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