Hydroxytyrosol: a new class of microbicide displaying broad anti-HIV-1 activity.
To investigate the toxicity and activity against HIV of 5-hydroxytyrosol as a potential microbicide.



The anti-HIV-1 activity of 5-hydroxytyrosol, a polyphenolic compound, was tested against wild-type HIV-1 and viral clones resistant to nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors and integrase inhibitors. In addition to its activity against founder viruses, different viral subtypes and potential synergy with tenofovir disoproxil fumarate, lamivudine and emtricitabine was also tested. 5-Hydroxytyrosol toxicity was evaluated in vivo in rabbit vaginal mucosa.



We have cloned pol gene from drug-resistant HIV-1 isolated from infected patients and env gene from Fiebeg III/IV patients or A, C, D, E, F and G subtypes in the NL4.3-Ren backbone. 5-Hydroxytyrosol anti-HIV-1 activity was evaluated in infections of MT-2, U87-CCR5 or peripheral blood mononuclear cells preactivated with phytohemagglutinin + interleukin-2 with viruses obtained through 293T transfections. Inhibitory concentration 50% and cytotoxic concentration 50% were calculated. Synergy was analysed according to Chou and Talalay method. In-vivo toxicity was evaluated for 14 days in rabbit vaginal mucosa.



5-Hydroxytyrosol inhibited HIV-1 infections of recombinant or wild-type viruses in all the target cells tested. Moreover, 5-hydroxytyrosol showed similar inhibitory concentration 50% values for infections with NRTIs, NNRTIs, protease inhibitors and INIs resistant viruses; founder viruses and all the subtypes tested. Combination of 5-hydroxytyrosol with tenofovir was found to be synergistic, whereas it was additive with lamivudine and emtricitabine. In-vivo toxicity of 5-hydroxytyrosol was very low even at the highest tested doses.



5-Hydroxytyrosol displayed a broad anti-HIV-1 activity in different cells systems in the absent of in-vivo toxicity, therefore supporting its candidacy as a potential new class of microbicides.
aAIDS Immunopathology Department, National Centre of Microbiology, Instituto de Salud Carlos III bPharmacology Department, Pharmacy Faculty, Universidad Complutense de Madrid cSeprox Biotech, Madrid, Spain.
Luis M
LM
Bedoya
Manuela
M
Beltrán
Patricia
P
Obregón-Calderón
Javier
J
García-Pérez
Humberto E
HE
de la Torre
Nuria
N
González
Mayte
M
Pérez-Olmeda
David
D
Auñón
Laura
L
Capa
Eduardo
E
Gómez-Acebo
José
J
Alcamí
D000818:Animals; D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D002478:Cells, Cultured; D004357:Drug Synergism; D005260:Female; D015497:HIV-1 / Q000187:drug effects*; D006802:Human Activities; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008826:Microbial Sensitivity Tests; D010626:Phenylethyl Alcohol / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology; D011817:Rabbits
D000890:Anti-Infective Agents; C005975:3,4-dihydroxyphenylethanol; D010626:Phenylethyl Alcohol
Lancet Infect Dis. 2014 Sep;14(9):820-9
25065857
Biochem Pharmacol. 2014 Jul 1;90(1):25-33
24727461
Science. 2010 Sep 3;329(5996):1168-74
20643915
J Virol. 1986 Aug;59(2):284-91
3016298
J Nutr Biochem. 2015 Apr;26(4):360-8
25620693
BMC Complement Altern Med. 2015 Mar 10;15:52
25879228
Proc Natl Acad Sci U S A. 2013 Apr 23;110(17):6626-33
23542380
PLoS Pathog. 2014 Jul 17;10(7):e1004146
25033082
Hum Reprod. 2014 Feb;29(2):242-52
24291662
Chembiochem. 2009 Jul 20;10(11):1806-9
19565596
J Med Virol. 2009 Feb;81(2):211-6
19107982
HIV Med. 2008 Mar;9(3):160-71
18217999
PLoS One. 2009;4(2):e4505
19229336
Clin Infect Dis. 2015 Nov 15;61(10 ):1601-3
26334052
N Engl J Med. 2015 Feb 5;372(6):509-18
25651245
N Engl J Med. 2011 Aug 11;365(6):493-505
21767103
N Engl J Med. 2010 Dec 30;363(27):2587-99
21091279
J Med Virol. 2007 Feb;79(2):127-37
17177310
J Antimicrob Chemother. 2010 Dec;65(12):2493-501
20947622
Mol Nutr Food Res. 2010 Jun;54(6):788-96
20024934
Biochem Biophys Res Commun. 2007 Mar 23;354(4):879-84
17261269
AIDS Res Hum Retroviruses. 2010 Sep;26(9):1019-25
20707647
Front Nutr. 2014 Oct 27;1:18
25988120
FEBS Lett. 2007 Jun 12;581(14):2737-42
17537437
Biochem Biophys Res Commun. 2007 Mar 23;354(4):872-8
17275783
AIDS. 2003 Sep 5;17(13):1871-9
12960819
Cell. 2000 Mar 3;100(5):587-97
10721995