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Title: The dynamics of SIV 2-LTR Circles in the Presence and Absence of CD8 + Cells

Abstract

CD8 +cells play a key role in HIV/SIV infection, but their specific mechanism(s) of action in controlling the virus are unclear. 2-LTR circles are extrachromosomal products generated upon failed integration of HIV/SIV. To understand the specific effects of CD8 +cells on infected cells, we analyzed the dynamics of 2-LTR circles in SIVmac251-infected rhesus macaques (RM) treated with an integrase inhibitor (INT). Twenty RMs underwent CD8 +cell depletion, received RAL monotherapy or a combination of both. Blood, lymph nodes (LNs) and gut biopsies were routinely sampled. Plasma viral loads (pVLs) and 2-LTR circles from PBMCs and LN lymphocytes were measured with qRT-PCR. In the CD8 depletion group, an ~1 log increase in pVLs and a slow increase in PBMC 2-LTRs occurred following depletion. In the INT group, a strong decline in pVLs upon treatment initiation and no change in 2-LTR levels were observed. In the INT and CD8 +cell depletion group, a similar increase in pVLs following CD8 depletion was observed, with a modest decline following INT initiation, and 2-LTR circles significantly increased in PBMCs and LNs. Analyzing the 2-LTR data across all treatment groups with a mathematical model indicates that the data best supports an effect of CD8 +cells inmore » killing cells prior to viral integration. Sensitivity analyses of these results confirm that effect, but also allow for additional effects, which the data does not discriminate well. Overall, we show that INT does not significantly increase the levels of 2-LTR circles. However, CD8 +cell depletion increases the 2-LTR levels, which are enhanced in the presence of an INT. CD8 +T cells play an essential role in controlling HIV and simian immunodeficiency virus (SIV) infection, but the specific mechanisms involved remain poorly understood. Due to failed viral infection, HIV and SIV can form 2-LTR extrachromosomal circles that can be quantified. We present novel data on the dynamics of these 2-LTR forms in a SIV-infected macaque model under three different treatment conditions: depletion of CD8 +cells; administration of the integrase inhibitor in a monotherapy, which favors the formation of 2-LTR circles; and combination of the two treatments. We used a new mathematical model to help interpret the data, and the results suggest that CD8 +cells exert a killing effect on infected cells prior to virus integration. These results provide new insights into the mechanisms of action of CD8 +cells in SIV infection. Here, confirmation of our results would be an important step in understanding immune control of HIV.« less

Authors:
 [1];  [2];  [1];  [1];  [1];  [1];  [1];  [1];  [3]
+ Show Author Affiliations
  1. Univ. of Pittsburgh, Pittsburgh, PA (United States)
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Fred Hutchinson Cancer Research Center, Seattle, WA (United States)
  3. Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Faculdade de Medicina da Univ. de Lisboa (Portugal)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
National Institutes of Health (NIH); USDOE
OSTI Identifier:
1435533
Report Number(s):
LA-UR-18-20170
Journal ID: ISSN 0022-538X
Grant/Contract Number:  
AC52-06NA25396; AI104373; RO1 HL117715; R01 AI119346; R01 HL123096; T32 AI065380
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
Journal of Virology
Additional Journal Information:
Journal Volume: 92; Journal Issue: 13; Journal ID: ISSN 0022-538X
Publisher:
American Society for Microbiology
Country of Publication:
United States
Language:
English
Subject:
47 OTHER INSTRUMENTATION; 60 APPLIED LIFE SCIENCES; Biological Science; simian immunodeficiency virus; 2-LTR circles; rhesus macaques; integrase inhibitor; raltegravir; CD8+ cell depletion

Citation Formats

Policicchio, Benjamin B., Cardozo, Erwing Fabian, Sette, Paola, Xu, Cuiling, Haret-Richter, George, Dunsmore, Tammy, Apetrei, Cristian, Pandrea, Ivona, and Ribeiro, Ruy M. The dynamics of SIV 2-LTR Circles in the Presence and Absence of CD8+ Cells. United States: N. p., 2018. Web. doi:10.1128/JVI.02100-17.
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Policicchio, Benjamin B., Cardozo, Erwing Fabian, Sette, Paola, Xu, Cuiling, Haret-Richter, George, Dunsmore, Tammy, Apetrei, Cristian, Pandrea, Ivona, & Ribeiro, Ruy M. The dynamics of SIV 2-LTR Circles in the Presence and Absence of CD8+ Cells. United States. doi:10.1128/JVI.02100-17.
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Policicchio, Benjamin B., Cardozo, Erwing Fabian, Sette, Paola, Xu, Cuiling, Haret-Richter, George, Dunsmore, Tammy, Apetrei, Cristian, Pandrea, Ivona, and Ribeiro, Ruy M. Wed . "The dynamics of SIV 2-LTR Circles in the Presence and Absence of CD8+ Cells". United States. doi:10.1128/JVI.02100-17. https://www.osti.gov/servlets/purl/1435533.
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@article{osti_1435533,
title = {The dynamics of SIV 2-LTR Circles in the Presence and Absence of CD8+ Cells},
author = {Policicchio, Benjamin B. and Cardozo, Erwing Fabian and Sette, Paola and Xu, Cuiling and Haret-Richter, George and Dunsmore, Tammy and Apetrei, Cristian and Pandrea, Ivona and Ribeiro, Ruy M.},
abstractNote = {CD8+cells play a key role in HIV/SIV infection, but their specific mechanism(s) of action in controlling the virus are unclear. 2-LTR circles are extrachromosomal products generated upon failed integration of HIV/SIV. To understand the specific effects of CD8+cells on infected cells, we analyzed the dynamics of 2-LTR circles in SIVmac251-infected rhesus macaques (RM) treated with an integrase inhibitor (INT). Twenty RMs underwent CD8+cell depletion, received RAL monotherapy or a combination of both. Blood, lymph nodes (LNs) and gut biopsies were routinely sampled. Plasma viral loads (pVLs) and 2-LTR circles from PBMCs and LN lymphocytes were measured with qRT-PCR. In the CD8 depletion group, an ~1 log increase in pVLs and a slow increase in PBMC 2-LTRs occurred following depletion. In the INT group, a strong decline in pVLs upon treatment initiation and no change in 2-LTR levels were observed. In the INT and CD8+cell depletion group, a similar increase in pVLs following CD8 depletion was observed, with a modest decline following INT initiation, and 2-LTR circles significantly increased in PBMCs and LNs. Analyzing the 2-LTR data across all treatment groups with a mathematical model indicates that the data best supports an effect of CD8+cells in killing cells prior to viral integration. Sensitivity analyses of these results confirm that effect, but also allow for additional effects, which the data does not discriminate well. Overall, we show that INT does not significantly increase the levels of 2-LTR circles. However, CD8+cell depletion increases the 2-LTR levels, which are enhanced in the presence of an INT. CD8+T cells play an essential role in controlling HIV and simian immunodeficiency virus (SIV) infection, but the specific mechanisms involved remain poorly understood. Due to failed viral infection, HIV and SIV can form 2-LTR extrachromosomal circles that can be quantified. We present novel data on the dynamics of these 2-LTR forms in a SIV-infected macaque model under three different treatment conditions: depletion of CD8+cells; administration of the integrase inhibitor in a monotherapy, which favors the formation of 2-LTR circles; and combination of the two treatments. We used a new mathematical model to help interpret the data, and the results suggest that CD8+cells exert a killing effect on infected cells prior to virus integration. These results provide new insights into the mechanisms of action of CD8+cells in SIV infection. Here, confirmation of our results would be an important step in understanding immune control of HIV.},
doi = {10.1128/JVI.02100-17},
journal = {Journal of Virology},
issn = {0022-538X},
number = 13,
volume = 92,
place = {United States},
year = {2018},
month = {4}
}
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DOI:  10.1128/JVI.02100-17
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