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ศ.ดร. พญ. รวงผึ้ง สุทเธนทร์ ศูนย์รวบรวมและวิเคราะห์เชื้อ เอช ไอวีแห่งประเทศไทย

HIV Pathogenesis Update 2011: Understanding the Role of Immune Activation & Inflammation in HIV Infection. ศ.ดร. พญ. รวงผึ้ง สุทเธนทร์ ศูนย์รวบรวมและวิเคราะห์เชื้อ เอช ไอวีแห่งประเทศไทย ภาควิชาจุลชีววิทยา คณะ แพทยศาสตร์ศิ ริราชพยาบาล มหาวิทยาลัยมหิดล. Implication for HIV Pathogenesis.

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ศ.ดร. พญ. รวงผึ้ง สุทเธนทร์ ศูนย์รวบรวมและวิเคราะห์เชื้อ เอช ไอวีแห่งประเทศไทย

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  1. HIV Pathogenesis Update 2011: Understanding the Role of Immune Activation & Inflammation in HIV Infection ศ.ดร.พญ. รวงผึ้ง สุทเธนทร์ ศูนย์รวบรวมและวิเคราะห์เชื้อเอชไอวีแห่งประเทศไทย ภาควิชาจุลชีววิทยา คณะแพทยศาสตร์ศิริราชพยาบาล มหาวิทยาลัยมหิดล

  2. Implication for HIV Pathogenesis • HIV disease is not a slow disease (lentivirus; lenti = slow), It is fast and furious • The damage done during the first weeks is devasting and likely permanent • The adaptive immune response does not control primary infection: the infection is self-limiting • Intervention is necessary prior to symptoms… (vaccination or prophylactic drug therapy) Mattapallil et al., Nature 434 (2005) Haase AT. Nature 2010;464:217-23.

  3. Mechanisms of CD4 Depletion and Dysfunction • Direct • Elimination of HIV-infected cells by virus-specific immune responses • Loss of plasma membrane integrity because of viral budding • Interference with cellular RNA processing • impaired regenerative capacity, coupled with the destruction of essential hematopoietic progenitor cells • Indirect • Syncytium formation • Apoptosis (infected and uninfected cells) • bystander activation-induced cell death (AICD) • chronic immune activation • Autoimmunity

  4. Immune activation in HIV infection results from dysregulated innate and adaptive immune responses to HIV, microbialproducts, coinfections and homeostatic signals Ford et al. 2009

  5. HIV/AIDS immunopathogenesis in acute HIV infection • Persistent immune activation plays a central part in driving immunopathogenesisand progression to AIDS • Early innate immune system: • failing early recognition and control of infection is a major importance in the pathogenesis of acute HIV infection, • allowing establishment of infection and profound damage to innate as well as adaptive immune activities, not least in the GALT

  6. Immune activation in acute HIV infection • HIV‑associated immune activation established in early HIV‑1 infection from: • direct viral infection of immune cells, • pro‑inflammatory cytokine production by innate cells • translocation of microbial products into the blood through damaged intestinal epithelium • Th17/TReg cells imbalance • chronic mycobacterial and viral co‑infections.

  7. Innate immunity • Innate immune activation • PRR-triggered inflammation and type I IFN production induced by HIV or opportunistic pathogens • HIV evades innate immune recognition • at early stages to establish chronic infection • allows some degree of innate PRR activation at later stages, where immune activation plays a detrimental role for the hostchronic immune activation • Innate IR difference in acute and chronic infection

  8. Summary of differences between nonpathogenic (sooty mangabeys) and pathogenic (rhesus macaques) SIV infection Ford ES, Puronen CE and Sereti I. 2009,4:206–214

  9. Mogensen et al. Retrovirology 2010, 7:54 DandekarS, George MD and Ba¨umler AJ. Th17 cells, HIV and the gut mucosal barrier. Current Opinion in HIV and AIDS 2010,5:173–178 Derdeyn C, Hunter E, et al. 2005, 2010 ElHedaA and Unutmaza D. Th17 cells and HIV infection. Current Opinion in HIV and AIDS 2010,5:146–150 HaaseAT. Nature 2010;464:217-23 . Innate immune recognition and activation during HIV infection

  10. Time frame, sites and major events in vaginal transmission Haase AT. Nature 2010;464:217-23.

  11. Representation of viral transmission across the mucosal barrier • 90% are initiated in the newly-infected heterosexual partner by a single genetic variant • MSMhas shown about 80% with maybe 20% having two, three, or four variants being transmitted.

  12. Mucosal immunity to prevent HIV transmission Target early virus (1 week) for vaccine and postexposure prophylaxis

  13. Target cell availability • CD4+ T-cell, macrophages and dendritic cells (lying just beneath the epithelium and deeper submucosa) • resting CD4 T cells outnumber macrophages and dendritic cells by 4 to 5:1 • HIV exposure at endocervical epithelium initiates signal that increases expression of MIP-3αin the epithelium that recruits pDCs

  14. Mucosal HIV-1 epithelial signalling at mucosa • pDCs recruit, from PRRs activated • MIP-1β, • CCR5+ CD4+ T cells influxed by MIP-1α and MIP-1β • Interferonsand chemokinesinhibitviral replication • Pre-existing vaginal inflammation also facilitates infection by thinning and disrupting the multilayered lining, and providing a pool of target cells for local expansion

  15. Principles in PRR signalling and transcription of cellular genes and HIV provirus • HIV pathogen-associated molecular patterns (PAMPs) ΞPattern recognition receptors (PRRs) stimulates intracellular signalling pathways (TLR7/8)---activation of transcription factors, NF-κB, IRF-1 (interferon regulatory factors) IFN-α , and AP-1 (antiviral and inflammatory genes) from pDCs and macrophage • NF-κB and AP-1 also activate transcription of the HIV provirus LTR to induce viral replication.

  16. DCs bridge innate and adaptive IR • DCs express several receptors for recognizing viruses, patternrecognition receptors (PRRs) such as the Toll‑like receptors (TLRs) and C‑type lectins. • DCs detect viruses in peripheral tissue sites and, following activation and viral uptake, migrate to draining lymph nodes, where they trigger adaptive immune responses and promote NK cell activation • Activated cDCsproduce cytokines such as interleukin‑12 (IL‑12), IL‑15 and IL‑18. IL‑12 is crucial for cDCs to induce T helper 1 (TH1) cell responses, which subsequently promote the potent cytotoxic T lymphocyte (CTL) responses that are necessary for clearing virus‑infectedcells

  17. cDCs and pDCs during HIV infection immunopathology high HIV concentration--internalization of HIV through lengerin -CD11c+ myeloid dendritic cells (mDCs/cDCs): located in skin, genital/gut mucosa -plasmacytoiddendritic cells (pDCs, CD11clo): blood, thymus, inflamed skin and mucosa and lymph nodes Altfeld M, Fadda L, Frieta D, Bhardwig N. Nature reviews Immunology 2011;11:176-186

  18. Activated cDCs • produce cytokines IL‑12, IL‑15, IL‑18 • IL‑12 is crucial for cDCs to induce T helper 1 (TH1) cell responses, promote the potent cytotoxic T lymphocyte (CTL) responses • DCs following activation and viral uptake, migrate to draining lymph nodes, trigger adaptive immune responses and promote NK cell activation

  19. Plasmacytoid Dendritic Cells (pDCs) • pDCs, CD11clo): may first encounter HIV during early local viral replication/spread. • Express CD4, CCR5, CXCR4, can be Infected by HIV • Inhibit HIV replication by secrete type 1 IFN • IFN-α and IDO (enzyme indoleamine (2,3)-dioxygenase)—reduce Th17, increase Treg • TLRs 7 for RNA viruses and 9 for unmethylatedCpG • pDCs=HIV gp120 inhibit TLR9-mediated response: pDC activation, IFN-α secrete, cytolytic activity of NK cells • Acute HIV infection (< 3 Ms) pDCs amount indirectly correlate with HIV viral load • Average no of pDCs in healthy = 2-18 cells/µL • LTNP—high pDCs

  20. pDCs action • PRRs (HIV RNA) signaling TLR7/8 on pDCs and macrophage to induce express • IFN-α • proinflammatory cytokines: IL-1, TNF-α, attract inflammatory cells • IFN-α from pDCs cause • Anti-HIV activities • Increase degradation of RNA • Arrest cell cycle progression • Increase antigen presentation • Induce apoptosis of HIV uninfected and infected CD4+ T cells via TRAIL (tumor necrosis factor-related apotosis inducing ligand) • Attract CCR5 CD4+ T lymphocytes • Suppress Th17 cells • Immune activation • IDO inhibits T-cell receptor (TCR)-triggered T-cell proliferation and can induce differentiation of naive CD4+ T cells into Tregs

  21. Dysregulation of DCs in HIV‑1 infection • Both cDCs and pDCs in blood decrease in HIV infection • From direct infection • Apoptosis • Redistribute DCs to lymphoid tissue • rapid decline in circulating DCs, particularly plasmacytoid DCs (pDCs), may be due to activation‑induced cell death • migration of activated DCs into lymphoid tissue, • an increase in DC numbers is observed • Produce IFN-α • depending on the stage of HIV infection, DCs may be affected by the microenvironment • chronic HIV infection, monocytes have been shown to upregulateprogrammed cell death protein 1 (PD1) and produce IL‑10 • partial maturation of cDCs from chronic immune activation by microbial translocation

  22. Innate immune detection of HIV PAMPs intracellular innate immune DNA sensors: -TLR9, DAI, POL III/RIG-I, LRRFIP1, IFI16, and HMGB -cytosolicSET complex, three nucleases (Ape1, NM23-H1, and TREX1) and HMGB2 bind HIV DNA And protect integration -TREX1, the most abundant cellular exonuclease, also inhibits the innate immune response to HIV DNA in T cells and macrophages by digesting excess HIV DNA Yan N, Lieberman J. Current Opinion in Immunology 2011;23:21-28

  23. TREX1 (3’-5’ exonuclease) inhibits innate immune detection of HIV DNA by metabolizing nonproductive RT products • nascent HIV capsid (CA) protein interacts with host cyclophilinA (CYPA) to trigger IFN via an IRF3-dependent pathway in monocyte-derived DCs (MDDCs) • This innate immune detection of nascent CA appears to be Dc specific and does not occur in CD4+ T cells. • HIV manages to avoid triggering innate immunity is by not replicating efficiently in DCs. • HIV infection of DCs may become more efficient during chronic infection, when proinflammatory cytokines are elevated

  24. Early innate immune responses to HIV‑1 • Acute-phase proteins and cytokines • The first detectable innate IR, occurring sometimes just before T0, was • an increase in the levels of some acute-phase proteins, such as serum amyloid A • Then, a cytokine response [proinflammatory cytokines (IL‑1)] and also by extrinsic factors such as lipopolysaccharide (LPS) • and a rapid increase in plasma viraemia T0 = time that viral RNA was first detectable (100 copies per ml) • McMichael AJ et al, 2010 Nature review Immunology

  25. Early innate immune responses to HIV‑1 • Viraemia increase and also cytokines and chemokines level • IL‑15, type I IFNs and CXC‑chemokineligand (CXCL10) increase rapidly but transiently • IL‑18, TNF, IFN-γ and IL‑22 increase rapidly and sustained at high levels, • increase in IL‑10 is slightly delayed • type I IFNs, IL‑15 and IL‑18 enhanceinnate and adaptive immune responses • cellular sources: infected CD4+CCR5+ T cells, activatedDCs, monocytes, macrophages, NK cells, NKT cells and HIV‑specific T cells intense cytokine response during acute HIV infection may also promote viral replication and mediateimmunopathology

  26. Potential roles of the innate immune system during HIV infection

  27. Microbial translocation is a cause of systemic immune activation in chronic HIV infection Nature Med 2006;12:1365

  28. HIV and innate immune activation - impact on viral control and immunopathology PRR = Pattern-recognition receptors PAMPS = Pathogen-associated molecular patterns

  29. Effect of IFN-α • Acute HIV infection • Pos effect • Anti-viral (inhibit HIV replication) • Activate NK cells • Initiate adaptive IR • Neg effect • Recruit T cells to mucosal infected sites • Chronic HIV infection • Pos effect • Induce apoptosis of infected cells • Neg effect • Persistently expressed in chronic infection; • causes CD4+ T celldepletion; • induces chronic immune activation

  30. NK cells and HIV infection • NK cells promote antiviral and antitumourimmunity by producing proinflammatorycytokines (IL-10, IFN-γ) and by lysing infected or transformed cells • Natural killer (NK) cells are defined as CD3CD56+ lymphocytes • NK cells interact with T cells and DCs to shape the magnitude and quality of adaptive immune responses • Activation of NK cells caused by • high levels of proinflammatorycytokines secreted by DCs and monocytes, including IL-15 and IFN-α • After this initial expansion of highly activated NK cells, NK cells become increasingly impaired, with persisting viral replication and disease progression • impairment of NK cell function with progressive HIV-1 disease is associated with an accumulation of CD56low NK cells that are anergicto stimulation

  31. DC-NK cell cross talk cDCs/HIV reduce secretion of IL-12, IL-15, IL-18—reduce NK activity Prolong innate immunity Altfeld M, Fadda L, Frieta D, Bhardwig N. Nature reviews Immunology 2011;11:176-186

  32. Seminal contributions to transmission • Exposure of cervical vaginal epithelium to semen (tolerance of allogeneic sperm) elicits increases in chemokines such as MIP-3α and pro-inflammatory cytokines (GM-CSF, IL-1, IL-6 and IL-8) that recruit neutrophils, dendritic cells, macrophages and lymphocytes, which accumulate beneath the cervical and uterine epithelium • a microenvironment conducive to transmission is created by the recruited cells, the immunosuppressive effects of TGF-β and prostaglandin E in semen, other transmission-enhancing factors in semen such as the amyloidfibresderived from prostatic acid phosphatase

  33. The balancing act in innate defences • These innate antiviral and inflammatory defense at the same time may facilitate transmission by • increasing target cell availability, • creating conditions for highly efficient cell-to-cell spread of infection (less sensitive to inhibition by interferon) • Mapping local expansion revealed growth by accretion of newly infected cells around foci of infected founder cells, and spread of infection along tracts of infiltrating inflammatory cells

  34. Mucosal defenses Th17/Treg Shacklett BL. CurrOpin HIV AIDS 2010;5:128-34.

  35. Impaired mucosal immune defenses in HIV-1 infection lead to systemic immune activation Proinflammatory cytokines, loss of Th17/Treg balance leads to increased epithelial permeability to microbial products Low perforin, high PD-1 (immune exhausation), E-cadherin ligate KLRG-1 inhibit CTL function

  36. Wegmann F. PLoSone 2011;6:e15861 Mucosal immunization

  37. Haase AT Annnual Rev Med 2011;127-139

  38. Problems of adjuvant for mucosal immunization • adjuvants for mucosal application may induce local inflammation, potentially increasing the HIV-1 transmission risk by recruitment of activated CD4+ T cells • Need adjuvant that promote immune responses whilst maintaining a non-inflammatory environment. • PRO 2000 is an anionic polymer • under investigation as a candidate microbicide and ineffective at preventing HIV-1 transmission • an excellent safety record for vaginal application with no evidence for local toxicity or irritation • suppress the generation of vaginal inflammatory mediators in women • Useful for formulating agent for vaginally-applied HIV-1 vaccine antigens

  39. Polyanion binding to gp120 selectively and reversibly masks antigenic surfaces containing positive charges, including the V3 loop and the CD4-induced (CD4i)-surface • Trimeric rgp140-PRO 2000 complexes: vaccine formulation • improve the antigenicity of gp140 by re-directing immune responses towards more conserved neutralization-relevant surfaces, • increasing antigen residency time and immunogenicity. • Since basic amino acids form the cleavage sites of most protect the glycoprotein from proteolytic digestion, highly conformational and discontinuous conserved neutralization epitopes still intact

  40. PRO 2000 • Polyanion PRO 2000 enhance mucosal immunogenicity of HIV-1 envelope glycoprotein (Env)-based antigens, promoting local and systemic immune responses. • Vaginal immunization with Env-PRO 2000 resulted in significantly increased titres of Env-specific mucosal IgA and IgG in mice and rabbits • PRO 2000 antagonized TLR4 activation, suppressing local production of inflammatory cytokines. • Since inflammation-mediated recruitment of viral target cells is a major risk factor in HIV-1 transmission, the immune modulatory and anti-inflammatory activities of PRO 2000 combined with its intravaginal safety profile suggests promise as an HIV-1 mucosal vaccine formulating agent.

  41. Immunomodulary activity of PRO 2000. Mononuclear cells derived from the vagina-draining Inguinal lymph nodes of vaginallyimmunized mice were cultured in the presence of 15 µg/ml of gp140

  42. PRO 2000 inhibits LPS signalling and inhibits the TLR4-MD2-lipid A interaction Murine embryonic fibroblast (MEF) TLR reporter cells were activated: TLR2 agonist Pam3CSK4,

  43. DCs-based HIV vaccine • myeloid DCs pre‑treated with inactivated HIV enhances immune control of HIV in patients, need functionally intact antigen‑presenting cells are required to limit viral replication • Adjuvants and vaccine vectors that target cDCs and pDCs simultaneously could promote adaptive immunity and limit TReg cell induction in order to control virus entry at mucosal sites, as well as systemically

  44. DCs-based HIV vaccine • DC‑based vaccine strategies that elicit HIV‑specific NK cell responses and stimulate the production of memory cells may be crucial for the success of future vaccines • the speed with which HIV gains entry into cells, innate defences need to be rapidly mobilized. • DCs target to activate specific NK cells and promote their cytolytic functions. • NK receptors, such as KIR3DS1, are important for controlling HIV disease, • NK cells can develop into protective virus‑specific memory cells

  45. Acute HIV infection: hiv spread to LYMPHOID TISSUE

  46. Peak viraemia • Free virus and/or virus‑infected cells reach the draining lymph node, where they meet activated CD4+CCR5+ T cells, which are targets for further infection • This process is augmented bycDCsthat bind and internalize virus through DC‑specific ICAM3‑grabbing non‑integrin (DC‑SIGn or CD209) and carry the virus to activated T cells • B cells may also be involved in the early spread of infection by binding the virus through the complement receptor CD21(also known as CR2)

  47. Peak viraemia • virus then replicates rapidly and spreads throughout the body to other lymphoid tissues, particularly gut‑associated lymphoid tissue (GALT), where activated CD4+CCR5+ memory T cells are present in high numbers • 20% of CD4+ T cells in the GALT are infected in acute HIV‑1 infection • up to 60% of uninfected CD4+ T cells at this site become activated and die by apoptosis, resulting in the release of apoptotic microparticles that can suppress immune function

  48. Immune activation • Activation of innate cells and B and T cells is a striking feature of acute HIV‑1 infection of humans and SIV infection of rhesus macaques • Immune activation is associated with early and extensive apoptosis of B and T cells, leading to the release of apoptotic microparticles into the blood • increased expression of tumour necrosis factor (TNF)‑ related apoptosis‑inducingligand(TRAIL; also known as TNFSF10) and FAS ligand (also known as CD95l), which kill bystander cells and are immunosuppressive

  49. Peak viraemia • ~80% of CD4+ T cells in the GALT can be depleted in the first 3 weeks of HIV‑1 infection • while HIV‑1 is replicating in the GALT and other lymphoid tissues, the plasma viraemia increases exponentially to reach a peak, usually more than a million RNA copies/ml of blood, at 14–21 days after SIV infection in macaques and at 21–28 days after HIV‑1 infection in human

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