HIV-1 Integration Landscape During Latent and Active Infection

Overview

Journal Cell

Publisher Cell Press

Specialty Cell Biology

Date 2015 Jan 31

PMID 25635456

Citations 290

Authors

Lillian B Cohn

Israel T Silva

Thiago Y Oliveira

Rafael A Rosales

Erica H Parrish

Gerald H Learn

Beatrice H Hahn

Julie L Czartoski

M Juliana McElrath

Clara Lehmann

Florian Klein

Marina Caskey

Bruce D Walker

Janet D Siliciano

Robert F Siliciano

Mila Jankovic

Michel C Nussenzweig

Affiliations

Soon will be listed here.

Abstract

The barrier to curing HIV-1 is thought to reside primarily in CD4(+) T cells containing silent proviruses. To characterize these latently infected cells, we studied the integration profile of HIV-1 in viremic progressors, individuals receiving antiretroviral therapy, and viremic controllers. Clonally expanded T cells represented the majority of all integrations and increased during therapy. However, none of the 75 expanded T cell clones assayed contained intact virus. In contrast, the cells bearing single integration events decreased in frequency over time on therapy, and the surviving cells were enriched for HIV-1 integration in silent regions of the genome. Finally, there was a strong preference for integration into, or in close proximity to, Alu repeats, which were also enriched in local hotspots for integration. The data indicate that dividing clonally expanded T cells contain defective proviruses and that the replication-competent reservoir is primarily found in CD4(+) T cells that remain relatively quiescent.

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References

Rose P, Korber B . Detecting hypermutations in viral sequences with an emphasis on G --> A hypermutation. Bioinformatics. 2000; 16(4):400-1. DOI: 10.1093/bioinformatics/16.4.400. View

Jordan A, Defechereux P, Verdin E . The site of HIV-1 integration in the human genome determines basal transcriptional activity and response to Tat transactivation. EMBO J. 2001; 20(7):1726-38. PMC: 145503. DOI: 10.1093/emboj/20.7.1726. View

Schroder A, Shinn P, Chen H, Berry C, Ecker J, Bushman F . HIV-1 integration in the human genome favors active genes and local hotspots. Cell. 2002; 110(4):521-9. DOI: 10.1016/s0092-8674(02)00864-4. View

Jordan A, Bisgrove D, Verdin E . HIV reproducibly establishes a latent infection after acute infection of T cells in vitro. EMBO J. 2003; 22(8):1868-77. PMC: 154479. DOI: 10.1093/emboj/cdg188. View

Han Y, Lassen K, Monie D, Sedaghat A, Shimoji S, Liu X . Resting CD4+ T cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals carry integrated HIV-1 genomes within actively transcribed host genes. J Virol. 2004; 78(12):6122-33. PMC: 416493. DOI: 10.1128/JVI.78.12.6122-6133.2004. View

Mitchell R, Beitzel B, Schroder A, Shinn P, Chen H, Berry C . Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences. PLoS Biol. 2004; 2(8):E234. PMC: 509299. DOI: 10.1371/journal.pbio.0020234. View

Bailey T, Elkan C . Fitting a mixture model by expectation maximization to discover motifs in biopolymers. Proc Int Conf Intell Syst Mol Biol. 1994; 2:28-36. 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

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

10.

Finzi D, Hermankova M, Pierson T, Carruth L, Buck C, Chaisson R . Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997; 278(5341):1295-300. DOI: 10.1126/science.278.5341.1295. View

11.

Chun T, Engel D, Berrey M, Shea T, Corey L, Fauci A . Early establishment of a pool of latently infected, resting CD4(+) T cells during primary HIV-1 infection. Proc Natl Acad Sci U S A. 1998; 95(15):8869-73. PMC: 21169. DOI: 10.1073/pnas.95.15.8869. View

12.

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

13.

Wu X, Li Y, Crise B, Burgess S, Munroe D . Weak palindromic consensus sequences are a common feature found at the integration target sites of many retroviruses. J Virol. 2005; 79(8):5211-4. PMC: 1069554. DOI: 10.1128/JVI.79.8.5211-5214.2005. View

14.

Holman A, Coffin J . Symmetrical base preferences surrounding HIV-1, avian sarcoma/leukosis virus, and murine leukemia virus integration sites. Proc Natl Acad Sci U S A. 2005; 102(17):6103-7. PMC: 1087937. DOI: 10.1073/pnas.0501646102. View

15.

Lewinski M, Yamashita M, Emerman M, Ciuffi A, Marshall H, Crawford G . Retroviral DNA integration: viral and cellular determinants of target-site selection. PLoS Pathog. 2006; 2(6):e60. PMC: 1480600. DOI: 10.1371/journal.ppat.0020060. View

16.

Ikeda T, Shibata J, Yoshimura K, Koito A, Matsushita S . Recurrent HIV-1 integration at the BACH2 locus in resting CD4+ T cell populations during effective highly active antiretroviral therapy. J Infect Dis. 2007; 195(5):716-25. DOI: 10.1086/510915. View

17.

Wang G, Ciuffi A, Leipzig J, Berry C, Bushman F . HIV integration site selection: analysis by massively parallel pyrosequencing reveals association with epigenetic modifications. Genome Res. 2007; 17(8):1186-94. PMC: 1933515. DOI: 10.1101/gr.6286907. View

18.

Brady T, Agosto L, Malani N, Berry C, ODoherty U, Bushman F . HIV integration site distributions in resting and activated CD4+ T cells infected in culture. AIDS. 2009; 23(12):1461-71. PMC: 2862484. DOI: 10.1097/QAD.0b013e32832caf28. View

19.

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

20.

Klein I, Resch W, Jankovic M, Oliveira T, Yamane A, Nakahashi H . Translocation-capture sequencing reveals the extent and nature of chromosomal rearrangements in B lymphocytes. Cell. 2011; 147(1):95-106. PMC: 3190307. DOI: 10.1016/j.cell.2011.07.048. View