HIV (L15/16) Flashcards
What viruses are part of the papovavirus family?
360 subunit papillomaviruses
Polyoma virus
SV40
How does a DNA tumor virus work?
When the viral DNA becomes stably incorporated into a host cell chromosome
What are the stages of the retroviral cycle?
- Entry into cell and loss of envelope
- Reverse transcriptase makes DNA/RNA and then DNA/RNA double helix
- Integration of DNA copy into host chromosome
- Transcription
- Translation
- Assembly of many new virus particles, each containing reverse transcriptase, into protein coats
What are the stages of HIV infection?
- Recognition of and attachment to the host cell
- Delivery of the viral nucleic acid into the host cell
- Mutate and reproduce to survive
What are the features of a HIV particle?
Cleaves precursors into viral protein Integration into host nucleus Receptor (CD4) and co-receptor on immune cells 72 projections ssRNA to RNA-DNA hybrid to dsDNA P17, 18, 24 P10 protease Reverse transcriptase MHC protein p32 integrase gp120, gp41 ssRNA
Describe the HIV-receptor interactions
The variable loop V3 in gp120 interacts with the co-receptor following binding to CD4
What does CD4 consist of?
4 Ig domains and a small cytoplasmic region
How is CD4 recognised by HIV?
Recognised by gp120 (V1/V2 loop region)
Co-receptor initially CCR5 on monocytes/macrophages gp120 (loop V3)
As infection progresses, variants recognising CXCR4 on TH cells arise
These variants may have only 1 AA change in gp120 (loop V3)
How does cell mediated adaptive immunity try to combat HIV?
Nearly all vertebrate cells, including Helper T cells, exhibit on their surface a sample of peptides derived from digestion of proteins in their cytosol
Peptides derived from cytosolic proteins are bound to class I MHC proteins
Cytotoxic T cells scan curfaces of all cells and kill those that exhibit foreign markings via recognition of the MHC1-peptide complex by the T-cell receptor and co-receptor CD8
Why does adaptive immunity fail for HIV?
HIV inhibits expression of MHC1 on the surface of the cells they infect, therefore not allowing it to be detected by cytotoxic T cells
How are helper T cells affected by HIV?
- Helper T cells are infected by HIV, leading to HIV proliferation, and eventually death of the T helper cell
- The infected Helper T cells are essentially invisible to the cytotoxic T cells and hence cannot be neutralised
How are natural killer cells affected by HIV?
Their natural killing ability is inhibited by high levels of MHC1 due to the fact that NK cells usually kills cells expressing low levels of MHC1
What are some of the strategies to combat HIV?
Inhibit integrase Inhibit reverse transcription or transcriptase Inhibit entry: receptor(s) or gp120/gp41 Inhibit protease Possible vaccines?
How does HIV protease work and how would you inhibit it?
HIV protease cleaves multidomain viral proteins into active form.
Dimer of 99 AA with active aspartases in the binding pocket and a flap which closes on peptide substrate binding.
Crixivian mimics the peptide substrate but includes a non-cleavable scissile bond
How is reverse transcription inhibited?
- An oxygen bridges the sugar of one nucleotide to the phosphate of the next
- The sugar’s OH and the phosphate’s OH react, making water and joining the 2 nucleotides
- The sugar of ZDV (an inhibitor) has no OH here
- No more nucleotides can add to the new DNA strand, so reverse transcription stops
What are the current inhibitor therapies?
One or more protease inhibitors
Reverse-transcriptase inhibitor
Triple-nucleotide regimens
Combination therapy
Describe the CD4-HIV interaction
CD4 binding site on gp120 very restricted and narrow which is difficult for Fab to penetrate and bind, and mutations surrounding the site prevent recognition
A phenylalanine residue (Phe43) on CD4 head is the key interacting residue
How is CCR5 inhibited?
The initial HIV co-receptor CCR5 normally responds to immune chemicals call beta chemokines. PSC-RANTES, a modiefied version of the chemokine RANTES which recognises CCR5, blocks access CCR5
Describe the gp120 initiation of fusion
Th gp41 interacts with the gp120 N and C termini via the 3 fold axis, to generate the functional oligomer
In the initial state of gp120 (on the surface of a virion), the V1/V2 loops partially occlude the CD4-binding site
Following CD4 binding, there is a conformational change with formation of the Phe43 cavity
In the next step, the chemokine receptor binds to the bridging sheet and the V3 loop causing an orientational shift of core gp120 relative to the oligomer. This triggers further changes, which ultimately lead to the fusion of the viral and target membranes.
