State of HIV Cure Research

1. State of HIV Cure Research Prof JG Hakim, Parirenyatwa CRS Leader Annual Research Day; 5th May 2017

3. cure

4. ART Success • Potentially 37 million need ART • 18 million are on ART • ART can effectively control HIV replication • Prevents development of AIDS • Prolongs life • Reduces HIV transmission risk

5. Limitations of current ART • Operational & logistical challenges of delivering life-long ART to 37 million people • Economic cost of this strategy is unsustainable • Life long adherence is a problem • ART drug resistance is a challenge • Drug toxicities are of concern • Persistent immune dysfunction have health consequences

6. HIV Cure Definition • Sterilizing cure • Complete eradication in an individual of all replication competent HIV • Challenging to achieve • Impossible to prove • Functional cure • Long-term remission • Long-term undetectable viraemia for some as yet undefined period without ART

7. Cases of post-treatment control and remission

8. Latency • Major barrier to curing HIV • Persistence of integrated viral DNA that is replication competent but transcriptionally silent. • HIV persist primarily as a latent genome in long-lived memory CD4+ T cells and to a lesser degree in naïve CD4+ T cells • Sanctuary sites • Lymph nodes, gut • Spleen, brain, genital tract, thymus • HIV persistence on ART may be influenced by; • Host genetics, age, gender, co-morbidities, co-infections, HIV disease progression state, microbiome

9. Mechanisms that maintain HIV latency in resting CD4 T+ cells Viral blocks in latently infected cells • Integration • Epigenetic silencing • Lack of cellular transcription factors • Incomplete elongation of Transcripts • Nuclear retention of transcripts • Micro RNAs limiting of viral proteins

14. Strategies to address HIV latency • Shock and Kill • Use latency-reversing agents egvorinostat and panobinostat • Permanently silence HIV provirus • Fully and irreversibly suppress HIV transcription-permanent silencing and lack of virus production when ART is discontinued • Enhancing capacity of the immune system to clear or control HIV • Active elimination of infected cells or control HIV persistence by T cells, antibodies, NK cells and/or macrophages • Broadly neutralizing antibodies may play a part • Therapies to reverse chronic inflammation • Enhance T cell function, reduce T cell proliferation, reduce virion production

15. Andrew Phillips Zimbabwe

19. International AIDS Society

20. Conclusion • There is need to control the HIV virus in the absence of ART: • ie HIV cure • Considerable progress has been made in the science that will underpin HIV cure • Most studies are animal studies and phase 1 and early phase 2 studies • It is important to ensure that HIV cure approach includes other considerations: • Ethical • Social science • behavioural • There remain important knowledge gaps and research questions but there is vigorous research in this area

21. Acknowledgements • Steve Deeks-slides, publications, leadership • Andrew Phillips • Antony Fauci • International AIDS Society • amfAR • Etc. • UZ-UCSF • Study Participants • EC • Senior staff • Staff • PariCRS

22. Thank You