1. Feedback meeting September 2017

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

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

4. 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

5. 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

6. 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

7. 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

8. 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

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

10. 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:

11. 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

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

13. 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

14. 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– Walker-Sperling VE, et al. J Virol 2015;89:9631–8.

15. 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

16. 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

17. 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)