Procyanidin trimer C1 derived from Theobroma cacao reactivates latent human immunodeficiency virus type 1 provirus.
Despite remarkable advances in combination antiretroviral therapy (cART), human immunodeficiency virus type 1 (HIV-1) infection remains incurable due to the incomplete elimination of the replication-competent virus, which persists in latent reservoirs. Strategies for targeting HIV reservoirs for eradication that involves reactivation of latent proviruses while protecting uninfected cells by cART are urgently needed for cure of HIV infection. We screened medicinal plant extracts for compounds that could reactivate the latent HIV-1 provirus and identified a procyanidin trimer C1 derived from Theobroma cacao as a potent activator of the provirus in human T cells latently infected with HIV-1. This reactivation largely depends on the NF-κB and MAPK signaling pathways because either overexpression of a super-repressor form of IκBα or pretreatment with a MEK inhibitor U0126 diminished provirus reactivation by C1. A pan-PKC inhibitor significantly blocked the phorbol ester-induced but not the C1-induced HIV-1 reactivation. Although C1-induced viral gene expression persisted for as long as 48 h post-stimulation, NF-κB-dependent transcription peaked at 12 h post-stimulation and then quickly declined, suggesting Tat-mediated self-sustainment of HIV-1 expression. These results suggest that procyanidin C1 trimer is a potential compound for reactivation of latent HIV-1 reservoirs.
Tokyo Medical and Dental University, Japan.
Takanori
T
Hori
Noguchi Memorial Institute for Medical Research, Ghana.
Jacob
J
Barnor
Nagasaki International University, Japan.
Tung
T
Nguyen Huu
Nagasaki International University, Japan.
Osamu
O
Morinaga
Tokyo Medical and Dental University, Japan.
Akiko
A
Hamano
Tokyo Medical and Dental University, Japan; Noguchi Memorial Institute for Medical Research, Ghana.
Jerry
J
Ndzinu
Noguchi Memorial Institute for Medical Research, Ghana.
Angela
A
Frimpong
Noguchi Memorial Institute for Medical Research, Ghana.
Keren
K
Minta-Asare
Noguchi Memorial Institute for Medical Research, Ghana.
Mildred
M
Amoa-Bosompem
Noguchi Memorial Institute for Medical Research, Ghana.
James
J
Brandful
Noguchi Memorial Institute for Medical Research, Ghana.
John
J
Odoom
Noguchi Memorial Institute for Medical Research, Ghana.
Joseph
J
Bonney
Noguchi Memorial Institute for Medical Research, Ghana.
Isaac
I
Tuffour
Noguchi Memorial Institute for Medical Research, Ghana.
Baffour-Awuah
BA
Owusu
Noguchi Memorial Institute for Medical Research, Ghana.
Mark
M
Ofosuhene
Noguchi Memorial Institute for Medical Research, Ghana.
Philip
P
Atchoglo
Centre for Plant Medicine Research, Ghana.
Maxwell
M
Sakyiamah
Centre for Plant Medicine Research, Ghana.
Richard
R
Adegle
Noguchi Memorial Institute for Medical Research, Ghana.
Regina
R
Appiah-Opong
Noguchi Memorial Institute for Medical Research, Ghana.
William
W
Ampofo
Tokyo Medical and Dental University, Japan.
Kwadwo
K
Koram
Noguchi Memorial Institute for Medical Research, Ghana.
Alexander
A
Nyarko
Centre for Plant Medicine Research, Ghana.
Laud
L
Okine
Centre for Plant Medicine Research, Ghana.
Dominic
D
Edoh
Centre for Plant Medicine Research, Ghana.
Alfred
A
Appiah
Nagasaki International University, Japan.
Takuhiro
T
Uto
Tokyo Medical and Dental University, Japan.
Yoshiyuki
Y
Yoshinaka
Tokyo Medical and Dental University, Japan.
Shin
S
Uota
Nagasaki International University, Japan.
Yukihiro
Y
Shoyama
Tokyo Medical and Dental University, Japan. Electronic address: shojmmb@tmd.ac.jp.
Shoji
S
Yamaoka
D044946:Biflavonoids / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002099:Cacao / Q000737:chemistry*; D002392:Catechin / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D002460:Cell Line; D015658:HIV Infections / Q000188:drug therapy / Q000378:metabolism / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D019169:Jurkat Cells; D020935:MAP Kinase Signaling System; D008301:Maleimides / Q000494:pharmacology; D008826:Microbial Sensitivity Tests; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D008517:Phytotherapy; D010946:Plants, Medicinal / Q000737:chemistry; D044945:Proanthocyanidins / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011533:Proviruses / Q000187:drug effects* / Q000502:physiology; D014775:Virus Activation / Q000187:drug effects*; D017735:Virus Latency / Q000187:drug effects
C465664:2-(1-(3-dimethylaminopropyl)-5-methoxyindol-3-yl)-3-(1H-indol-3-yl)maleimide; D044946:Biflavonoids; D007211:Indoles; D008301:Maleimides; D016328:NF-kappa B; D044945:Proanthocyanidins; D047428:Protein Kinase Inhibitors; C479583:procyanidin C; D002392:Catechin; D011493:Protein Kinase C
HIV; Latency; Procyanidin; Reactivation