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Well-mixed plasma and tissue viral populations in RT-SHIV-infected macaques implies a lack of viral replication in the tissues during antiretroviral therapy

Kearney, MF and Anderson, EM and Coomer, C and Smith, L and Shao, W and Johnson, N and Kline, C and Spindler, J and Mellors, JW and Coffin, JM and Ambrose, Z (2015) Well-mixed plasma and tissue viral populations in RT-SHIV-infected macaques implies a lack of viral replication in the tissues during antiretroviral therapy. Retrovirology, 12 (1).

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Abstract

© 2015 Kearney et al. Background: Determining the anatomic compartments that contribute to plasma HIV-1 is critical to understanding the sources of residual viremia during combination antiretroviral therapy (ART). We analyzed viral DNA and RNA populations in the plasma and tissues from macaques infected with SIV containing HIV-1 RT (RT-SHIV) to identify possible sources of persistent viremia and to investigate the effect of ART on viral replication in tissues. Tissues were collected at necropsy from four pigtailed macaques infected for 30 weeks with a diverse population of RT-SHIV. Two animals (6760 and 8232) were untreated and two animals (8030 and 8272) were treated with efavirenz, tenofovir, and emtricitabine for 20 weeks. Results: A total of 1800 single-genome RT-SHIV pol and env DNA and RNA sequences were analyzed from the plasma, PBMCs, axillary and mesenteric lymph nodes, spleen, thymus, small intestine, bone marrow, lung, and brain. Analyses of intracellular DNA and RNA populations revealed that the majority of proviruses in tissues from untreated animal 8232 were not expressed, whereas a greater proportion of proviruses in tissues were expressed from 6760. Few intracellular RNA sequences were detected in treated animals and most contained inactivating mutations, such as frame shifts or large deletions. Phylogenetics showed that RT-SHIV DNA populations in tissues were not different from virus in contemporary plasma samples in the treated or untreated animals, demonstrating a lack of anatomic compartmentalization and suggesting that plasma viremia is derived from multiple tissue sources. No sequence divergence was detected in the plasma or between tissues in the treated animals after 20 weeks of ART indicating a lack of ongoing replication in tissues during treatment. Conclusions: Virus populations in plasma and tissues did not differ significantly in either treated or untreated macaques, suggesting frequent exchange of virus or infected cells between tissues and plasma, consistent with non-compartmentalized and widely disseminated infection. There was no genetic evidence of ongoing replication in tissues during suppressive ART.


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Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Kearney, MF
Anderson, EM
Coomer, C
Smith, L
Shao, W
Johnson, N
Kline, Ccjk14@pitt.eduCJK14
Spindler, J
Mellors, JWjwm1@pitt.eduJWM1
Coffin, JM
Ambrose, Zzaa4@pitt.eduZAA4
Date: 11 November 2015
Date Type: Publication
Journal or Publication Title: Retrovirology
Volume: 12
Number: 1
DOI or Unique Handle: 10.1186/s12977-015-0212-2
Schools and Programs: School of Medicine > Infectious Diseases and Microbiology
School of Medicine > Medicine
Refereed: Yes
Date Deposited: 26 Jul 2016 19:26
Last Modified: 02 Feb 2019 16:57
URI: http://d-scholarship.pitt.edu/id/eprint/28961

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