HIV .pptx

describes the pathogenesis of hiv aids

1. Define & Describe Pathogenesis and pathology of HIV AIDS DR Yasam JM Sai 2 nd year jr resident Deparment of General Medicine MIMS Moderators Dr P.CH. Mishra Proff and HOD Deparment of General Medicine MIMS Dr T. Mouleeswara Kumar Associate Proffesor Department of General Medicine MIMS

2. Outline Introduction Definition Modes of transmission Lifecycle Phases of HIV infection CD 4 & CD 8 Cell escape Viral receptors and coreceptors Lymphoid organs Cellular targets and immune response

3. Introduction Major public health issue claimed 40.1 million lives so far and with estimate of around 38.4 PLWHA Ist case in 1981 unexplained P.jiroveci in healthy MSM in losangels Kaposi sarcoma with or without opportunistic infections in 26 healthy MSM individuals HIV virus isolation in 1983 ELISA in 1985

4. Definition HIV disease is a spectrum ranging from primary infection, with or without the acute syndrome, to the relatively asymptomatic stage, to advanced stages associated with opportunistic diseases The definition and staging criteria of AIDS are complex and comprehensive and were established for surveillance purposes rather than for the practical care of patient The current CDC classification system for HIV infection and AIDS categorizes patients based on clinical conditions associated with HIV infection together with the level of the CD4+ T lymphocyte count. A confirmed HIV case can be classified in one of five HIV infection stages (0, 1, 2, 3, or unknown ) Advanced HIV disease (AIDS) is classified as stage 3 if one or more specific opportunistic illness has been diagnosed

5. PATHOPHYSIOLOGY AND PATHOGENESIS The hallmark of HIV disease is a profound immunodeficiency resulting quantitative and qualitative deficiency of helper T cells ( which has CD4 ) Multiple mechanisms responsible for cellular depletion and/or immune dysfunction of CD4+ T cells include 1.Direct infection and destruction of these cells by HIV 2.Indirect effects such as immune clearance of infected cells ; 3.cell death associated with aberrant immune activation and inflammation 4.Immune exhaustion due to persistent cellular activation

6. Eclipse phase ( virus not detected in plasma ) - few to several days Dissemination and viremia ( DETECTABLE ) - starts with draining lymphnodes and then to other lymphoid compartments - easy ascess to CD4 T cell targets -high level plasma viremia Ultimate target - GALT which is firmly established then finally viremia is seen in bloodstream and blood transmission starts with in 1 year

7. PRIMARY INFECTION AND INITIAL DISSEMINATION OF VIRUS Early exposure does not result in infection due to -- Mucosal barrier -- Submucoal defence Finally virus crosses the barrier by -- Transportation on Langerhans cells reach target CD4 cells and virus multiplies in lymphoid cells of Mucosa , Submucosa For infection to become established R0 ≥ R1

8. Viral genetic bottle neck Some glycoprotein of the viral envelop also has influence on transmission Founder viruses R5 strains , V1-V2loop sequences and few N glycosylation sites these are sensitive to neutralising antibodies so not seen In circulating viremia When infects new partner they diversify and start accumulating at Glycosylation sites and becomes resistant

9. ESTABLISHMENT OF CHRONIC INFECTION BY In Early diagnosed and treated people -- successful in escaping immune mediated clearance --Survives on immune activation and can not be eliminated from body completely ---Constantly producing low level of virion despite treatment In untreated patient --continues replication for about 10yrs for clinical illness to manifest Clinical latency is not accompanied by microbiological latency

10. Long time non progressors & Elite controllers Long time non progressors are Long term survivors but not vice versa described in 1990s in 5-15% cases for survivors more than 10yrs CD4 T cell counts in normal range plasma cell viremia is low clinically stable Elite controllers extremely low levels of plasma viremia and normal CD4 count HLA B57-01 and HLAB27 -05 over expression cases

11. Escape of HIV from Effective Immune System Control Escape control by CD8+ cytolytic T lymphocytes (CTLs) - happens in early stages This allows virus to stay onestep ahead of host immune response due to – high level of replication than the CD8 responses leading to exhaustion of CD8 leads to upregulation of immune checkpoints -- PD 1 ( programmed death molecule ) TIGIT _ Tcell immunoreceptor with Ig and ITIM domains, TIM 3 _ T cell Ig and mucin containing molecule 3 , Lag 3_ lymphocyte activating gene downregulation of HLA class I molecules on the surface of HIV-infected cells by the viral proteins Nef , Tat, and Vpu Escape from CD 4 T cell HIV preferentially infects activated CD4 T cell due to loss of viral specific Th cell responses 40-70% of all CD4 Th memory cells are eliminated in GALT invasion leading to exhaustion and upregulation of immune checkpoint CTLA 4 and thereby goes unrecognised by host

12. Mechanisms to evade neutralising antibodies Principal targets of neutralising antibodies against HIV gp120 & gp41 Hyper variability of primary sequence of envelope Extensive glycosylation of envelope Masking of neutralising epitopes Exhauation of B cells

13. Obstacles to eradicate virus Viral reservoir : a pool of latently infected CD4 T cell may not be recognised or completely after ART by CTL response carry an integrated form of HIV DNA in host genome Preintegration latency HIV enters a resting CD4 T cell proviral DNA fails to integrate to host genome for hours to days if activated prior to decay continues along with replication cycle Reservoir of HIV infected cell lymphoid tissue , peripheral blood and CNS

14. Viral dynamics Administration of reverse transcriptase and protease inhibitors to HIV-infected individuals in clinical studies. Treatment with these drugs resulted in a decline in the level of plasma viremia , which typically fell by well over 90% within 2 wks T he decrease in plasma viremia that results from treatment with ART correlates closely with a decrease in virus replication in lymph nodes Thus confirming that lymphoid tissue is the main site of HIV replication and the main source of plasma viremia

15. CCR5 & CXCR4 R5 virus –transmitting virus predominant during early stages infects monocytes , macrophages , microglia of brain chemokines RANTES (CCL5), MIP-1α (CCL3), and MIP-1β (CCL4), which are the natural ligands for CCR5, block entry of R5 . . viruses X4 virus – increases viremia causes rapid decline In CD4 T cell infection preceded by dual R5X4 SDF-1 , the natural ligand for CXCR4, blocks entry of X4 viruses.

16. Integrin α 4 β7 An accessory receptor for HIV plays an important role in the transmission of HIV at mucosal surfaces Gut homing receptor for peripheral T cells genital tract and gut binds in its activated form to a specific tripeptide in the V2 loop of gp120 resulting in rapid activation of leukocyte function associated antigen 1 (LFA-1), the central integrin thus establishment of virologic synapses, which facilitate efficient cell-to-cell spread of HIV

17. THE ROLE OF IMMUNE ACTIVATION AND INFLAMMATION IN HIV PATHOGENESIS

18. Lymphoid organs Early HIV Arctitecture : Preserved B cell , TFH causes hyperplasia Virions to be seen by EM are attached to follicular dendritic cell FDC network Late stage of HIV Disrupted Collagen deposition occurs fibrosis EM shows destruction of FDC

19. R ole of Immune activation Immune activation and inflammation in individuals with HIV contribute to the replication of HIV, the induction of immune dysfunction, and the increased incidence of chronic conditions such as premature cardiovascular disease Conditions Associated with Persistent Immune Activation and Inflammation in Patients with HIV Accelerated aging syndrome Bone fragility Cancers Cardiovascular disease Diabetes Kidney disease Liver disease Neurocognitive dysfunction

20. Induction of immune system is reflected by hyperactivation of B cells leading to hypergammaglobulinemia ; increased lymphocyte turnover; activation of monocytes; expression of activation markers and immune checkpoint receptors on CD4+ and CD8+ T cells; increased activation-associated cellular apoptosis and pyroptosis ; lymph node hyperplasia, particularly during the chronic phase prior to disease progression ; increased secretion of proinflammatory cytokines, particularly IL-6 and type I interferons ; elevated levels of high-sensitivity C-reactive protein, CXC chemokine ligand 10 (CXCL10), d-dimer, neopterin , β2 - microglobulin , soluble (s) CD14, sTNFR , sCD27, sCD163, and sCD40L ; autoimmune phenomena

21. Induction of immune system Functional exhaustion reduced capacity to proliferate and perform effector function upregulation of inhibitory receptors on HIV specific T cells by PD-1, LAG 3, TIM 3( CD4 , CD8) CTLA -4 on CD4 2B4 & CD 160 on CD8 T cell T reg dysfunction or depleted CD4 , FOXP3 , CD25 LAG3 overexpression on exhausted T cell cell death apoptosis by Env , Tat, Vpr upregulation of death receptors Fas /CD95 TNRF 1 or trail receptors 1&2 Intrinsic apoptosis secondary to HIV induced stress downredulation of BCL 2 Othermechanisms autophagy , necrosis , necroptosis , pyroptosis

22. Autoimmune Phenomena Due to chronic immune activation and the dysregulation of B and T cells The increased occurrence and/or exacerbation of certain autoimmune disease psoriasis , idiopathic thrombocytopenic purpura , autoimmune hemolytic anemia , Graves’ disease, antiphospholipid syndrome, and primary biliary cirrhosis . IRIS has been increasingly observed in infected individuals, particularly those with low CD4+ T-cell counts . IRIS is an autoimmune-like phenomenon characterized by a paradoxical deterioration of clinical condition, which is usually compartmentalized to a particular organ system, in individuals in whom ART has recently been initiated. It is associated with a decrease in viral load and at least partial recovery of immune competence, which is usually associated with increases in CD4+ T-cell counts

23. CYTOKINES AND OTHER SOLUBLE FACTORS IN HIV PATHOGENESIS A potent proinflammatory “cytokine storm” is induced during the acute phase of HIV infection. Cytokines and chemokines that are induced during this early phase include the type I interferon IFN-α, IL-15, and CXCL10, followed by IL-6, IL-12, and TNF-α, and a delayed peak of the anti-inflammatory cytokine IL-10 . cytokines that are elevated during the chronic phase of HIV infection and linked to immune activation include IFN-γ, the CC-chemokine RANTES (CCL5), macrophage inflammatory protein (MIP)-1β (CCL4), and IL-18. Plasma levels of IP-10 are predictive of disease progression whereas the proinflammatory cytokine IL-6, marker of monocyte/macrophage activation soluble CD14 (sCD14), and coagulation marker d-dimer are associated with increased risk of all-cause mortality in HIV-infected individuals . In particular, IL-6, sCD14, and d-dimer are associated with increased risk of cardiovascular disease even in individuals receiving ART. IL-18 has also been shown to play a role in the development of the HIV-associated lipodystrophy syndrome

24. CELLULAR TARGETS OF HIV The principal targets of HIV and are the only cells that can be productively infected with HIV. CD4 T cell CD4 cells of myeloid lineage Circulating DC epidermal langerhan cell B cell CD34 monocyte precursor

25. CD 4 T cell The defects are both quantitative and qualitative and ultimately impact virtually every limb of the immune system, indicating the critical dependence of the integrity of the immune system on the inducer/helper function of CD4+ T cells . Cd4 Th17 cells of gut defence is lost as well as TH1 shift TFH cells are highly susceptible to HIV infection. However, in contrast to TH17 and most other CD4+ T-cell subsets, the number of TFH cells is increased in lymph nodes of HIV-infected individuals, especially those who are viremic The presence of these T- reg cells correlates with lower viral loads and higher CD4+/CD8+ T-cell ratios. A loss of this T- reg capability with advanced disease may be detrimental to the control of virus replication.

26. Monocyte / macrophages A number of other abnormalities of circulating monocytes have been reported in HIV-infected individual many of which may be related directly or indirectly to aberrant in vivo immune activation

27. Dendritic and langerhan cell studies have shown increased lymphoid tissue recruitment of DCs associated with lymphoid hyperplasia and inflammation . The mDCs are also involved in the initiation of adaptive immunity in draining lymph nodes by presenting antigen to T cells and B cells secreting cytokines such as IL-12, IL-15, and IL-18 that activate other immune cells, although these functions are perturbed in HIV infection.

28. NK cell Prototypical member of innate lymphoid cells (ILCs) that collectively provide tissue homeostasis and immunosurveillance against virus-infected cells act by direct killing of infected cells and secretion of antiviral cytokines and chemokines During chronic HIV infection, both NK cell cytotoxicity and cytokine secretion become impaired NK cells may also serve as sources of HIV-inhibitory soluble factors, including CC- chemokines such as MIP-1α (CCL3), MIP-1β (CCL4), and RANTES (CCL5).

29. summary

30. MCQ 1) which the natural ligand for CXCR4 blocks entry of X4 viruses? RANTES (CCL5 ) MIP-1α (CCL3 ) MIP-1β (CCL4 ) SDF -1

31. Risk of Mycobavterium avium complex ,HIV wasting syndrome occurs if CD4 count A) below 100 cells/ cubic millimeter B)below 200 cells/ cubic millimeter C)between 200-500cells/ cubic millimeter D)above 500 cells/ cubic millimeter

32. Elite controllers all are true except a)extremely low levels of plasma viremia b) normal CD4 count c)HLA B57-01 and HLAB27 -05 over expression cases d) they are long term survivors