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Immunology of HIV: What can we learn from LTNPs / Elite Controlers ?

Immunology of HIV: What can we learn from LTNPs / Elite Controlers ?. Pr Brigitte Autran Inst. of Researches Immunity, Cancer and Infection , Université Pierre et Marie Curie - Hôpital Pitié-Salpêtrière, France brigitte.autran@psl.aphp.fr. Univ . Hosp Pitié-Salpétrière. AIDS

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Immunology of HIV: What can we learn from LTNPs / Elite Controlers ?

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  1. Immunology of HIV:What can we learn from LTNPs / Elite Controlers ? Pr Brigitte Autran Inst. of Researches Immunity, Cancer and Infection , Université Pierre et Marie Curie - Hôpital Pitié-Salpêtrière, France brigitte.autran@psl.aphp.fr Univ. HospPitié-Salpétrière

  2. AIDS Opportunistic Infections ARV CD4/mm3 Pl VL Immune Responses Immune Activation 200 • HIV and Immune Deficiencies : • Are CD4 defects & AIDS the only complication of the HIV infection? • The collateral damages of Immune activation… 0 3-6 m 8-10 years B Autran EACS 09

  3. tat, Chronic Inflammation/activation plays a key role in immunopathology of HIV Appay V et al, J Pathol 08

  4. LTNPs and HIV / Elite Controllers:Models of functional Cure of HIV? • Who are they ? • Definition? • Control of CD4 and HIV : isit stable ? • Control of Immune Activation ? • How do they control the virus ? : Is it the Virus or the Host ? • Which virus characteristics ? • WhichImmunity ? • Are they a model for : • Vaccines ??? • Cure of HIV ? EACS B Autran 2013

  5. Which definitionfor LTNP and HIV / Elite Controllers ? LTNPs: 1st evidence: 1993: LTS (Long TermSurvivors): SanFranciscoCohort: S Buchbinder & J Levy (1994) Immuno/Clinicaldefinition: > 1994: LTNPs: Seropositivity > 7-8 years No AIDS, Normal CD4 counts : >500, >600/mm3 No Treatment (VL not available) HIV / Elite Controllers(Suppressors): 1st evidences: 2000s: HIV Controlers: O. Lambotte 2005 / HIV Suppressors: J. Blanke 2005 Elite Controllers : S Deeks & B Walker 2007 VirologicalDefinition: Seropositivity > 8-10 years Plasma Viral Load < 400 or 500 cp / mLover 90% measures +/- undetectability No Treatment (AIDS symptoms or CD4 non necessary) EACS B Autran 2013

  6. Which Epidemiologyfor LTNP and HIV / Elite Controllers ? LTNPs: 1993: LTS SanFranciscoCohort: 7%? S Buchbinder (1994) Others: < 5%, <2%, …. HIV / Elite Controllers: late 90s: HIV / Elite Controlers: ??? < 1% French Hospital Data Base (FHDH): Grabar.. D Costagliola, AIDS 2009 46,880 HIV+ patients: LTNP: Sero+ >8y , CD4 nadir > 500 = 0.4% Elite LTNP: idem + CD4 nadir > 600, CD4 slope+ = 0.05% HIV Controlers: >10y , 90% VL<500cp/ml= 0.22% Elite Controllers: idem HIC + last VL<50 cp= 0.15% Data from FHDH: • Elite LTNP: • = 40% HIC • = 32% EC • = 60% detectableplVL • Elite Controlers: • = 46% LTNP • = 12% Elite LTNP • = 25% CD4 < 500/mm3 EACS: B Autran 2013

  7. French Cohort of LTNPs: ALT –ANRS CO15: • Recruitment: 1994 – 96 : • InclusionCriteria: Seropositivityknown > 8 years • CD4>600/mm3 for > 5 years and + CD4 slope • Lack of HIV-relatedsymptoms • Lack of ARV • N=71: medianseropositivity: 9 y • Evolution: very slow decrease in CD4 over an 18 yearsFollow-up: Nb CD4>600 Years Number subjects 1 71 46 (65%) 2 61 28 (46%) 3 44 17 (27%) 4 30 12 (40%) 2001-12 5 24 8 (33%) 9 (44%) 18 EACS B Autran 2013

  8. HIV – Elite Controllers, LTNPs • The Virusor the Host? • Deletions ? • Evolution and escape ? • What is the key parameter ? • Production or Reservoir ? EACS B Autran 2013

  9. 1000000 100000 10000 1000 HIV RNA 100 10 1 1 10 100 1000 10000 100000 HIV DNA ALT-ANRS CO15 cohort:HIV characteristics at entry: It is NOT the Virus ! • Low but Heterogeneous viral production: • Medianplasma VL = • 10 000 cp/mLat entry (20-880,000) • Slow increase: • Candotti et al. 1999, 2000 • R5-dependent HIV Type: • All isolates: NSI (Candotti J Gen Virology1999) • No HIV genedeletionin: • env, nef, gag, LTR but a Vif signature (Candotti, Vigne, J Virol 2000) • SIMILAR FINDINGS • in OTHER LTNP COHORTS Viremic Slow Progressors Viremic Controlers • Low Reservoir (cell associated HIV-DNA) • correlated to virus production Elite Controlers B.A.EACS 2013

  10. Low HIV Reservoir (HIV-DNA) in PBMC : associated with a low risk of HIV disease progression HIV DNA Log copies/106 PBMC PRIMO Progressors PRIMO LTNPHIV-controllers infection SEROCO treatedANRS Co-15 ANRS Co-18 10 S Lewin & C Rouzioux et al. AIDS 2011

  11. HIV / Elite Controllers, LTNPs Do they control T-cell activation ? • LowImmune Activation in Elite Controlers with undetectable plVL: • CD4 activation as low as in ARV-suppressed patients, CD8 activation higher Hunt, JID 2008

  12. HIV – Elite Controllers, LTNPs • The Virusor the Host? • Is it all in the Genes ? • Immune Responsegenes • Adaptive Immunity • InnateImmunity • Is it the anti-HIVImmunity ? EACS B Autran 2013

  13. ImmuneGenetics and control of the HIV Reservoirs:Genome-wide analysis in Elite Controllers and LTNP • HLA-B57 (HCP5) • is the strongest Marker • for low HIV reservoirs • (Dalmasso et al.) • The HLA locus in Chromosome 6 • is the strongest genetic marker for: • HIV controlers vs Acute infection,(Dalmasso et al.: 2009) • Elite Controlers (Pereyra et al. 2010) • LTNP(GISHEAL: French & Italian)vs Acute infection(Guergnon et al:2011) Lower Reservoir (HIV-DNA) in B27+/57+ vs negatives B Descours et al. Clin. Inf. Dis 2011 13 EACS B Autran 2013

  14. ANRS-CO15 (ALT) cohort: Immune Genetics of LTNPs : It is the HOST ! • A composite of HLA + chemokine /chemoreceptorsgene mutations CCR5 D32(hzg) + SDF-1 wt + HLA-B27+, DR6-+ 3 of the HLA-A3, B14, B57 + DR7 Significantlypredicts 80% of LTNP vs Progressors(Magierowska et al.Blood, 2000) • Association HLA-B57 and lowpl VL: • SIMILAR FINDINGS for HLA-B57 in all LTNP / HIC & EC cohorts • (M Carrington, 1999, Deeks & Walker, 2007, ….) • Othergeneticparameters??? Mutations of the KIRDL1 gene (M Carrington 2005), CX3CR1gene (Faure 2001) No genepolymorphisms in TRIM-5, APOBEC3G, FcgR • Genome Wide Association Studies (GWAS) HIV-RNA Cp/mL • Protective HLA • enriched during Follow-up: • 59% at Year0 vs 75% at year5 • Distinct influences: • HLA-B57 and B14 associated • to HIV control • HLA-B27 associated • to LTNPs • Antoni G, AIDS 2013 HIV-DNA Cp/Million PBMC 5 4 P=0.01 P=0.003 3 2 Median log10 HIV 1 0 + - + - + - + - + - + - + - + - TOTAL HLA B12 n=13 B14 n=14 B27n=14 B57n=19 EACS B Autran 2013

  15. CD8 T cells ? • Specificity ? • Function ? • Gene associations ? • Correlates of protection ? • Is it the hen or the egg ??? • CD4 T cells ? • Function ? • Other parameters ? HIV – Elite Controllers, LTNPs • The Virusor the Host? • Is it Immunity ? • T cell adaptive Immunity: EACS B Autran 2013

  16. 10 4 16000 10 3 Spearman0.836 p<0.0001 14000 10 2 12000 p24 (ng/ml) 10000 10 1 8000 IFNg SFC Total /106 PBMC 10 0 6000 4000 10 -1 2000 HIC Control VIR ART 0 CD4 T cells 0 1 2 3 4 5 CD4:CD8 1:1 p24 log decrease (CD4 vs CD4:CD8 1:1) Mean The ANRS Co-18 Cohort of HIV Controllers:CD8 T cells mediate a strong anti-viral activity • CD8 T cellsfrom HIC • inhibit HIV production • Saez-Cirion, PNAS 2008 • Somecorrelationbetweenanti-viralfunctions • of CD8 T cellsfrom HIC • HIV inhibition and IFN-g production • Saez-Cirion, JI 2009 EACS B Autran 2013

  17. LTNP - ANRS-CO15 cohort: Robust HIV-specific CD8 T cells • Strong CD8 T cells against HIV-Gag : • CD8 T cells anti-Gag- but not Nef • correlate with low HIV reservoirs • Martinez et al. JID 2005, Jie et al. AIDS 2010 17 EACS B Autran 2013

  18. HIV Transcriptionally active HIV Transcriptionally inactive Anti gag CD8 T cells Inflammation ++ Activation ++ HLA-B27/57 neg TN TTM TEM TCM Antigens Antigens Antigens HLA-B27/57pos TEM TN TCM TTM A model for an immune control of the HIV Reservoirs in HLA-B27/57+ LTNPs EACS B Autran 2013

  19. HIV – Elite Controllers, LTNPs • The Virusor the Host? • Is it Immunity ? • Antibodies ? • Neutralizing ? • Others ? EACS B Autran 2013

  20. ANRS CO-15 ALT and antibodies against HIV Env CD4 CCR5, CXCR4 VIH • HIV-specificantibodies: against HIV-enveloppe: • Neutralizing Abs:: • Positivelycorrelated to the VL: N’Go et al, AIDS Res Hum Retrov.2003 • Reactivity against the MPER of gp41 Braibant et al. AIDS 2006 • 2F5-like et 4E10 like Abs in 60% sera Braibant et al. Virol. 2011 • Reactivity against gp120: particular structural characteristics • Isotype: IgG2: anti-gp41: • Best correlate of protection againstdisease progression • N’Go et al., AIDS Res Hum Retrov. 2003 • Martinez et al. J Inf Dis. 2005 • Inhibition of the NK cell-mediatedlysis of CD4 T cells: Anti-3S (gp41): • Debré et al. block NK celllysis and correlatewithdisease progression • Vieillard et al. AIDS 2007 gp41 gp120 DC-SIGN Cell Membrane EACS B Autran 2013

  21. 10,000 1,000 100 r = - 0,304 ; p= 0,026 r = - 0,461; p= 0,0001 10 10,000 1,000 1 100 2 3 4 5 1 Anti-HIV IFNg+ SFC/million PBMC 10 0 1 12 24 36 48 60 0 1 2 4 6 HIV-1 RNA (log copies / ml) Proviral DNA (log cp/106 cells) LTNP , HIC and EC: Robust HIV-specific CD4 T cells 100 80 • LTNPs: Gag-specific Th1 CD4 T cells • associated with control of HIV & CD4 • The best marker of protection / progression: • in association with anti-gp41 IgG2 Abs • Martinez et al. JID 2005 60 Proportion remaining LTNP (CD4>600) 40 P= 0.02 > 170 SFC and IgG2 (n=5) > 170 SFC, No IgG2 (n=11) < 170 SFC, and IgG2 (n=8) < 170 SFC, No IgG2 (n=29) 20 Time from inclusion (months) EACS B Autran 2013

  22. HIV / Elite Controllers, LTNPs A model for HIV vaccines ? • LTNPs, HIC & ECs: • Strong T cellImmunity to HIV • WeakNeutralizing Abs but otheranti-HIV Abs associatedwith: • low VL (IgG2) • stable CD4 (anti-gp41/3S) EACS B Autran 2013

  23. Are HIV / Elite Controllers, LTNPs a model for HIV Cure? Current AntiRetroVirals Can we decrease the HIV Reservoirs? and stop ART? Functional Cure ? NO AIDS Persistence of HIV Reservoirs or eradicate HIV Sterilizing Cure ? EACS B Autran 2013

  24. Hot Topic in 2013: Models of Cure ? 01 02 03 04 05 06 07 08 09 10 11 12 13 • Sterilizing cure ? • CCR5 defective stem cellgraft( Berlin patient ) OR1 KPV CXK 2000 1500 CD4+ T cells/mm3 RNA copies/ml 1000 500 Models of Functionnal cure • Elite Controllers and Long term non progressors • Infected for 10-30 years • Never treated ; Genetic Background; • StrongCD4 and CD8 response/HIV • Preserved central-memory CD4 T cells • Lowimmune activation • Post-TreatmentControlers(Visconti) • Control HIV without ARV for median 3.5 years • After ARV for 5 yearsstartedat acute infection • No genetic background; Immunity ??? • Preserved central-memory CD4 T cells • Low Immune activation 0 01 02 03 04 05 06 07 08 09 96 98 00 02 04 06 08 10 Year Year Year OR8 MWP OR2 2000 1500 RNA copies/ml CD4+ T cells/mm3 1000 500 98 99 00 01 02 03 04 05 06 07 08 09 10 02 03 04 05 06 07 08 09 10 0 Year Year 01 02 03 04 05 06 07 08 09 10 11 12 13 Year GXR JOGA 2000 1500 CD4+ T cells/mm3 1000 RNA copies/ml 500 OR3 0 04 05 06 07 08 09 10 98 99 00 01 02 03 04 05 06 07 08 09 Year Year Year 96 98 00 02 04 06 08 10 12 Hoqueloux et al. AIDS 2010, J Antimicrob. Ther. 2013, Saez-Cirion et al. PLosPathogens, 2013 EACS B Autran 2013

  25. Hot Topic in Sept 2013: Potential strategies to reduce HIV reservoirs: Lessons from LTNPs and HIC /ECs Stimulate Anti-HIV immunity ??? NKT CD8 APC Immune Activation Residual Replication Reduce Systemic Inflammation HIV Reservoirs Latency What can we learn from LTNPs, HIC & ECs for Controling Latency ??? EACS B Autran 2013

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