriptase PCR assay. Clin Diagn Lab Immunol. 2003; 10(6):1123-8. PMC: 262429. DOI: 10.1128/cdli.10.6.1123-1128.2003. View