M10: Failure of the Body's Defenses

What are some mechanisms that pathogens may use to evade the immune system?

• Genetic variation

• Gene conversion

• Hiding (latency)

• Subversion

What virus is a notorious example of genetic mutation?

Influenza

What is influenza virus?

RNA virus that uses an RNA dependent RNA polymerase to replicate and transcribe its RNA in host cells

• no proofreading bc of so much mutations

Where do most mutations occur?

Most mutations occur in hemagglutinin and neuraminidase glycoproteins on the viral envelope (involved in host-cell binding and endocytosis)

What is antigenic drift?

A mechanism of influenza evolution where gradual small mutations/changes in influenza’ structure occur until our antibodies can no longer recognize them

Causes relatively mild and limited outbreaks (epidemics)

What is antigenic shift?

A less common mechanism of influenza evolution that occurs when two influenza A strains (not in B) from different species infect the same host, leading to the formation of a recombinant influe

Causes pandemics (Spanish influenza) 

What protozoan is notorious for using gene conversion?

Trypanosomes

How does Trypanosomes infect humans?

Once in humans → rapid replication produces many clones with dominant VSG and a subset of minority VSG

Dominant VSG will be cleared however minority then rapidly divides

This becomes a chronic cycle of antibody production and antigen clearance leading to deposition of immune complexes and inflammation

i.e. African sleeping sickness → neurological damage + coma

What virus is notorious for hiding (latency)?

Herpesviruses

What is HHV-1?

Human herpes simplex virus-1 is a common human pathogen that causes little damage

What is the process of infection of HHV-1?

1) Infects epithelial cells of the face, leading to lytic phase where epithelial cells die and form blisters

2) Goes into dormant state which then travels along sensory neuron axon to the cell body in the trigeminal ganglion

3) Remains latent state until reactivated, causing reemergence of the virus

How does mycobacterium tuberculosis do subversion?

Phagocytized then stays inside vesicular system of macrophages (cannot be broken down)

How does Listeria monocytogenes do subversion?

Engulfed but escapes phagosome → enters cytoplasm of dendritic or macrophage cell to replicate

How does Toxoplasma gondii do subversion?

Creates its own impenetrable vesicle (even when engulfed) that cannot be fused with other vesicles

How does Treponema pallidum do subversion?

Coats itself in human proteins

How does superantigens contribute to subversion?

Potent toxins that can produce an overexaggerated immune response by activating several different T cell clones

• 2-20% of CD4 T cell clones

• excessive production of IL-2, IFN-y, TNF-a

“Distracts immune system” - Staphy/Strepto

How can superantigens activate CD4 T cells easily? (site wise)

By binding to different sites, superantigens can substitute for: peptide antigens, the TCR, co-receptor, and co-stimulatory receptor to to fully activate CD4 T cells

How can superantigens activate CD4 T cells easily? (chain wise)

Each superantigen engages different VB chains which activates different CD4 T cells

• S. aureus toxic shock syndrome toxin 1 (TSST-1) binds to TCR B chains from the VB2 gene

• S. aureus enterotoxin B (SEB) binds to TCR B chains from the VB1.1, 3.2, 6.4, and 15.1 genes

What 3 sites do superantigens bind to on CD4 cells?

• antigen binding site of MHC II

• VB of TCR

• CD28, without affecting B7:CD28 binding

How does interfering with IgA-stimulated phagocytosis involved in subversion?

S. aureus secretes SSLPs which binds to complement proteins/antibodies blocking IgA from binding to the receptor on macrophages to be recognized to be engulfed

What are immunodeficiencies?

Occur when a component of the immune system is unable to function, preventing the immune system from fully functioning

What are the two forms of immunodeficiencies?

Primary: Arise from inherited genetic mutation

Secondary: Arise from environmental factors (chemotherapy/immunosuppressive drug treatment/HIV)

What is HIV?

Human immunodeficiency virus (HIV) is an RNA virus that causes an infection that lasts throughout life without clearance

What does HIV target?

The target host cells are CD4+ because they activate T/B cells, activating macrophages, enhancing neutrophils, and targeting parasites

• their destruction leads to the progressive shutdown of the immune system (AIDS)

What is HIV-1?

• Originated from SIVCPZ that infects chimpanzees native to the Cameroon

• Endemic to Western-Central Africa and spread to pandemic proportions by 1980s

• Main cause of AIDS globally

What is HIV-2?

• Originated from SIVSM that infects sooty mangabeys native to Guinea Bissau, Gabon, and Cameroon

• Rare in US but endemic to Western Africa

• Significantly less infectious, progresses to AIDS more slowly

How is HIV a retrovirus?

HIV uses its RNA to create a DNA intermediate to incorporate into host cell transcription and translation machinery

What is the mechanism of HIV infection?

Glycoprotein spikes on the envelope (gp120 and gp41) bind to immune cell receptors (macrophages, dendritic cells, NK cells) until it presents it to a T cell where it then would attach to CD4+ to start replicating/hijacking

How is p64 reverse transcriptase involved in HIV infection?

Converts HIV's RNA genome into double-stranded DNA

What happens during acute HIV infection?

First 2-4 weeks

• Eclipse period = first 10 days when clinical markers for HIV are undetectable

• Some experience acute retroviral syndrome (ARS) with flu-like symptoms

What happens during chronic HIV infection?

Clinical latency

• Infection is established

• Body developed positive IgG response (detectable by Western Blot) but is unsuccessful bc HIV mutates so much

• without ART, typical progressors advance to AIDS in 10-12 years

What is considered AIDS in the phases of infection for HIV?

When CD4 cell count is below 200 cells/uL blood and/or one or more opportunistic infections

• malignancies (non-Hodgkin’s lymphoma, Kaposi’s sarcoma)

• managed with antimicrobial prophylactic regimens

What are the 7 classes of ART?

(Use at least 3 compounds to jointly block HIV infection)

1. Nucleoside reverse transcriptase inhibitors (NRTIs)

2. Non-nucleotide reverse transcription inhibitors (NNRTIs)

3. Protease inhibitors (PIs)

4. Fusion inhibitors (FIs)

5. CCR5-blocking entry inhibitors

6. Integrase inhibitors (INIs or INSTIs)

7. Pharmacokinetic (PK) enhancers

NRTIs and NNRTIs do what?

prevent production of cDNA

PIs do what?

inhibit viral proteases

FIs and CCR5-blocking entry inhibitors do what?

Prevent the virus from being able to attach to the host cell allowing the genome to enter

INIs or INSTIs do what?

Prevent viral cDNA from being integrated into your own DNA

Why is antiretroviral therapy (ART) effective in controlling HIV infection but not considered a cure?

ART suppresses viral replication, preventing disease progression, but latent HIV reservoirs remain in infected cells and can reactivate if treatment stops.

Which of the following best explains why HIV vaccine development has been challenging and how broadly neutralizing antibodies (bNAbs) may offer a potential solution?

HIV has a high mutation rate and extensive antigenic diversity, making it difficult to target with a vaccine, whereas bNAbs recognize conserved viral regions less prone to mutation.

How does Staphylococcus aureus evade phagocytosis using superantigens and SSLP7?

Superantigens hyperactivate T cells, leading to immune system dysregulation, while SSLP7 binds to IgA and C5, blocking opsonization and complement-mediated phagocytosis.

Which of the following correctly matches an HIV structural component with its role in infection of CD4 T cells, macrophages, and dendritic cells?

gp120 binds to CD4 and coreceptors (CCR5 or CXCR4), facilitating viral entry, while gp41 mediates membrane fusion.

Which of the following describes a common strategy used by bacteria and protozoans to subvert the immune response within the vesicular system?

They either escape from the phagosome, modify the vesicle to prevent lysosomal fusion, or survive within the harsh environment of the phagolysosome.

Match each phase of HIV infection with the key events and immune response characteristics that occur during that phase.

1) Acute Phase

2) Chronic Phase

3) AIDS

1) initial spike in viremia, CD4 T cell count drops, strong immune response with temporary viral control

2) persistent but lower levels of viral replication, slow decline of CD4 T cells, immune exhaustion develops

3) gradual depletion of CD4 T cells, weakened immune response, opportunistic infections appear

Which of the following best describes the course of herpes simplex virus type 1 (HSV-1) infection?

After an initial lytic infection, HSV-1 establishes latency in sensory neurons, where it can later reactivate due to stress or immunosuppression.

Which of the following best describes the difference between antigenic drift and antigenic shift in the influenza virus?

Antigenic drift occurs due to gradual mutations in the viral genome, while antigenic shift results from the reassortment of genetic material between different strains of the virus.