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

cure

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

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

HIV Cure Definition Sterilizing cure Functional 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

Cases of post-treatment control and remission

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

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

Strategies to address HIV latency Shock and Kill Use latency-reversing agents eg vorinostat 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

Andrew Phillips Zimbabwe

International AIDS Society

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

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

Thank You