Immunology of HIV Infection Michael F. Para, MD Professor of Internal Medicine Division of Infectious Diseases 1 1

Learning Objectives  Describe the steps HIV uses to enter cell  Compare the clinical signs of acute HIV infection to other acute viral infections  Explain the humoral and cell mediated immune response to HIV  Describe how HIV/AIDS is diagnosed and what 2 assays are used to follow HIV’s course  Describe the changes in the host’s immune response after treatment with antiretroviral drugs. 2

Two way interaction of HIV and immune system It infects immune system and immune system attacks it 3 HIV micrograph and schematic

Early Events of Infection Process  Mucosal route of infection via dendritic cells (macrophages)  Langerhans cells (dendritic cells of macrophage line)  reside in skin and submucosal tissues  express surface CD4 and HIV co-receptors and can be infected by HIV  Other dendritic cells may just bind HIV via intracellular adhesion molecules like the ligand, DC Sign, and be transported to the lymph node 4

T-cell Area of Lymph Node 5

Early Events of Infection Process  APCs traffic to lymph node & interface with CD4+ T cells enhancing HIV infection of the CD4+T cells  Within days of infection a large cellular reservoir of HIV infected CD4+ T cells, dendritic cells, tissue macrophages, monocytes, and Langerhans cells, develops.  STD/mucosal injury/inflammation predisposes to viral entry, & increases risk of infection 6

How does HIV get into cells? HIV Entry – Three Step Process Virus attaches to receptor then co-receptor then fuses 7 Cellular co-receptor Is CCR5 or CXCR4 Chemokine receptors Initial cellular receptor Is CD4 molecule gp41 folds on itself pulling viral envelope into cell membrane leading to fusion gp41 inserts into cell membrane

HIV Co-receptors  2 major HIV co-receptors - CCR5 and CXCR4  Both are chemokine receptors  Most sexually transmitted HIV use CCR5 co-receptor CCR5 more prevalent on macrophages and LC Viruses using CCR5 are called macrophage tropic. Viruses binding to CXCR4 are called lymphotropic  CCR5 delta 32 is a polymorphism (genetic variant) 32 base pair deletion in CCR5 molecule Mutation in 15% of people of European descent 1% of this population is homozygous they are resistant to macrophage tropic HIV virus strains 8

HIV Replicative Cycle 10 HIV may remain “dormant” till T cell activated, HIV preferentially infects & replicates in “activated” CD4 cells cytokines With error prone replication, virus always changing

HIV plasma levels during acute infection 11 Virus spike Viral spike earliest indicator of HIV infection with depletion of gut CD4+. Acute mononucelosis-like syndrome follows in 50% of patients

Chronic HIV Infection – ongoing CD4+ T cell loss 12 CD4+ T cell loss is (1) directly from HIV replication (2) ongoing immune activation with CD4 cell apoptosis (3) from attack by HIV specific CD8+ T cells (4)low thymic output CD4 cell loss plus immune dysfunction CD4 count measure of immune deficit

Host Immune Response to HIV 13 Viral Set point Set point, useful for prognosis, predicts rate of CD4 cell fall

Humoral Immune Response to HIV 15 Seroconversion window

16 Control negatives ?? positive Control negatives ?? positive Viralproteinsseparatedby Mol weight Overlay pt serum then add labelled anti-IgG to reveal the binding of HIV antibodies Ab to gp41 or gp120 and p24 needed for to be + test Western Blot for detection of HIV antibodies

Humoral Immune Response to HIV 17 window Antibodies generated to HIV do not neutralize virus

Cellular Immune Response to HIV 19 Initial responses to HIV include large rise in HIV specific CD8+ CTL The broader CTL response the lower the set-point and better prognosis.

Cell mediated Immunity to HIV  CD8+ cells  CD8+ CTL can directly kill HIV infected cells & block HIV. Initially there is massive expansion of CD8+ CTL that are specific for HIV. Suppression of viremia follows the appearance of these CTL Broader CTL responses to HIV result in lower viral set point. Function of CD8+ CTL is dependent on CD4+ cells.  CD4+ cells  HIV specific CD4+ are generated during acute infection. Activated CD4 are preferentially infected & depleted by HIVVast majority are eliminated soon after they are generated. Loss of CD4+ cells specific for HIV target is distinct to HIV Lack of HIV specific CD4+ cells leads to inadequate maintenance of HIV specific CD8+ CTL that leaves the host incapable of killing new HIV variants are they arise. 20

Mechanisms of Immune Protection & Evasion 21 Host Protection Genetic factors as delta 32, HLA genotype, breadth of CTL response Viral Evasion HIV infects the very cells required to eradicate it. Error-prone RT, generates many HIV variant (mutants) new HIV variants can evade the Ab and CD8+killer cells made against the initial viral epitopes, these variants will now multiply HIV infected cells also evade CTLs by NEF (HIV protein) induced down regulation of Class I molecule on CD4 During HIV infection state immune activation exists increased in T and B cell turnover increased levels of pro-inflammatory cytokines.

Dynamics of HIV-1 Replication in patient on Antiretroviral Therapy (ART) 23

Immune Reconstitution but no Eradication 24 With antiretroviral therapy, HIV in plasma falls + CD4 rise (150 cells first year) With less HIV Ag stimulation, the elevated CD8+ cell counts & CD8 activation markers and HIV specific CTL activity fall As CD4+ count slowly rises there is gradual lessening of immunosuppression with reduced susceptibility to infection and return to health. Even with suppression of viremia below detectable levels, replication-competent HIV remains latent in CD4 cell and will rebound to high levels if antiretroviral therapy is stopped.

Summary  HIV gp120 binds to the cells CD4 molecule. The viral gp120 then binds to coreceptor CCR5 or CXCR4. The gp41 then fuses with the cellular membrane and virus enters cell.  Acute HIV infection resembles other acute viral infection with fever, swollen lymph glands, sweats, and sore throat.  The body responds to HIV by making antibodies to the viral envelope and capsid and other viral proteins. Cellular immunity is directed against the structural components particularly the capsid.  HIV is diagnosed by the presence of antibodies to viral components in the blood of an infected person. The HIV RNA level (viral load) is used to monitor response to therapy and severity of infection. The CD4 count is used to monitor how much damage the virus has done to the immune system.  With treatment, the viral RNA level falls and death of the CD4 cells caused by the virus stops. The CD4 cells are gradually replenished and the CD4 cell count then rises. 25

Questions?? 26 Dr Michael Para

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