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3-E Gill Street, Woburn, MA 01801, USA Tel: (001) 781-932-6933 Fax (001) 781-932-6865 Web site: www.aphios.com E-

Combination Therapy for Treating HIV Latency Trevor P Castor 1 , Santiago Moreno 2 , Eduardo Munoz 3. ________________________________________________________________________

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3-E Gill Street, Woburn, MA 01801, USA Tel: (001) 781-932-6933 Fax (001) 781-932-6865 Web site: www.aphios.com E-

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  1. Combination Therapy for Treating HIV Latency Trevor P Castor1, Santiago Moreno2, Eduardo Munoz3 ________________________________________________________________________ 1 Aphios Corporation, Woburn, MA, USA; 2Departamento de Biología Celular, Fisiología e Inmunología, Universidad de Córdoba, Facultad de Medicina, Avda de Menéndez Pidal s/n, 14004 Córdoba, Spain; 3Department of Infectious Diseases, Ramon y Cajal Hospital, 28034 Madrid, Spain 3-E Gill Street, Woburn, MA 01801, USA Tel: (001) 781-932-6933 Fax (001) 781-932-6865 Web site: www.aphios.com E-mail: tcastor@aphios.com

  2. Aphios means “Virus-Free” in Greek • CFI virus inactivation technology for enveloped virus such as HIV and nonenveloped viruses such as B19 and EMC to improve the safety of human plasma and recombinant proteins • Molecular flashlight technology for inactivating viruses in red blood cells • HIV therapeutic vaccine using CFI and PNS technologies • HIV therapeutics from marine organisms (10,000+ screens) • APH-0812* (Bryostatin-1) being readied for clinical trial on HIV latency in Spain; initial dosing by IV formulation to be followed by oral dosing of nanoparticle formulation using PNS technology w/wo HDAC inhibitors • *MoisésPérez, AmayaGarcía de Vinuesa, Gonzalo Sanchez-Duffhues, Nieves Marquez, M. Luz Bellido, M. ÁngelesMuñoz-Fernandez, Santiago Moreno, Trevor P. Castor, Marco A. Calzado and Eduardo Muñoz. Bryostatin-1 Synergizes with HistoneDeacetylase Inhibitors to Reactivate HIV-1 from Latency, Current HIV Research, 2010

  3. % Cytoprotection Against HIV-1 versus Concentration and EC50 for Bryostatins and 3TC Bryostatin 1, with an absolute purity > 98.7%, had a Selective Index of 43.56 and an EC50 of 0.026 M versus 0.165 M for 3TC

  4. Bryostatin-1 from Bugula neritina • Trace quantities of bryostatin-1 (~ 5 to 10 ppm) are found in Bugula neritina (bryozoan) • Selective activity against leukemias; directly stimulates bone marrow progenitor cells • Unique and unusual mechanism; may be a modulator of the protein kinase C activity • Phase II clinical trials against melanomas, lymphomas and renal cancers

  5. Internal membranes Bryostatin-1 targets PKCs- C1 domain Anti- tumour activity Activates the NF-kB pathway Activates the ERK pathway C-1 Reactivates HIV-1 pathway

  6. BRYOSTATINS ANTAGONIZE HIV-1 LATENCY Bryostatins 1, 2, 3 and AB antagonize HIV-1 latency in a concentration dependent manner. Jurkat-LAT-GFP cells were stimulated with increasing concentrations of the Bryostatins (x-axis) for 12 h and analyzed by flow cytometry. Results are represented as the percentage (y-axis) of GFP+ cells ± SD of three different experiments. Bryostatins-1, -2 and -3 were equally potent in reactivating HIV-1 from latency (EC50 ~ 10 nM) and Bryostatin-AB was slightly less sensitive (EC50 ~16.7 nM)

  7. 1 µM 0.1 µM Bryostatin BRYOSTATIN REACTIVATES HIV-1 IN HAART-TREATED PATIENTS A) A) #1 #1 #1 300 300 300 300 300 300 #5 #5 #5 Viral copy number Viral copy number Viral copy number 4 4 4 4 4 4 # # # # # # 150 150 150 150 150 150 1 1 1 1 1 1 6 6 6 # # # # # # # # # 3 3 3 3 3 3 # # # # # # 6 6 6 # # # 3 3 3 3 3 3 # # # # # # #5 #5 #5 #1 #1 #1 #2 #2 #2 #3 #3 #3 #4 #4 #4 #5 #5 #5 6 6 6 # # # 4 4 4 4 4 4 2 2 2 2 2 2 # # # # # # 2 2 2 2 2 2 # # # # # # # # # # # # 0 0 0 0 0 0 Control Control Control B) B) #2 #2 #2 #4 #4 #4 1000 1000 1000 #1 #1 #1 #3 #3 #3 #4 #4 #4 750 750 750 #1 #1 #1 Viral copy number Viral copy number Viral copy number 500 500 500 #2 #2 #2 #3 #3 #3 250 250 250 0 0 0 Bryostatin Control Control Control

  8. Conclusions • Bryostatin-1 at 10 nM does not induce IκBα phosphorylation and degradation or JNK activation (signal transduction pathways that may result in negative side effects) but fully reactivates HIV-1 latency • Bryostatin-1 also down-regulates the expression of the human HIV-1 receptors CD4 and CXCR4 and prevents de novo HIV-1 infection as measured by virus-induced cytotoxicity assays (EC50 of 26 nM) • Bryostatin-1 also synergizes with Histone Deacetylases (HDAC) inhibitors (valproic acid and TSA) to antagonise HIV-1 latency, reducing the concentration of Bryostatin-1 to 1 nM • Bryostatin-1 and their derivatives with HDAC inhibitors can be used for the treatment of HIV-1 latency; while HDACis can be used in continuous dosing protocol, Bryostatins can be used in a cyclical dosing protocol

  9. Dr. Trevor P. Castor, PhD, CEO (001) 781-932-6933 tcastor@aphios.com www.aphios.com Proprietary & Confidential

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