HEATHER Feedback Meeting John Thornhill

Sanctuary Sites

Barriers to HIV cure: Tissue reservoirs HIV infects CD4+ cells Dormant memory T cells in lymph nodes and blood2 Various tissues (especially in lymph nodes and gut Major reservoirs Some become resting cells; ‘reservoir’ Most CD4+ T cells infected with HIV die due to the effects of the virus; however, a small sub-set of so-called ‘resting’ memory T cells that harbour the virus persist indefinitely – this is known as latent infection1 Latent HIV infection may also occur in cell populations other than memory CD4+ T cells, including naive CD4+ T cells, tissue macrophages, astrocytes, thymocytes and perhaps haematopoietic progenitor cells2-6 In essence, latency can be defined as ‘the maintenance in the host genome of integrated viral DNA that is replication-competent but transcriptionally silent’1 The inability of the immune system to recognise cells harbouring latent virus and to eliminate cells actively producing virus is the biggest challenge to cure treatments The HIV reservoir is established during primary infection. Early treatment can reduce the total size of the reservoir; however, a stable population of latently infected CD4 cells transits into the long-lived latent reservoir, and is unaffected by early combination ART (cART)1. Cellular reservoirs7: In addition to the CD4+ T cells reservoir in the lymph nodes, there are different cellular reservoirs for different anatomical reservoirs eg. microglia in the CNS. Anatomical reservoirs7,8 GALT is one of the major anatomical reservoirs The lymph nodes, CNS and the blood are also important anatomical reservoirs of latent virus References Deeks SG, et al. Nat Rev Immunol 2012;12(8):607–14. Stebbing J, et al. N Engl J Med 2004;350(18):1872–80. Wightman F, et al. J Infect Dis 2010;202:1738–48. Kitchen SG, Zack JA. J Virol 1997;71:6928–34. Carter CC, et al. Nature Med 2010;16:446–51. Churchill MJ, et al. Ann Neurol 2009;66(2):253–58. Alexaki A, et al. Curr HIV Res 2008;6(5):388–400. Yukl SA, et al. J Infect Dis 2010;202(10):1553–61 Created from Coiras M, et al. Nat Med 2009;7:798–812. 1. Rouzioux C, et al. JID 2005;192:46-55. 2. Deeks SG, et al. Nat Rev Immunol 2012;12(8):607–14

HEATHER gut sub-study Started enrolling in May 2016 20 individuals enrolled 5 people have had 2 biopsies (1 year apart) Aims to look at the Reservoir in the gut How large is it Where is it in the gut Are certain cells more important than others Closed to recruitment

The Size of the Reservoir

The HIV reservoir still very rare Other markers of HIV and the reservoir are important Some of the markers have drugs which target them

Markers than indicate the presence of a reservoir or infected cell are found more often in the gut New Drugs can target some of these flags or markers Might be important for eliminated the reservoir in sanctuary sites like the gut Some of these drugs have side effects and may not be suitable for PLWH HIV CD4 Cell Level of PD-1 is x5 times higher in the gut

Future Work Complete all the biopsies for the HEATHER study See if the reservoir is stable over time Do these markers reflect the reservoir in the gut Look at the gut reservoir in people who have received drugs aimed to reduce the reservoir