Feedback meeting September 2017

THANK YOU!! For attending regular study visits For giving blood For sticking with us For spending your evening tonight with us….

HIV attaches to any cell with certain receptors on its surface and inserts virus genetic material into the cells own DNA

ART does not eradicate HIV Circulating virus Antiretroviral therapy reduces the amount of circulating virus to undetectable levels by conventional viral load tests. However, whenever treatment is interrupted, HIV rapidly comes back, indicating that even if it was invisible for months of years, HIV persists during ART. Time HIV persists during ART

Barriers to an HIV cure HIV persistence in tissues Latently infected cells are rare and undistinguishable from uninfected cells Latently infected cells are diverse Eradication strategy should reach tissues Eradication strategy should be specific Eradication strategy should target all infected cells As I briefly mentioned earlier, in addition to T cell survival, proliferation of infected cells is another mechanism by which HIV persists during ART. Several important studies published this year

What is HEATHER trying to do? To find new and better ways to measure the HIV reservoir To understand where the viral reservoir is still detectable (from tissue samples, gut and spinal fluid samples) To understand how quickly viral load responds to immediate ART in acute infection when ART is started straight away To Understand how the immune system responds to early ART To look towards new ways to reduce and remove the viral reservoir cells

No best measure of viral reservoir (low VL; virus alive?) Latent infection Productive infection HIV DNA 2-LTR circles Integrated DNA Infectious Units (IUPM) Cell associated RNA US RNA and MS RNA HIV RNA (SCA) Lewin and Rouzioux, AIDS 2011

To find new and better ways to measure the HIV reservoir New laboratory experiments We know that the measure of blood total HIV DNA is not good enough at predicting whether someone could control virus without ART, we need new tests

To understand where the viral reservoir is still detectable; gut and brain (PET and CSF) PET study brain scans and HIV reservoir

Human immunodeficiency virus (HIV) DNA copy numbers per 106 CD4+ T cells N = 8 HIV+ on ART HIV DNA highest in all 4 Gut biopsy sites compared with blood (5-10x) Ratio RNA/DNA peaked in terminal ileum greater ratio of productive to latently infected cells reflecting ongoing viral replication Human immunodeficiency virus (HIV) DNA copy numbers per 106 CD4+ T cells (A). HIV DNA copy numbers were measured in peripheral blood mononuclear cells (PBMCs) and total gut cells by use of real-time polymerase chain reaction (PCR), normalized to total cell numbers by DNA mass (using a NanoDrop 1000 spectrophotometer) and normalized to CD4+ cells by flow cytometry. Total unspliced HIV RNA levels per 106 CD4+ T cells (B) were measured using quantitative reverse-transcription PCR, normalized to cell numbers by glyceraldehyde phosphate dehydrogenase and normalized to CD4+ cells by flow cytometry. Whiskers represent the maximum and minimum, upper and lower box borders represent the 75th and 25th percentile, respectively, and the horizontal line indicates the median. Steven A. Yukl et al. J Infect Dis. 2010;202:1553-1561

To understand how quickly viral load and viral reservoir responds to immediate ART in acute infection Time on HAART (years) Log HIV DNA copies/million cells

To Understand how the immune system responds to early ART FluAge study, looking at immune responses to Flu vaccine recriuting now!

What are we doing in the UK toward an HIV Cure To look towards new ways to reduce and remove the viral reservoir cells What are we doing in the UK toward an HIV Cure

Principles of reservoir activation ‘Shock and kill’ strategies target the reactivation of latent viruses in the presence of cART to decrease the size of the viral reservoir1 Memory CD4+ T cell Latently infected cell is reactivated Trigger viral reactivation Immune system cART ‘Shock’ ‘Kill’ HIV genome HIV RNA HIV proteins HIV virus particles Dying infected cell Uninfected cell The kinetics of HIV-1 reactivation indicate a 5-h window between transcription and virus release2 HIV-specific CD8+ T-cell responses likely have a short time frame to eliminate residual latently infected CD4+ T cells that become reactivated after discontinuation of ART2 ART, antiretroviral therapy; cART, combined anitiretroviral therapy. 1. Deeks SG. Nature 2012;487:439–40. 2. Walker-Sperling VE, et al. J Virol 2015;89:9631–8.

Immediate standard ART Individual with defined PHI Primary outcome: total proviral DNA in CD4+ cells Secondary outcomes Undetectable viral load Randomisation ARM 1 ARM 2 Vaccines HDACi Immediate standard ART (irrespective of CD4) + integrase inhibitor 24 weeks 16 weeks Study Design Primary outcome Total proviral DNA Secondary outcomes Safety RNA transcripts HIV replication competent assays HIV-specific CD8 killing Immune activation

Funders CHERUB studies Prospective HIV Chemotherapy Cohort Study Put together funders: MRC NIHR BRC, Viiv, GSK, MSD, AmFAR, Guys charity foundation Then below names of clinical studies: HEATHER, RIVER, IVIG, Maraviroc, CHERUByc Chemotherapy, Prospective HIV Chemotherapy Cohort Study IVIG in Primary HIV Infection

IS PHI the best time to move towards an HIV cure? Thanks Community of people living with HIV and Simon Collins, Damien Kelly CHERUB collaboration John Frater Nicholas Chomont RIVER trial management team Funders: MRC, NIHR BRC, AmFAR, Industry partners (MSD, GSK)