1. Interventions to Reduce Immune Activation
Professor Olivier Lambotte
Department of Clinical Immunology
Hôpital Bicêtre
ImVA Inserm/CEA U1184
Université Paris Sud

2. Conflict of Interest
BMS
MSD
Astra Zeneca
Janssen

3. Immune Activation is persistent in patients on combined ART
%38+DR+
HDs
ART-treated patients
Viremic patients
0.007
0.001
<0.0001
Hunt et al JID 2003, Noel et al AIDS 2014

4. Immune Activation has numerous consequences
Cardiovascular diseases
Loss of CD4 T cells
Fibrosis of the lymphoid tissue
Cancer
Incomplete immune reconstitution on ART
Immune Activation
Neurocognitive impairment, and …
Hunt et al. JID 2008
Osteopenia
Duprez DA, PLoS One 2012
Borges AH, AIDS 2013

5. Immune Activation is a pathologic process shared by different diseases with the same consequences
HIV infection
Cancer
Auto-immune diseases
Similar therapeutic interventions ?

6. Persistent Immune Activation on ART has numerous sources
HIV Persistence and HIV proteins
Microbial Translocation
Loss of Th17 and Th dysregulation
Immune Activation
Co-infections B/C, CMV
CD4 T cell depletion
Sexually Transmitted Infections
Activation of IFN type I pathway
Ageing, Tabacco…
Impact of HIV and ART on metabolism

7. What is the best target? Immune Activation
HIV Persistence and HIV proteins
Microbial Translocation
Loss of Th17 and Th dysregulation
Immune Activation
Co-infections B/C, CMV
CD4 T cell depletion
Sexually Transmitted Infections
Activation of IFN type I pathway
Ageing, Tabacco…
Impact of HIV and ART on metabolism

8. 1 - Intervention on viral persistence
HIV Persistence and HIV proteins
Immune Activation
HIV persists in HIV reservoirs despite cART
Different CD4 T cell subsets are latently infected with infectious virus
TCM > TTM > TEM > Tnaive > Tscm (Lambotte et al, AIDS 2002, Chomont et al. Nat Med 2009, Buzon et al Nat Med 2014)
HIV persists in TISSUES despite cART
In lymphoid tissues: infected Tfh (Banga et al. Nat Med 2016)
In non-lymphoid tissues, infected CD4 T cells and macrophages in the gut, the genital tract, the adipose tissue, or the brain (Chun et al JID 2008, Yukl et al. JID 2013, Damouche et al. Plos Pathogen 2015, Lamers et al. Infect Genet Evol 2011, Deleage et al; Am J Pathol 2011)
Positive correlation between % infected CD4 T cells and % activated CD4+ DR+ T cells (Cockerham et al. Plos One 2014)
Activated CD4 T cells expressing PD-1 and immune check-points are enriched with HIV-infected cells (Chomont et al. Nat Med 2009, Fromentin et al. Plos Pathogen 2016)
Impact of HIV proteins as Nef on the immune activation (Schindler et al. 2006)
= HIV persistence is tightly associated with immune activation
Image HIV

9. 1 - Intervention on viral persistence
HIV Persistence and HIV proteins
Immune Activation
The lymphocyte HIV reservoirs persist via several mechanisms
Long Half-life of reservoir cells (Finzi et al Nat Med 1999)
Homeostatic cell proliferation (Hosmane et al. JEM 2017, Chomont et al. Nat Med 2009)
Inefficiency of HIV-specific CD8 T cells to reduce the number of infected cells (ex: the difficulty for HIV-specific CD8 T cells to gain access to Tfh in germinal centers (Fukazawa et al Nat Med 2015))
Insufficient drug bioavailability favoring residual replication (Fletcher et al. PNAS 2014, Lorenzo-Redondo et al. Nature 2016)

10. 1 - Intervention on viral persistence
HIV Persistence and HIV proteins
Immune Activation
Possible interventions on these mechanisms
Long Half-life: Latency Reversing Agents strategies (review in Margolis et al. JID 2017)
Homeostatic cell proliferation: mTOR inhibitors (Stock et al. Am J Transplant ), anti-bcl2 as venetoclax (Cummins et al. JVirol 2017)
Inefficiency of HIV-specific CD8 T cells to reduce the number of infected cells: boost anti-viral immunity with anti-PD1… (review in Velu et al. Retrovirology 2015)
Residual viral replication:
Develop long-acting antiretroviral drugs with excellent bioavailability
Use broadly neutralizing antibodies (Lu et al. Nature 2016…)
Add ref

11. 1 - Intervention on viral persistence and other settings
Immune Activation
HIV persistence and HIV proteins
Possible interventions with known drugs++
Long Half-life: Latency Reversing Agents strategies ONCOLOGY
Homeostatic cell proliferation:
mTOR inhibitors = TRANSPLANTATION / ONCOLOGY
anti-bcl2 as venetoclax ONCOLOGY
Inefficiency of HIV-specific CD8 T cells to reduce the number of infected cells: boost anti-viral immunity with anti-PD1… ONCOLOGY

12. 2 - Intervention on microbial translocation in HIV infection
Loss of Th17 and Th dysregulation
Early loss of Th17 in the gut mucosa (Lederman et al. JID 2011, Li et al. Nature 2005)
Loss of Innate lymphoid cells (Kloverpris et al. Immunity 2016)
Loss of MAIT cells (Cosgrove et al. Blood 2013)
Profound modification of the microbiome (Dillon et al. Mucosal Immunol 2014)
Excess of IDO leads to suppressive activity on Th17 cells (Favre et al. Sci Transl Med 2010)
→ Translocation of microbial products + chronic inflammation of the mucosa = activation of innate immune cells (monocytes/Macrophages) and lymphoid cells

13. 2 - Intervention on microbial translocation in HIV infection
Loss of Th17 and Th dysregulation
Interventions are possible
Early ART has allowed partial restoration of Th17 in gut (Schuetz et al. Plos Path 2014)
Use of therapeutic probiotics could be useful as Fecal Microbiota Transplantation (reviewed in Mudd et al. JID 2016)
Use of IL-21 has showed a restoration of IL17-producing cells (Micci et al. JCI 2015)
Use of anti-PD1(Shetty et al. JCI 2012)
To test: IFNa a target? It could be involved in loss of innate lymphoid cells (Zhang et al. JCI 2015)
To test: Use of IDO inhibitors

14. 2 - Intervention on microbial translocation in other settings
Loss of Th17 and Th dysregulation
Use of therapeutic probiotics in intestinal bowel diseases
Fecal Microbiota Transplantation is a key treatment in the refractory Clostridium Difficile infection
Use of IDO inhibitors: several phases I in cancer (Beatty G et al. Clin Cancer Research 2017)

15. 3 - Intervention on CD4 T cell depletion
CD4 T cell depletion is associated with immune activation from various mechanisms (Hunt et al. JID 2016)
CD4 T cell depletion in HIV is associated with fibrosis of lymphoid organs (Sanchez et al. JID 2015)
CD4 T cell depletion is associated with low number of stem cells (Sauce et al. Blood 2011)
Interventions are possible
Antifibrotic agents as Angiotensin Converting Enzyme inhibitors and Angiotensin Receptor Antagonists
IL-7 (Janus)
Add ref

16. 4 - Intervention on IFN type 1 pathway
Activation of IFN type I pathway
Janus role of the IFN-I pathway…
Good in Primary infection but a sustained IFN-I signature is deleterious in the long term
Role in CD4 T cell depletion
Add ref
Sandler et al. Nature 2014, Jacquelin et al. JCI 2009, Freeman et al. JID 2016;

17. 4 - Intervention on IFN type 1 pathway
Activation of IFN type I pathway
Janus role of the IFN-I pathway: good in primary infection but deleterious in the long term
Some interventions are possible but « touchy »…
Hydroxychloroquine, chloroquine (Piconi et al. Blood 2015)
IFNR2 et IFNAR blockade
in Hu-mice (Cheng et al. JCI 2017, Zhen et al. JCI 2017)
delayed HIV rebound
decrease HIV DNA
Ruxolitinib
(JAK1/JAK2 inhibitor)

18. 4 - Intervention on IFN type 1 pathway
Activation of IFN type I pathway
IFN type 1 pathway is involved in auto-immune diseases such as Systemic Lupus Erythematosus
Some interventions are effective
Hydroxychloroquine is a major treatment in LUPUS
IFN blockade (IFN or IFNAR) is a promising treatment in LUPUS
Ruxolitinib is the treatment of myeloproliferative disorders (FDA EMA AMM approval)

19. 5 - Intervention on METABOLISM ↔ on adipose tissue
Impact of HIV and ART on metabolism
Pro-inflammatory effect of HIV proteins (vpr, nef)
HIV-Infected CD4 T cells and macrophages
Direct proinflammatory impact of NRTI and protease inhibitors
Microbial translocation
Production of inflammatory cytokines, Leptine
Anti-inflammatory Pro-inflammatory
Giralt et al, Clinical endocrinology and metabolism, 2011, Caron-Debarle at al- Trends mol med, 2010, Damouche et al. Plos Pathogen 2015

20. 5 - Intervention on metabolism and the immune system: the statins
Anti-inflammatory action (on T cells and inflammatory cytokines) well-evidenced in cardiology (Arnaud et al. Trends Cardio Med 2005, Mira et al. JI 2008)
Large use in medicine with a well-known safety profile
A large number of clinical trials in HIV infection as the SATURN trial
Phase 3 trial, rosuvastatin (10mg/d) significantly reduced monocyte activation at W24 and T cell activation at W52
Do exercise and get a normal BMI!
Funderburg et al. JAIDS 2015, Longenecker C et al. CID 2014

21. 6 - Intervention on co-infections: easy?
YES!
Immune Activation
Co-infections B/C, CMV
Sexually Transmitted Infections
Sexually transmitted infections as HSV drive local and systemic inflammation
HCV and HBV co-infections are associated with a chronic inflammation
Intervention is « easy »: DETECT and TREAT these infections then AVOID re-infection…

22. 6 - Intervention on co-infections: easy?
Immune Activation
Co-infections B/C, CMV
Sexually Transmitted Infections
CMV is another story…
Intervention is difficult: valganciclovir and long-term treatment with well-tolerated new anti-CMV drugs…
Hunt et al. JID 2011, Gianella S et al. JID 2016

23. 7 - Intervention on lifestyle
Immune Activation
LIFESTYLE
Malnutrition and Obesity are associated with immune activation: food assistance / Weight loss with exercise programs
Treat co-morbidities (diabetes, dyslipidemia…)
Smoking is associated with immune activation (Gonçalves et al. Inflam Res 2011)
Alcool abuse can lead to liver cirrhosis with increase of microbial translocation (Schnabl et al. Gastroenterology 2014)
Metamphetamine use (Salamanca et al. Front Neurosci 2015)
Intervention seems logical but not so easy for the patient
Add ref

24. How to put these interventions into practice…
Lifestyle
Do physical exercice, stop smoking
Treat other infections
HCV, HBV, STI, be vaccinated against S pneumoniae, Flu…
Optimize your cART
Start ART early, prefer anti-integrase and NNRTI ?, no viral blip, avoid drug interactions which could decrease the ARV concentrations…
Optimize your adipose tissue and your lipid profile
Have a normal BMI, use of statin and if necessary, low dose aspirin
Optimize your gut
Trials with probiotics, IL-21…
Try to reduce IFN-I signature
Trials with anti-IFNAR,…
Try to reduce HIV reservoirs
Trials with LRA, bNAbs, immune checkpoints inhibitors, mTORi, anti-fibrotic agents…

25. Conclusion
The combination of these strategies is mandatory to act on different actors of immune activation
Reduction of immune activation is inseparable from reduction of HIV reservoirs
Reduction of immune activation is a major objective in “HIV cure” strategies and in the improvement of the care of HIV-infected patients

26. Interventions to reduce Immune Activation in patients on cART
The future
The reality
The dream

27. Intervention to reduce Immune Activation in patients on cART
The end… Thank you!

28. Intervention on viral replication
HIV Replication and HIV proteins
Immune Activation
HIV persists in HIV reservoirs as HIV DNA but also HIV RNA, and HIV proteins suggesting low-grade viral replication in anatomic reservoirs
Cell-associated HIV RNA in Tfh cells in LN (Banga et al. Nat Med 2016)
HIV p24 in microglial cells
(Lamers et al. Infect Genet Evol 2011)
HIV gag RNA in CD4 T cell in genital tract (Deleage et al. Am J Pathol 2011)

29. Cockail of 3 broadly neutralizing antibodies + 2 LRAs (vorinostat + BETi) + anti-CTLA4

30. Hatano et al. Plos Path 2013
Impact of cART on immune activation in EC: evidenced on CD8 T cells (but not on CD4), non significant trend for DDi, hsCRP andsCD14

31. 5 - Intervention on METABOLISM
Impact of HIV and ART on metabolism
Malnutrition and Obesity are associated with immune activation: food assistance / Weight loss with exercise programs
Koethe J et al, JID, 2016