Downloaded 27 times
ELITE CONTROLLERS
- 1. ELITE CONTROLLERS OFELITECONTROLLERS OF HIV INFECTIONHIV INFECTION Siddhesh U. SapreSiddhesh U. Sapre M.Sc. VirologyM.Sc. Virology Roll no: 17Roll no: 17 National Institute of Virology, INDIANational Institute of Virology, INDIA Presented at: National AIDS Research Institute, INDIAPresented at: National AIDS Research Institute, INDIA 1
- 2. WHO ARE ELITECONTROLLERS OF HIV?WHO ARE ELITE CONTROLLERS OF HIV? Genetic determinants of HIV-1 infection and progression to AIDS: susceptibility to HIV infection , G. Kaur and N. Mehra, Tissue Antigens 73, 289–301 A population of naturally selected long term HIV infected individuals, with viremia below detectable level, poor depletion of immune cells and functionality and do not develop the disease in the absence of ART. CD4 count: stable (in spite of threshold) Viral loads: <50 copies/mL persistently for more than 12 months (in CSF, as less as 2.5 copies/ mL) Prevalence: 0.3% population (out of which, only 1% actually maintain their ELITE status for > 10 yrs.)2
- 3. Unravelling the mechanismsof durable control of HIV 1‑ : Bruce D. Walker and Xu G. Yu, VOLUME 13 | JULY 2013 3
- 4. MECHANISMS RESPONSIBLE FORTHEMECHANISMS RESPONSIBLE FOR THE ELITE STATUSELITE STATUS • Humoral responseHumoral response, such as, such as titre and breadthtitre and breadth of HIV neutralising antibody, in ECof HIV neutralising antibody, in EC does not appear to be differentdoes not appear to be different when compared to the natural progressorswhen compared to the natural progressors (thus, excluding a protective role in the early and chronic phase of(thus, excluding a protective role in the early and chronic phase of infection in ECs).infection in ECs). • Hence, theHence, the Cell Mediated ImmunityCell Mediated Immunity plays aplays a crucial rolecrucial role in the maintenance ofin the maintenance of ELITE statusELITE status of these individuals byof these individuals by the following mechanisms:the following mechanisms: 1.1. HLA polymorphismsHLA polymorphisms 2.2. CD8+ T lymphocytesCD8+ T lymphocytes 3.3. Mucosal ImmunityMucosal Immunity 4.4. NK cellsNK cells 5.5. CD4+ T lymphocytesCD4+ T lymphocytes 6.6. Regulatory T cellsRegulatory T cells 7.7. Th 17 cellsTh 17 cells 8. T cellsγδ 9.9. Extracellular Soluble factors: Cytokines & chemokines; DefensinsExtracellular Soluble factors: Cytokines & chemokines; Defensins 4
- 5. 5 Emerging Concepts onthe Role of Innate Immunity in the Prevention and Control of HIV Infection: Margaret Ackerman et al., Annual Reviews in Medicine 2012, 63:113–30
- 6. Trends in MicrobiologyFebruary 2015, Vol 23, No.2 6
- 7. ELITE CONTROLLERSELITE CONTROLLERS AIDSevents have also been described in few ECs experiencing drop in CD4 T cell count despite maintenance of undetectable viral load. No main viral genetic defects or viral polymorphisms are responsible for the spontaneous control of HIV replication in ECs (synonymous substitutions occur in gag, pol, nef genes as a result of low level ongoing replication) GB virus C inhibits HIV replication in vitro infected cells and persistent coinfection with GBC virus is associated with prolonged survival. Humoral response, such as titre and breadth of HIV neutralising antibody, in EC does not appear to be different when compared to the natural progressors (thus, excluding a protective role in the early and chronic phase of infection in ECs). 7
- 8. Unravelling the mechanismsof durable control of HIV 1‑ :Bruce D. Walker et al., Nature Reviews: Immunology, VOLUME 13 | JULY 2013 8
- 9. HIV & HLAHIV& HLA 9
- 10. CD8+ T LYMPHOCYTESAND HIVCD8+ T LYMPHOCYTES AND HIV • HLA-B 57 & HLA-B 27HLA-B 57 & HLA-B 27: expression in Ecs (HIV specific CD8+ T cells: expression in Ecs (HIV specific CD8+ T cells proliferative capacity andproliferative capacity and cytotoxic activitycytotoxic activity • Polyfunctional CD8+ T cellsPolyfunctional CD8+ T cells:: degranulationdegranulation and release of Perforin & Granzyme B , cytokines:and release of Perforin & Granzyme B , cytokines: IFN- ,γ TNF- , IL-2 and MIP-1α β • Viral loadViral load Inversely proportional to CD8+ T cell levelsInversely proportional to CD8+ T cell levels • Viral load is similar in ECs and progressors,Viral load is similar in ECs and progressors, except for higher polyfunctional CD8+ T cellsexcept for higher polyfunctional CD8+ T cells • CD8+ T cellsCD8+ T cells capacity to expandcapacity to expand andand ‘er in number in ECs‘er in number in ECs and LTNPsand LTNPs • HIV specific polyfunctional CD8+ T cellsHIV specific polyfunctional CD8+ T cells= in differentiation stage of central memory T cells= in differentiation stage of central memory T cells expand rapidly by HIV Gag stimulationexpand rapidly by HIV Gag stimulation • HLA-B 27 restricted CD8+ T cellsHLA-B 27 restricted CD8+ T cells== stronger avidity, poly-functionality and clonal turnoverstronger avidity, poly-functionality and clonal turnover • CD100/ Sema4D expression in ECs= vs. progressors, non-controllers and HAART adhered patientsCD100/ Sema4D expression in ECs= vs. progressors, non-controllers and HAART adhered patients 10
- 11. MUCOSAL IMMUNITYMUCOSAL IMMUNITY •CD8+ T cell responseCD8+ T cell response= in= in HLA-B 57HLA-B 57 && HLA-B 27 restricted Gag epitopesHLA-B 27 restricted Gag epitopes (p24 &(p24 & p17)+ otherp17)+ other non-immunodominant epitopesnon-immunodominant epitopes present inpresent in bloodblood andand rectal mucosarectal mucosa with level ofwith level of poly-functionality of CD8+ T cell of ECspoly-functionality of CD8+ T cell of ECs as seen anatomicallyas seen anatomically • CD8+ T cellsCD8+ T cells Lymph nodesLymph nodes andand gastrointestinalgastrointestinal withwith PD-1PD-1 (characteristic of(characteristic of immune exhaustionimmune exhaustion && reduced ability to clear chronic infectionreduced ability to clear chronic infection • Depletion of CD8+ T cellsDepletion of CD8+ T cells: from: from ECsECs toto progressorprogressor statusstatus 11
- 12. NK CELLS &HIVNK CELLS & HIV • KIR3DL1 & KIR3DSKIR3DL1 & KIR3DS delayed progressiondelayed progression to AIDS when interacting withto AIDS when interacting with HLA-BHLA-B allelesalleles • ECs expressingECs expressing HLA-Bw4*80I (target cells)HLA-Bw4*80I (target cells) ++ KIR3DL1 (NK cells)KIR3DL1 (NK cells) higher target NKhigher target NK cell cytotoxicitycell cytotoxicity vs. CD8+ T cells from same individualsvs. CD8+ T cells from same individuals • SNP in HLA-C promoter regionSNP in HLA-C promoter region expression of HLA-C transcriptexpression of HLA-C transcript CD4 counts,CD4 counts, Viral load control, slow disease progression= Virus controlViral load control, slow disease progression= Virus control 12
- 13. CD4+ T LYMPHOCYTES& HIVCD4+ T LYMPHOCYTES & HIV • CD4+ T cells / Th cells induce: -long term maintenance of HIV specific CD8+ memory T cells -Ab production from B cells -macrophages to develop enhanced microbicidal activity to recruit neutrophils, eosinophils, basophils to the sites of infection and inflammation -expression of cytokines and chemokines to orchestrate the full panoply of immune responses • Ag naïve T cell Th1, Th2, Th17 or T reg cells • ECs: avg. 750 CD4+ T cells/mL Spontaneous control of HIV infection (controlled level is due to uncompromised functional thymus gland process and extra-thymic process) • Chronic immune activation (markers: CD38, HLA-DR, and/ or Ki67 expression) responsible for disease progression (Chronic activation low in ECs) • ECs IFN- , IL-2γ response towards Gag protein, in spite of CD4+ T cells (vs. progressors and HAART treated individuals) (Gag293-312 peptide from avidity MHC/TCR interaction) • CD4+ T cellsCD4+ T cells CD28, PD-1, CTLA-4CD28, PD-1, CTLA-4Cell cycle arrest & termination of T cell activationCell cycle arrest & termination of T cell activation 13
- 14. REGULATORY T CELLS& TH 17 CELLSREGULATORY T CELLS & TH 17 CELLS • TregsTregs secrete levels ofsecrete levels of TGF- , IL-10 & IL-35β self-Ag tolerance: lower in ECs , high in progressors • Activity & expansion of TregActivity & expansion of Treg maintained by Th17 cells(required for inflammation &maintained by Th17 cells(required for inflammation & immune response to infectious agents)immune response to infectious agents) • Th17 cellsTh17 cells production of IL-22production of IL-22 stimulation of epithelial cells (mucosalstimulation of epithelial cells (mucosal immunity)immunity)production of Antimicrobial proteins to clear out fungi (Candida) andproduction of Antimicrobial proteins to clear out fungi (Candida) and bacteria (cytokine, chemokine release & neutrophil recruitment)bacteria (cytokine, chemokine release & neutrophil recruitment) • PB loss of Th17/ imbalance in the TH17/Treg ratioPB loss of Th17/ imbalance in the TH17/Treg ratio maintained above optimal bymaintained above optimal by ECs: similar to those of uninfected individualsECs: similar to those of uninfected individuals 14
- 15. CYTOKINES & CHEMOKINESCYTOKINES& CHEMOKINES 15
- 16. DEFENSINSDEFENSINS • Cellular Source=Neutrophils,Cellular Source= Neutrophils, NK cells and epithelial cells,NK cells and epithelial cells, DCs: exert antimicrobial +DCs: exert antimicrobial + detrimental effectsdetrimental effects • Defensinsα inhibit multiple steps of HIV life cycle (act as an innate immune response to infection at mucosal sites like cervico-vaginal tissue • Immature DCs from ECsImmature DCs from ECs α Defensins (levels of α defensins= independent of viral load) Primate Defensins: Robert Lehrer, Nature Reviews Microbiology, VOL 2 September 2004 16
- 17. REFERENCESREFERENCES • Cell-mediated immunityin elite controllers naturally controlling HIV viral load:Cell-mediated immunity in elite controllers naturally controlling HIV viral load: Luca GenoveseLuca Genovese et al.,et al., Frontiers in Immunology, April 2013 | Volume 4 | Article 86Frontiers in Immunology, April 2013 | Volume 4 | Article 86 • Sprouty-2 regulates HIV-specific T cell polyfunctionalitySprouty-2 regulates HIV-specific T cell polyfunctionality: Yen Ling Chiu: Yen Ling Chiu et al., The Journal of Clinicalet al., The Journal of Clinical Investigation, Volume 124 No.1 January 2014Investigation, Volume 124 No.1 January 2014 • Elimination of HIV-1-infected cells by broadly neutralizing antibodiesElimination of HIV-1-infected cells by broadly neutralizing antibodies: Timothee Bruel: Timothee Bruel et al.,Natureet al.,Nature CommunicationsCommunications • Long-Term Nonprogressor and Elite Controller Patients Who Control Viremia Have a HigherLong-Term Nonprogressor and Elite Controller Patients Who Control Viremia Have a Higher Percentage of Methylation in Their HIV-1 Proviral Promoters than Aviremic Patients Receiving HighlyPercentage of Methylation in Their HIV-1 Proviral Promoters than Aviremic Patients Receiving Highly Active Antiretroviral TherapyActive Antiretroviral Therapy:Juan Antonio Palacios:Juan Antonio Palacios et al., Journal of Virology, December 2012 Volumeet al., Journal of Virology, December 2012 Volume 86 Number 2386 Number 23 • Emerging Concepts on the Role of Innate Immunity in the Prevention and Control of HIV InfectionEmerging Concepts on the Role of Innate Immunity in the Prevention and Control of HIV Infection:: Margaret AckermanMargaret Ackerman et al., Annual Reviews in Medicine 2012, 63:113–30et al., Annual Reviews in Medicine 2012, 63:113–30 • The HIV-1 Antisense Protein (ASP) induces CD8 T cell responses during chronic infectionThe HIV-1 Antisense Protein (ASP) induces CD8 T cell responses during chronic infection: Anne Bet: Anne Bet etet al., Retrovirology 2015 12:15al., Retrovirology 2015 12:15 • Chronic Immune Activation in HIVChronic Immune Activation in HIV: Denise Hsu: Denise Hsu et al., Encyclopedia of AIDS 2014et al., Encyclopedia of AIDS 2014 17
- 18.