PMID- 20942961
OWN - NLM
STAT- MEDLINE
DCOM- 20101201
LR  - 20211020
IS  - 1743-422X (Electronic)
IS  - 1743-422X (Linking)
VI  - 7
DP  - 2010 Oct 13
TI  - Cell line-dependent variability in HIV activation employing DNMT inhibitors.
PG  - 266
LID - 10.1186/1743-422X-7-266 [doi]
AB  - Long-lived reservoirs of Human Immunodeficiency Virus (HIV) latently infected 
      cells present the main barrier to a cure for HIV infection. Much interest has 
      focused on identifying strategies to activate HIV, which would be used together 
      with antiretrovirals to attack reservoirs. Several HIV activating agents, 
      including Tumor Necrosis Factor alpha (TNFalpha) and other agents that activate via 
      NF-kB are not fully effective in all latent infection models due to epigenetic 
      restrictions, such as DNA methylation and the state of histone acetylation. DNA 
      methyltransferases (DNMT) inhibitors like 5-aza-2'deoxycytidine (Aza-CdR) and 
      histone deacetylase (HDAC) inhibitors like Trichostatin A (TSA) have been 
      proposed as agents to enhance reactivation and have shown activity in model 
      systems. However, it is not clear how the activities of DNMT and HDAC inhibitors 
      range across different latently infected cell lines, potential models for the 
      many different latently infected cells within an HIV patient. We determined HIV 
      activation following treatment with TNFalpha, TSA and Aza-CdR across a range of well 
      known latently infected cell lines. We assessed the activity of these compounds 
      in four different Jurkat T cell-derived J-Lat cell lines (6.3, 8.4, 9.2 and 
      10.6), which have a latent HIV provirus in which GFP replaces Nef coding 
      sequence, and ACH-2 and J1.1 (T cell-derived), and U1 (promonocyte-derived) cell 
      lines with full-length provirus. We found that Aza-CdR plus TNFalpha activated HIV at 
      least twice as well as TNFalpha alone for almost all J-Lat cells, as previously 
      described, but not for J-Lat 10.6, in which TNFalpha plus Aza-CdR moderately 
      decreased activation compared to TNFalpha alone. Surprisingly, a much greater 
      reduction of TNFalpha-stimulated activation with Aza-CdR was detected for ACH-2, J1.1 
      and U1 cells. Reaching the highest reduction in U1 cells with a 75% reduction. 
      Interestingly, Aza-CdR not only decreased TNFalpha induction of HIV expression in 
      certain cell lines, but also decreased activation by TSA. Since DNMT inhibitors 
      reduce the activity of provirus activators in some HIV latently infected cell 
      lines the use of epigenetic modifying agents may need to be carefully optimized 
      if they are to find clinical utility in therapies aimed at attacking latent HIV 
      reservoirs.
FAU - Fernandez, Guerau
AU  - Fernandez G
AD  - Center for Cancer and Immunology Research, Children's Research Institute, 
      Children's National Medical Center, Washington, DC, USA.
FAU - Zeichner, Steven L
AU  - Zeichner SL
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20101013
PL  - England
TA  - Virol J
JT  - Virology journal
JID - 101231645
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (Hydroxamic Acids)
RN  - 0 (Tumor Necrosis Factor-alpha)
RN  - 147336-22-9 (Green Fluorescent Proteins)
RN  - 3X2S926L3Z (trichostatin A)
RN  - 776B62CQ27 (Decitabine)
RN  - EC 2.1.1.- (DNA Modification Methylases)
RN  - M801H13NRU (Azacitidine)
SB  - IM
MH  - Azacitidine/analogs & derivatives/pharmacology
MH  - DNA Modification Methylases/*antagonists & inhibitors
MH  - Decitabine
MH  - Enzyme Inhibitors/*pharmacology
MH  - Genes, Reporter
MH  - Green Fluorescent Proteins/genetics/metabolism
MH  - HIV/*growth & development
MH  - Humans
MH  - Hydroxamic Acids/pharmacology
MH  - Jurkat Cells
MH  - Tumor Necrosis Factor-alpha/pharmacology
MH  - *Virus Activation
MH  - Virus Latency/*drug effects
PMC - PMC2964676
EDAT- 2010/10/15 06:00
MHDA- 2010/12/14 06:00
PMCR- 2010/10/13
CRDT- 2010/10/15 06:00
PHST- 2010/06/30 00:00 [received]
PHST- 2010/10/13 00:00 [accepted]
PHST- 2010/10/15 06:00 [entrez]
PHST- 2010/10/15 06:00 [pubmed]
PHST- 2010/12/14 06:00 [medline]
PHST- 2010/10/13 00:00 [pmc-release]
AID - 1743-422X-7-266 [pii]
AID - 10.1186/1743-422X-7-266 [doi]
PST - epublish
SO  - Virol J. 2010 Oct 13;7:266. doi: 10.1186/1743-422X-7-266.