About OMICS Group Conferences

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1 About OMICS Group OMICS Group International is an amalgamation of Open Access publications and worldwide international science conferences and events. Established in the year 27 with the sole aim of making the information on Sciences and technology Open Access, OMICS Group publishes 4 online open access scholarly journals in all aspects of Science, Engineering, Management and Technology journals. OMICS Group has been instrumental in taking the knowledge on Science & technology to the doorsteps of ordinary men and women. Research Scholars, Students, Libraries, Educational Institutions, Research centers and the industry are main stakeholders that benefitted greatly from this knowledge dissemination. OMICS Group also organizes 3 International conferences annually across the globe, where knowledge transfer takes place through debates, round table discussions, poster presentations, workshops, symposia and exhibitions.

2 About OMICS Group Conferences OMICS Group International is a pioneer and leading science event organizer, which publishes around 4 open access journals and conducts over 3 Medical, Clinical, Engineering, Life Sciences, Pharma scientific conferences all over the globe annually with the support of more than 1 scientific associations and 3, editorial board members and 3.5 million followers to its credit. OMICS Group has organized 5 conferences, workshops and national symposiums across the major cities including San Francisco, Las Vegas, San Antonio, Omaha, Orlando, Raleigh, Santa Clara, Chicago, Philadelphia, Baltimore, United Kingdom, Valencia, Dubai, Beijing, Hyderabad, Bengaluru and Mumbai.

3 Developmentofaptamerbased HIV-1 entryinhibitorprophylactic drugs Grace London CSIR, Biosciences Emerging Health Technologies Platform Pretoria, South Africa 2 nd International Conference and Exhibition on Pathology

specificity Small in size and fold in 3 D structure (e.

4 Properties of Aptamers Aptamers are antibodies nucleic acids with properties of Generated by simple in vitro process called SELEX High affinity and specificity Small in size and fold in 3 D structure (e.g RNA aptamers) Joubert et al., 21 Resistant to nucleases and chemically stable Low toxicity and non-immunogenic

5 Applications of aptamers Marro et al., 25 Rotherham et al., 212 Rusconi et al., 24 Green et al., 21 Appl. Microbiol. Biotechnol., 25, Nov 11, 1-8

6 Anti-gp12 aptamers as HIV-1 entry inhibitors Apt 1 Apt 2 Apt 1 bind gp12 trimer Apt 2 bind recombinant gp12 Apt = aptamer Khati et al., 23; Cohen et al., 28

7 HIV-1 entry and inhibitors HIV HIV gp41 gp12 CCR5 CXCR4 gp12- CD4 receptor binding CD4 gp12 Co-receptor binding gp41 Mediated Fusion HIV Host Cell Pierson and Doms., Current Top Microbiol Immunol (23) 281 pp 1-27

8 Outline of the study 1. Evaluate efficacy of anti-gp12 aptamer subtype C 2. Test toxicity 3. Map aptatope s HIV-1 on 4. Tes t gp12 synergy with other entry inhibitors agains t HIV- 1

Aptamers inhibit entry of HIV-1 subtype C Env pseudoviruses Aptamer IC 5 Env clone Stages of disease Geographic location Apt 1 Apt 2 CAP45.2..G3 Acute/early S.Africa 2.6.3 ZM233M.

9 Aptamers inhibit entry of HIV-1 subtype C Env pseudoviruses Aptamer IC 5 Env clone Stages of disease Geographic location Apt 1 Apt 2 CAP45.2..G3 Acute/early S.Africa ZM233M.PB6 Acute/early Zambia ZM249M.PL1 Acute/early Zambia >5.6 ZM53M.PB12 Acute/early Zambia ZM19F.PB4 Acute/early Zambia 14.1 >5 ZM197M.PB7 Acute/early Zambia CAP21.2.E8 Acute/early S.Africa ZM135M.PL1a Acute/early Zambia 2.8 NT ZM214M.PL5 Acute/early Zambia DU Acute/early S.Africa DU Acute/early S.Africa DU422.1 Acute/early S.Africa >5.3 CAP8.2..F6 Acute/early S.Africa CAP61.2..F1 Acute/early S.Africa.3.4 CAP63.2..A9J Acute/early S.Africa CAP J Acute/early S.Africa 29.1 >5 CAP J Acute/early S.Africa CAP G3J Acute/early S.Africa RP1.12* Acute/early S.Africa RP4.3 Acute/early S.Africa >5.5 COT6.15 Chronic S.Africa.9 >5 COT9.6 Chronic S.Africa 6.1 >5 DU151.2 Acute/early S.Africa >5 >5 DU123.6 Acute/early S.Africa >5 >5 Conc Acute/early S.Africa 5.1 CAP Acute/early S.Africa CAP26.2..E8 Acute/early S.Africa CAP D3 Acute/early S.Africa RP6.6 Acute/early S.Africa CAP88.2..B6J Acute/early S.Africa IN Acute/early India 18.2 NT IN Acute/early India.2 NT 5 nm = No inhibition NT = Not titred * viruses using CXCR4 coreceptor Apt 1 = inhibited 84 % viruses Mean IC ± 8.1 nm Apt 2 = inhibited 79 % viruses Mean IC 5.4 ±.3 nm % viruses neutralized 84% 79% Mean IC 5 (nm) 6.6 ± ±.3

10 Aptamers inhibit entry of PBMC HIV-1 subtype C Virus control Apt 2 Aptamer[nM] Aptamer][nM] Mean IC 8 in PMBC = 8 ± 11.8 nm Aptamer[nM] Aptamer [nm]

11 Aptamers subtype inhibit entry of HIV-1 C in Macrophages Du422 IC 8 = 6 Du42 nm IC2 8 = 6 nm COT9 IC 8 = 29 COT nm IC 8 9 = 29 nm UCLA1 (nm) Virus 5. Du422 COT *** p Control < IC NS 8 = 6 nm IC 8 9= 29 nmvir UCLA1.1 * u p s 1 (nm) <C o. n t 5 rol 5. IC NS: not NS 2 significant UCLA1 Virus control (nm) 1 *** p <.1 Virus Apt 2Control )l * p < 2.. m *** p < CoNnStr NS: not * p <.5 Control significant Apt UCLA1 (nm) ol Aptamer [nm] NS: not significant amer [nm] UCLA1 (nm) Contr ADA 1 SW ol Control P24 (ngpm24l)(ngml) P24 (ngml) p24 (ng/ml) p24 (ng/ml) IUCC8LA=12( UCIC L8A1 = (n 3 M ) n6mn) SW11 M nmada3. IC 8 4 = 26 U n C M LA1 IC 6 UCLA1 (nm) (nm) 8 = nm 3 4 IC ADA 8 SW14 = 26 nm 2 IC IC 8 8 = 3 nm Control p24 (ng/ml)p24 (ng/ml) ntrol 1 Co Control UCLA1 (nm) 1 UCLA1 2 (nm) Contr ol Contro l AptaUmCeLrA[n1M(n]M) er[nm] p24 (ng/ml) UCLA1 (nm) p24 (ng/ml) p24 (ng/ml) p24 (ng/ p24 (ng/ml) Control AptamU CLA1 (nm) UCLA1 (nm) Control Control Mean IC 8 in MDM = 23 ± 1.4 nm

12 Aptamers exhibit no cytotoxicity TZM-bl MTS based-assay PBMC MTS based-assay 1 1 % Cell Viability % Cell Viability 2 2

13 Aptamers interact with conserved residues on gp12 Aptamers bind to amino acids within the coreceptor (CoRbs) CCR5 binding site Mufhandu, H et al., J. Virol.(212,)86(9), pp. 4989

14 Synergy of aptamers with inhibitors HIV-1 entry Du156 T2 ZM249 T2 1 1 U A C p L t A T b 2 1 % inhibition Du156 T ZM249 T 2 2 UACpLtA21 TT22 UCLA1+T2 UCLA1 T2 %%inihnibhiit % bioint I i n o h n i Du172 b µm Lo 2 g 5 Synergism :CI=.3.9 Antagonism:CI=>1.1 SW7 b UCLA1+b12 UCLA1 b UCLA1+b12 Apt 2 + b12 UCLA1 Apt T b bition Du172 b12 µm (Log)( SW7 b µm (Log)

15 Summary agains t Antigp12 subtype C isolates( A s concentration efficacious in RN aptamer are nanomolar) HIV- 1 They interact with conserved residues on gp12, delay virus resistance Not toxic in different cell types Synergy with other entry inhibitors, combination therapy with other drugs Anti-gp12 aptamers can be developed as entry inhibitor drugs

Acknowledgements Collaborators NICD (Lynn

Institute, USA (Dennis Burton) Reagents Los

16 Acknowledgements Collaborators NICD (Lynn Morris) UKZN (Alexander Pym) UCT & GSH (B. Mayosi) University of Oxford, UK (William James) Funding The Scripps Research Institute, USA (Dennis Burton) Reagents Los Alamos National Lab, USA (Basil I Swanson) IAVI NIH AIDS Reagents

17 Let Us Meet Again We welcome you all to our future conferences of OMICS Group International Please Visit:

About OMICS Group Conferences

About OMICS Group Conferences About OMICS Group OMICS Group International is an amalgamation of Open Access publications and worldwide international science conferences and events. Established in the year 2007 with the sole aim of