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Unit 3 �Immunodeficiency Diseases/HIV

MLAB 1335 – Immunology

Part Five – Immunodeficiency Diseases and HIV

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Immunodeficiency Disease

Immunodeficiency is defined as

Disorders where parts of the immune system are missing or dysfunctional
Symptoms can be mild to severe with recurrent infections

Two types

Primary immunodeficiency – inherited dysfunctions of the immune system

Most important demonstrate X-linked inheritance

Secondary immunodeficiency – acquired as in AIDS, caused by HIV

Current infections
Cancers
Autoimmune disorders
Immunosuppressive drugs

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Primary Immunodeficiency

Nine categories, we will focus on a few
Defects in antibody-mediated immunity

Recurrent infections with pyogenic bacteria
Primarily in respiratory and intestinal tracts
Examples include recurrent sinusitis and otitis media
More severe problems if agammaglobulinemia

Defects in T-cell mediated immunity

Recurrent infections with intracellular pathogens
Viruses, fungi, and intracellular bacteria

Defects in phagocyte function

Pyogenic bacterial infections, especially the skin
Range from mild to lethal

There are nine categories, but we will only speak of these in generalities. The defects in antibody-mediated immunity result in recurrent infections with pyogenic bacteria. These primarily affect the respiratory and intestinal tract. Examples include recurrent sinusitis and otitis media. More severe problems include agammaglobulinemia.

Defects in T-cell mediated immunity result in recurrent infections with intracellular pathogens such as viruses, fungi, and intracellular bacteria.

Defects in phagocytic functions cause recurring pyogenic bacterial infections, especially with skin involvement. These can range from mild to lethal.

Primary immunodeficiencies (PIDs) must be suspected in the clinical arena and are diagnosed with the help of screening tests to measure WBC count and immunoglobulin levels. From there, specialized testing including flow cytometry is used to determine different subsets of lymphocytes. Laboratory results will correlate with specific PIDs. For example, newborn screening is used to detect SCID, a combine immunodeficiency disease involving defective T-cell function. In Bruton’s tyrosine kinase deficiency, patients have decreased serum concentration of the immunoglobulins and decreased numbers of CD19+ B cells.

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Secondary Immunodeficiency

Secondary immunodeficiency – acquired as in AIDS, caused by HIV

Current infections
Cancers
Autoimmune disorders
Immunosuppressive drug therapy

AIDS

Acquired immunodeficiency syndrome

Caused by the human immunodeficiency virus (HIV)
A retrovirus – an RNA virus that inserts a DNA copy of its genome into the host cell in order to replicate (make DNA from their RNA) using reverse transcriptase
Discovered by Luc Montagnier of France and Robert Gallo of US in 1983-1984.
No cure

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HIV

Infection in humans came from a chimpanzee in Central Africa from contact with infected blood (hunting)
May have jumped from chimpanzees to humans as early as 1800s
Probably in the US in mid to late 1970s
Symptoms – within 2 to 4 weeks after infection

Fever
Chills
Rash
Night sweats
Muscle aches
Sore throat
Fatigue
Swollen lymph nodes
Mouth ulcers

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HIV - Anatomy of the virus

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HIV - Structural Genes

The genome of HIV has three main structural genes which code for specific products

gag – Codes for nucleocapsid and core proteins

p55 – a precursor protein providing four core structural proteins

p6, p9, p17 and p24

env – Codes for viral envelope

Glycoproteins gp160, gp120, and gp41

pol – codes for enzymes necessary for HIV replication

Reverse transcriptase p51

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HIV - Replication

HIV attaches to the host-cell CD4 antigen

Serves as a receptor for the virus by binding gp120 glycoprotein on the outer envelope of HIV

T-helper cells are the main target for HIV – highest number of CD4 molecules on their surface

Bind with T-helper antigen with HIGH affinity

After fusion, virus enters cell, uncoating occurs and exposes viral genome

Reverse transcriptase produces complementary DNA from viral RNA
THEN…

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HIV - Replication

Double-stranded DNA is created and integrated into the host cell genome as a provirus

Can remain latent for long periods before replication

Viral DNA is transcribed into genomic RNA; mRNA which sends message to create viral proteins for assembly into new viral particles

Virions acquire envelope when break out of host cell

Viral replication occurs almost always in antigen-activated T-helper cells

Replication occurs rapidly leading to a high rate of mutations

This diversity LIMITS the host’s capability of mounting an immune response

The double-stranded DNA is created and integrated into the host cell genome as a provirus and can remain in that state for long periods of time before replication. When replication occurs, the viral DNA is transcribed and messenger RNA (mRNA) is created. The mRNA sends a message to the ribosomes and the viral proteins are produced. The viral proteins are then assembled into new viral particles. As the new viruses leave the T-helper cell, they acquire an envelope.

Viral replication occurs almost always in antigen-activated T-helper cells, although there are other cells that have the CD4 antigen. The other cells such as the macrophage, do not have many CD4 antigens on their surface, so they are not as likely a candidate to be infected.

HIV replication is very fast and with this speed comes a high rate of mutation (mistakes). This diversity because of mutation limits the host’s ability to mount an effective immune response.

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HIV - Replication

HIV is seen at the arrows, infecting a T-helper cell

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HIV - Replication

Viral production may slow down as the host’s immune response develops
Host produces neutralizing antibodies, prevents virus from infecting close cells

Host develops HIV-specific CTLs that lyse virus-infected target cells
Innate defenses also activated
Can reduce level of HIV replication, not enough to eliminate virus

Due to virus capability to mutate and alter antigens

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HIV - Downfall of immune system

HIV infection – decline in CD4 T-helper cells

Results in immunodeficiency affecting cell-mediated and humoral antibody responses to antigens

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HIV – course of disease

If untreated HIV

Acute phase of flu-like symptoms
Latent, asymptomatic period – may last up to 10 years
AIDS

Profound immunosuppression
Life-threatening opportunistic infections
Malignancies

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HIV – course of disease

CDC guidelines/definitions of the course of disease
Stage 1 – Acute HIV infection

HIV positive, flu-like symptoms

Stage 2 – Chronic HIV infection

CD4 count falls below 500, persistent opportunistic infections

Stage 3 – Acquired Immunodeficiency Syndrome (AIDS)

Extreme weight loss, fever, opportunistic infections, unusual cancers, CD4 count less than 200

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AIDS�

Stage 3 – AIDS

Patients receive an AIDS diagnosis �when the CD4 cell count drops below �200 cells/mm³ or if they develop �opportunistic infections

Patients with AIDS can have a �high viral load and can be VERY infectious

Without treatment, patients with �AIDS survive ~ three years

Photo of Kaposi’s sarcoma - a rare cancer of the blood vessels

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HIV testing�

What is the window period for the HIV test?

Antibody tests can usually detect HIV 23 to 90 days after exposure. Most rapid tests and self-tests are antibody tests.
A rapid antigen/antibody test done with blood from a finger stick can usually detect HIV 18 to 90 days after exposure.
An antigen/antibody lab test using blood from a vein can usually detect HIV 18 to 45 days after exposure.
A nucleic acid test (NAT) can usually detect HIV 10 to 33 days after exposure.

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HIV - Testing

Rapid antigen/antibody screening tests – ready in 30 minutes or less

ELISA method, must confirm with high specialized testing if positive

NAT – nucleic acid testing - commonly used for confirmatory testing

Three molecular methods

Reverse-transcriptase PCR - a testing method that converts HIV RNA into cDNA and then is amplified
Real-time PCR method – amplifies a DNA sequence complementary to a portion of the HIV RNA genome
Branched chain DNA, which amplifies a labeled signal bound to a test plate

Western Blot

Used from 1985 to 2014, to confirm ELISA positives
Identified specific amino-acid sequences in proteins
Labor intensive

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HIV - Treatment

Antiretroviral therapy (ART)

Suppresses the virus’s replication

About 80% are virally suppressed at their last test (HIV surveillance report 2017)
Drugs such as nucleoside reverse transcriptase inhibitors block HIV replication cycle

Multiple drug therapy

Combinations of at least two of the antiretroviral drug classes

Vaccine?

HIV rapidly mutates with no ideal animal model to study vaccine effects

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Ending slide