Exam #6: Viral STIs Flashcards
List the characteristics of HIV. What is the difference between HIV-1 & HIV-2?
Retroviridae \+ssRNA Enveloped 2 Types= HIV-1 & HIV-2 (HIV-1 is more common worldwide & HIV-2 is more endemic to West Africa - Slower decline in CD4 T-cells - Longer asymptomatic period - Lower mortality
Note that the genome consists of a homodimer of two identical sequences; thus, it is functionally diploid.
Describe the structure of HIV. What proteins are associated with each part of the HIV structure?
+ssRNA (2x copies)
Enveloped= gp120 (attachment) & gp41 (fusion)
Matrix protein= p17
Nucelocapsid= p24
Genome= pol gene that encodes reverse transcriptase
List the stages retrovirus lifecycle.
Attachment (gp120) Fusion (gp41) Reverse transcription (pol gene) Integration (integrase) Transcription of provirus New genome & mRNA Budding
How does HIV attach? What cells does HIV attach to?
- gp120 binds CD4
- CD4 is found on T-lymphocytes, monocytes, & macrophages
- Conformational change in gp120 to allow binding to co-receptor (CCR5 or CXCR4)
What is the difference between R5-tropic HIV & X4-trophic HIV?
After attachment, gp120 undergoes a conformational change that allows binding to a co-receptor
- CCR5= person to person transmission
- CXCR4= more rapid progression to AIDS
What is the significance of CCR5 deletions in HIV?
Deletion in the CCR5 gene augments disease pathogeniticity
- Heterozygous= longer asymptomatic to R5
- Homozygous= no infection with R5 (1% of the Caucasian population)
However, can be infected with CXCR4
How does HIV fuse with the plasma membrane?
Gp41 mediates fusion between the viral envelope & plasma membrane by bringing the two close together
What codes for Reverse Transcription? What is the function of Reverse Transcriptase?
- pol gene
- Produces dsDNA linear copy of RNA HIV
*Note that this is associated with a high error rate because this is what allows for rapid evolution during the time course of disease e.g. resistance to antivirals
How does HIV integrate into the host genome?
- dsDNA moves into the nucleus
- viral integrase causes DNA copy to be incorporated into the host DNA
Viral DNA integrated into the host genome is called “provirus”
How does HIV egress?
- Viral envelope proteins are incorporated into the plasma membrane to form lipid rafts
- Virions acquire envelope as they bud from the cell, giving the the appearance of spheres with an electron dense ring surrounding
What is maturation?
Virion maturation= viral protease cleaves gag & gag-pol that is essential for infectivity
How is HIV transmitted? What is the risk associated with each mode of transmission?
Sexually
- Male-to-female is most effective
- Most common route
- Presence of other STIs increases risk
Perinatal= 1/4
- 25-30% before birth
- 50-65% at birth i.e. HIGHEST at birth
- 12-20% during nursing
Exposure to blood or body fluids
- Needle stick= 0.3%
- Mucous membrane= 0.09%
Note that the exposure risk to healthcare workers is less than that of Hepatitis B & C
What are the difference stages of HIV infection?
- Acute Infection= mononucleosis-like symptoms
- Chronic Phase= host immune response curtails plasma viremia; asymptomatic but chronic lymphadenopathy
- AIDS= opportunistic infections
Draw the graph of viral load, CD4 T-cell, & anti-HIV antibody through the course of the disease.
N/A
What symptoms are seen in acute HIV syndrome?
3-6 weeks post infection
Fever Malaise Arthralgia Lymphadenopathy Sore throat Rash
*May not have detectable levels of anti-HIV antibodies at this time.
What are the characteristics of chronic HIV infection?
- Low viermia
- HIV escape from immune response
- Patient asymptomatic
10 years in the absence of antivirals
What is the HIV-set point? Why is it important?
Level of the virus in the blood 1 year following infection
- Lowest= fewest individuals progressing to AIDS in 10 years following infection
- Highest load= most individuals progressing to AIDS in 10 years
How does HIV kill T-cells?
- Copious budding
- Interference with cellular processes
- Other mechanisms
How is AIDS defined?
CD4 T-cell count less than 200
List some common HIV associated infections.
- Oral Hairy Leukoplakia
- Peumonia
- Thrush
- CMV retinitis
- Neoplasms
- Diarrhea
What causes Oral Hairy Leukoplakia?
EBV
What causes HIV associated Pneumonia?
Pneumocystis carinii
Mycobacterium tuberculosis
What causes HIV associated Thursh?
Candida albicans
What causes HIV associated CMV retinitis?
Cytomegalovirus
What causes HIV associated Neoplasms?
Kaposi’s sarcoma
B-cell lymphomas
What causes HIV associated diarrhea?
Cryptosporidium
Isopsora belli
Draw the sequence & appearance of laboratory markers for HIV-1 infection.
1) HIV-RNA
2) HIV-1 p24 antigen
3) HIV antibody
Draw the algorithm for HIV testing.
1) Screen (HIV 1/2 antigen/antibody immunoassay for HIV p24 antigen & HIV1-2 antibodies)
2) Confirmatory test to differentiate HIV-1 & HIV-2
3) If negative or indeterminate, then nuclei acid testing to detect RNA genome
How is HIV NAAT used?
To follow the course of antiretroviral treatment
What are the different classes of anti-retrovirals?
Entry inhibitors or chemokine coreceptor antagonists Fusion inhibitors Reverse Trascriptase Inhibitors Integrase Inhibitors Protease Inhibitors
Describe the mechanism of action of the Entry inhibitors.
Chemokine receptor antagonists
- Bind to the co-receptor (CCR5 or CXCR4) & prevent interaction with gp120
Describe the mechanism of action of the Fusion inhibitors.
- Bind gp41 & prevent conformational change needed for fusion of the viral envelope with cellular plasma membrane
Describe the mechanism of action of the Reverse Transcriptase Inhibitors.
NRTIs i.e. “Nuceloside reverse transcriptase inhibitors”
- Nucloside analogs incorporated into the growing DNA chain during synthesis of provirus & cause early termination
NNRTIs i.e. “Nonnucleoside reverse transcriptase inhibitors”
- Reverse transcriptase antagonists
Describe the mechanism of action of the Integrase Inhibitors
Inhibit viral integrase to prevent DNA incorporation/ formation of the provirus
Describe the mechanism of action of the Protease inhibitors.
Act on the enzyme needed to cleave gag & gag-pol during virion maturation
What is the standard of care for ARV therapy?
Combination of drugs from three classes
- 2x NRTIs +
1) NNRTI
2) PI
3) II
