Embed Size (px)
Citation preview
Immunology of HIV Infection
Michael F. Para, MDProfessor of Internal Medicine
Division of Infectious Diseases
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
3HIV 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 ProcessVirus attaches to receptor then co-receptor then fuses
7
Cellular co-receptorIs CCR5 or CXCR4
Chemokine receptors
Initial cellular receptorIs CD4 molecule
gp41 folds on itself pulling viral envelope intocell membrane leading to fusion
gp41inserts intocellmembrane
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’s 3 step entry process
9
HIV Replicative Cycle
10HIV may remain “dormant” till T cell activated,
HIV preferentially infects & replicates in “activated” CD4 cells
cytokines
With error pronereplication, 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
12CD4+ 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 countmeasure of immune deficit
Host Immune Response to HIV
13
Viral Set point
Set point, useful for prognosis, predicts rate of CD4 cell fall
immune suppression
Humoral Immune Response to HIV
15
Seroconversionwindow
16 Control negatives ?? positive
ViralproteinsseparatedbyMol weight
Overlay ptserum thenadd labelledanti-IgG to revealthe binding ofHIV 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
HIV infection
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 ProtectionGenetic factors as delta 32, HLA genotype, breadth of CTL response
Viral EvasionHIV 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.
better suppression of HIV
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
Survey
We would appreciate your feedback on this module. Click on the button below to complete a brief survey. Your responses and comments will be shared with the module’s author, the LSI EdTech team, and LSI curriculum leaders. We will use your feedback to improve future versions of the module.
The survey is both optional and anonymous and should take less than 5 minutes to complete.
Survey
