THE IMMUNOPATHOGENESIS OF HIV INFECTION Lymphotropic virus Year of report Cases per million East Centre West * HIV infections newly diagnosed per million population, by year of report ( ) and geographic area, WHO European Region* * Austria, Belgium, France, Italy, Netherlands, Portugal, Spain excluded: national data not available EuroHIV Update at 31 December 2002 HIV infections newly diagnosed, reported in 2002: characteristics of cases by geographic area WHO European Region West* Centre East Number of diagnosed cases Rate per million population Percent < 30 years old 30% 52% 77% Percent female 35% 33% 33% Main transmission mode Heterosexual Low level Drug Homosexual epidemic injection THE HUMAN IMMUNODEFICIENCY VIRUS (HIV) 10359bp DNA gp120 gp41 CD4 binding Membrane fusion RECEPTORS AND CO-RECEPTORS I. CD4 is a high affinity receptor for HIV gp120 CD4 CCR5 CCR5 co-receptor on monocytes, macrophages and T cells R5 strain of the virus in initial infection CD4 CXCR4 CXCR4 co-receptor on T cells X4 strain of the virus in initial infection Conformational change of gp120 Conformational change of gp41 MEMBRANE FUSION TROPISM OF HIV IS MEDIATED BY CO-RECEPTORS M-tropicT+M-tropicT-tropic CCR5 CXCR4 Macrophage Dendritic cell Th1 cell microglia CD4 Macrophage Dendritic cell Th1 cell Th2 cell microglia Dendritic cell Th1 cell Th2 cell 9% of the Caucasian population is heterozygous for a deletion mutant of the CCR5 gene, which results in an unfunctional protein People homozygous for an inherited defect of the CCR5 gene are resistant to HIV infection 1% of the Caucasian population HHV-6 infection induces CD4 expression (NK, CD8+ T sejtek) Galactosyl-ceramide (alternative receptor) vagina and gut epithelial cells Certain HIV strains use CD8 for entry! (CD4 tropism remained) endocytosis Immune complex Fc (HCMV) HIV RECEPTORS AND KORECEPTORS II. DEPLETION OF CD4+ CELLS IN HIV INFECTION LIFE CYCLE OF HIV CD4 co-receptor internalization degradation of nucleocapsid viral RNA reverse transcription provirus DNA integrated provirus viral RNA Synthesis of viral proteins viral RNA Release of virions MistakesEnzyme 1 Mutation in 10 5 bp Reverse Transcriptase DNA-Polymerase 1 Mutation in 10 8 bp THE CAUSE OF HIV VARIABILITY THE VIRAL REVERSE TRANSCRIPTASE LACKS PROOF READING MECHANISMS OF TYPE POSSESSED BY CELLULAR DNA NEW VIRAL VARIANTS (quasi species) CO-EXIST IN AN INDIVIDUAL NEGATIVE SELECTION OF NEUTRALIZING AND CYTOTOXIC EPITOPES THE COURSE OF HIV INFECTION CD4+ T CELL DEPLETION IN HIV INFECTION Loss of CD4+ T cells in lymphoid organs 1.Direct cytopathic effect of HIV lytic cycle in activated CD4+ T cells 2.Killing by virus-specific CD8+ T lymphocytes CD4+HIV+ targets 3.Uninfected CD4+ T cells bind gp120 CD4 + TCR signaling apoptosis 4.Syncytia formation gp120 of infected T binds to uninfected T fusion 5.Inhibited T cell development Impaired T cell function in the periphery 1.Suppressed T cell proliferation 2.Reduced Th1 cytokine production, Th2 bias 3.Inefficient antigen presentation due to HIV infected macrophages 4.Selective loss of CD4+ memory cell population no recall response to opportunistic infections 5. Virus associated malignancies THE EFFECT OF HIV INFECTION ON CD4+ T CELLS NF- B Apoptosis HIV reservoire Ag presentation T cell survival Perforin IFN Effector function Proliferation IL-2 Apoptosis TAR PKR Lytic/inhibitory enzymes Apoptosis TAT FasL IL-2 Bcl-2 OPPORTUNISTIC INFECTIONS AND TUMORS IN HIV INFECTION KAPOSI SARCOMA AND HERPES SIMPLEX VIRUS INFECTION IN HIV PATIENTS HIV-1-SPECIFIC CD4+ HELPER, CD8+ CYTOTOXIC T CELLS AND VIRAL LOAD PROGRESSIVENON-PROGRESSIVE HAART THERAPY PRIOR OR AT THE TIME OF SEROCONVERSION? Zidovudin can protect against transmission to the infant Goulder 1999, Altfeld &Rosenberg 2000