First Aid, Chapter 8, Immunologic Disorders, Acquired (Secondary) Immunodeficiencies

Question 1

What are the basic steps in the HIV life cycle?

Answer 1

Viral entry

Reverse transcription

Integration

Transcription

Maturation

Viral packaging and budding

Question 2

What are the key events in viral entry of HIV into a cell?

Answer 2

HIV gp120 binds to CD4 and chemokine coreceptor CCR5 or CXCR4 on the host cell surface

Coreceptor binding -> conformational change in gp41 -> fusion of HIV membrane with host cell membrane -> entry of viral genome into cytoplasm

Question 3

What are the key events in reverse transcriptase of the HIV life cycle?

Answer 3

Activation of enzymes within viral nucleoprotein complex Viral reproductive cycle begins HIV ssRNA -> dsDNA by reverse transcriptase

Question 4

Describe the key events during integration in the HIV life cycle?

Answer 4

Proviral DNA enters nucleus and is integrated into the host DNA by enzyme integrase

Question 5

Describe the key events during transcription and translation in the HIV life cycle?

Answer 5

Proviral DNA transcribes into genomic RNA or mRNA; then translated into viral proteins in the cytoplasm

Question 6

Describe the key events during maturation in the HIV life cycle?

Answer 6

HIV protease cleaves the viral polyprotein into functional peptides and becomes infectious

Question 7

Describe the key events during viral packaging and budding in the HIV life cycle?

Answer 7

Packaging RNA transcripts within a nucleoprotein complex. Enclosing within the host’s membrane envelope and released from the cell.

Question 8

What are the 2 types of HIVs? Which is more common? Which is more virulent?

Answer 8

HIV-1: More virulent, more infective, the majority of HIV infections globally

HIV-2: Largely confined to West Africa, lower infectivity

Question 9

What is the virus structure of HIV?

Answer 9

Two identical ssRNAs

Several enzymes packaged in a core; composed of nucleocapsid p24 and outer membrane p17

All are surrounded by a host-derived lipid bilayer membrane with two glycoprotein projections: gp120 and gp41 (Figure 8-4)

Question 10

What cells can HIV infect?

Answer 10

HIV crosses mucosal surfaces to infect susceptible cells (CD4– +T cells, monocytes/macrophages, dendritic cells, and neurons).

Question 11

At what point of its life cycle can HIV go into latency? For how long?

Answer 11

During latency period, the integrated proviral DNA may remain transcriptionally inactive for months or years.

Question 12

What is HIV coreceptor tropism? Which strains use which receptors and at what stages of the disease?

Answer 12

Receptor: CCR5
Host cells: Monocytes/macrophages
Strain: M-tropic (monocytotropic) or R5 strain of virus
Stage: Acute infection

Receptor: CXCR4
Host cells: T cells T-tropic (T-cell lymphotropic) or X4 strain of virus
Stage: Advanced HIV disease

Question 13

What are the immune responses in acute HIV viremia?

Answer 13

HIV infects CD4+ T lymphocytes, macrophages, and dendritic cells.

Infected cells migrate to the regional lymphoid tissues in 3–5 days.

Direct cell-to-cell contact between virus-harboring cells and susceptible cells within germinal centers leads to a brisk increase in viral replication within 14 days after exposure.

Question 14

What are specific immune responses to HIV?

Answer 14

The most effective, adaptive immune response to HIV infection during the acute phase is the expansion of HIV-specific cytotoxic T lymphocytes (CTLs).

Antibody responses to HIV antigens are detectable within a few weeks after infection

Neutralizing antibodies against gp120 develop 2–3 months after infection, but are not effective.

Question 15

Why does CD4+ T cell lymphopenia occur in HIV?

Answer 15

There are three main mechanisms:

1) Direct viral killing of infected cells (cytopathic effect)
2) Increased apoptosis of infected cells
3) Killing of infected cells by HIV-specific CTLs.

Question 16

Why does hypergammaglobulinemia occur in HIV?

Answer 16

Although the hypergammaglobulinemi a is partly due to antibody against the HIV itself, it is also in part attributable to polyclonal activation of B cells.

Question 17

What are the most immunogenic HIV molecules?

Answer 17

The most immunogenic HIV molecules are gp120 and gp40. The virus can attach to dendritic cells through the binding of gp120 to the adhesion molecule DC-SIGN (dendritic cell-specific intercellular adhesion molecule-grabbing nonintegrin).

Question 18

What is the significance of CCR5Δ32 mutation?

Answer 18

Double-allelic mutations confer resistance to the CCR5 strain of HIV (resistant to infection despite being repeatedly exposed to HIV through sexual contact). Single allelic mutations are long-term nonprogressors (slow disease).

Question 19

What is the sensitivity and specificity of ELISA for HIV? When are there false positives? When are there false negatives?

Answer 19

High sensitivity, moderate specificity; therefore require a confirmatory test.

Used as a screening tool for both HIV-1 and 2

False-positive: Autoimmune diseases, multiple pregnancies, multiple blood transfusions, following immunizations

False-negative: Window period (can be up to 6 months after infection)

Question 20

What is the sensitivity and specificity of the rapid HIV test for HIV?

Answer 20

High sensitivity, moderate specificity; therefore require a confirmatory test Detect anti-HIV antibody in blood/oral fluid. Turnaround time

Question 21

What are the sensitivity and specificity of western blot for HIV? What are the downsides? What is a positive test considered? What should you do for an indeterminate or negative test?

Answer 21

Confirmatory test (high sensitivity, high specificity)

Expensive and labor intensive.

Used to confirm a reactive EIA/ELISA test or rapid HIV test

A positive WB test requires two of three major bands: anti-p24, anti-gp41, and anti-gp160/gp120

Follow-up indeterminate or negative test by repeating WB in 4 weeks or considering WB for HIV-2. If results continue to be indeterminate, then virologic testing recommended

Question 22

What in an indirect immunofluorescent antibody assay used for with HIV testing? How is it done?

Answer 22

Confirmatory test

Specimens evaluated by fluorescence microscopy

Question 23

Is HIV DNA by PCR sensitive? Specific? Where does HIV DNA by PCR detect HIV-1 DNA? When is it used?

Answer 23

Moderate sensitivity, high specificity Detects HIV-1 DNA within the PBMC

Used mainly in acute viral syndrome when antibody test is negative and in exposed infants

Question 24

Is HIV RNA by PCR sensitive? Specific? What does it do? When is it used?

Answer 24

Moderate sensitivity, high specificity Quantifies viral load; reported as RNA copies/mL Provides indication for treatment and gauges therapeutic response.

Question 25

What HIV testing should be done in HIV-1 exposed infants? When should it be done? Are umbilical cord samples recommended to be tested?

Answer 25

At birth, within 14–21 days of age; 1–2 months of age and 4–6 months of age to identify or exclude HIV-1 infection.

An antibody test by ELISA between 12–18 months should be performed to definitively exclude HIV-1 infection.

Antibody tests in infants younger than 18 months old are not routinely recommended due to the presence of passively acquired maternal antibody.

Umbilical cord blood sample is not recommended due to high false positive rate.

Question 26

What type of prophylaxis should be used in infants with HIV and when should it be used?

Answer 26

Pneumocystis jiroveci pneumonia (PJP) prophylaxis beginning at 4–6 weeks of age is recommended for infants determined to be infected with HIV-1 until at least 1 year old.

Question 27

What class of medication are maraviroc and enfuviritde? What phase of the HIV life cycle do they target? What do they bind?

Answer 27

Entry inhibitors (fusion inhibitors)

Target binding, fusion, and entry of virion

Maraviroc (binds to CCR5) and enfuvirtide (binds to gp41)

Question 28

What class of medication is raltegravir? What phase of the HIV cycle does it inhibit? What is the mechanism of action?

Answer 28

Integrase inhibitors (II)

Integration of viral DNA into the DNA of the infected cell

Inhibit enzyme integrase

Question 29

What class of medication are Zidovudine, didanosine, abacavir, and tenofovir? What phase of HIV cycle do they inhibit? What is the mechanism of action?

Answer 29

Nucleoside or nucleotide reverse transcriptase inhibitors (NRTI or NtRTI)

Reverse transcription

Incorporated into the newly synthesized viral DNA to terminate the DNA strand

Question 30

What class of medication are Efavirenz, nevirapine delavirdine and etravirine? 
What phase of HIV cycle do they inhibit? What is the mechanism of action?

Answer 30

Nonnucleoside reverse transcriptase inhibitors (NNRTI)

Reverse transcription

Bind directly to enzyme reverse transcriptase and inhibit its function

Question 31

What class of medication are Ritonavir, indinavir, nelfinavir, lopinavir, and atazanavir? What phase of HIV cycle do they inhibit? What is the mechanism of action?

Answer 31

Protease inhibitors (PIs)

Viral assembly

Inhibit activity of protease

Question 32

What medication should HLA B57 be checked prior to starting and why?

Answer 32

It is recommended to screen for HLA-B5701 before starting a patient with abacavir. Abacavir challenge is absolutely contraindicated if there is a history of hypersensitivity reaction or positive HLA-B5701 testing, since it can result in a severe and potentially lifethreatening reaction.

Question 33

Which HLA allele is associated with an increase risk in abacavir hypersensitivity?

Answer 33

HLA-B*5701

Question 34

What should be done prior to starting HAART in a patient with low CD4 and an OI?

Answer 34

If patients have a low initial CD4+ Tlymphocyte count and OI at the time of HIV diagnosis, they should receive treatment to control the OI before HAART is initiated.

Question 35

When does immune reconstitution inflammatory syndrome (IRIS) occur? What is the mechanism? In what setting does it occur? What are the clinical manifestations?

Answer 35

A paradoxical deterioration in clinical status, usually 4–8 weeks after HAART initiation.

Attributed to the reactivation of the immune response (cytokine storm) to an existing opportunistic infection (OI) when the CD4 count rapidly increases.

Most common OIs associated with IRIS include TB and Pneumocystis jiroveci pneumonia (PJP), although CMV, herpes zoster, and Mycobacterium avium complex (MAC) can be associated with IRIS.

Patients present with new or worsening systemic manifestations, such as fever and malaise or local reactions in organs (e.g., lungs/CNS) depending on the location of the OI.

Question 36

Who is at high risk for immune reconsitution inflammatory syndrome?

Answer 36

Subjects at high risk for IRIS include:

Those starting HAART for the first time

CD4+ T lymphocytes

Question 37

When should prophylaxis for pneumocystis jiroveci be used in HIV? What is the medication?

Answer 37

CD4

Question 38

When should prophylaxis for mycobacterium avium complex (MAC) be used in HIV? What is the medication?

Answer 38

CD4

Question 39

When should toxoplasma gondii prophylaxis be used in HIV? What is the medication?

Answer 39

CD4

Question 40

When should histoplasma capsulatum prophylaxis be used in HIV? What is the medication?

Answer 40

CD4

Question 41

When should coccidoides species prophylaxis be used in HIV? What is the medication?

Answer 41

CD4 counts

Question 42

What are the aims of potential HIV vaccines?

Answer 42

Candidate HIV vaccines aim at inducing neutralizing antibodies, CTLs, and strong mucosal responses.