HIV Part 1 Flashcards
AIDS (Aquired Immunodeficieny Syndrome)
- HIV + Opportunistic infections
- Immunocompromised individuals
- Low levels of CD4 T helper cells
HIV (Human Immunodeficiency Virus)
- HIV-1 and HIV-2 subtypes
- Vaccines against all sub types is important
- High mutation rates- variants
- Variants- changes to which cell type they infect
- All similar structure and replication process
HIV structure
- Retrovirus (Lentifamily)
- 2 single stranded RNA- bound by molecule of reverse transcriptase
- In genome - p10 protease and p32 integrase
- Surrounded by nucleocapsid - inner layer of protein p24, outer layer of protein p17
- > p24 = core antigen capsid protein
- > both: Gag (group specific antigen) polyprotein complex)
- Outer most portion- lipid membrane derived from host cell
- > contains gp120 and gp41 = envelope proteins
What are its viral envelop proteins?
g120
gp41
What proteins make up the nucleocapsid?
Inner = p24
Outer=p17
p24 and p17 form what complex?
GAG polyprotein complex
What proteins what in the genome of HIV?
p10- protease
p32- integrase
What does GAG encode for?
- Created as a larger molecule =p53 = GAG precursor polyprotein
- To become function its broken down by protease to produce -Structural capsid proteins
- > p24 = core antigen capsid protein
p17
Matrix protein - 131 amino acids
p7
Nucleo-capsid protein - 55 amino acids
Role of the GAG protein
- outermembrane
- assemby of new HIV virus particles
- Brings viral RNA and viral proteins and host proteins together
- triggers process of forming new virus particles
- breaks awat from host cell surface
- infect other cells
What side chains are found on gp120?
Glycans
What receptor does HIV target and where is it expressed?
- CD4+ receptor
- On CD4+ T helper cells, some on monocytes and dentritic cells
2 stages of HIV viral infection
- Binding - gp120 (viral envelope) to CD4+ receptor
- Fusion
What type of receptors are CD4+ Receptor
Glycoproteins
* Co-receptor of T cell receptor (TCR)
Upon viral recognition of CD4+ R, what it secreted to fight off infection?
- B cells
- T killer
- CD4+ T helper (HIV target)
Normal function of CD4
- Major histocompatability complex II (MHCII) molecules on antigen presenting cell
- Present antigen (piece from bacteria)
- CD4+ and TCR bind to MHCII at different region
- Brings it closer- enabled Lck kinase to phosphorylate ITAMS on CD3 complex on TCR.
- Phosphorylated ITAMS recruit ZAP70 enymze
- Activates downstream signal transduction via tyrosine phosphorylation in T cell
- > phorphorylation of proteins
- NF-Kappab (NK-kb) activation
- Leads to T cell activiation- immune response against presented antigen
Possible diagram question- Life Cycle of HIV
1). Binds to CD4 +ve cells through gp120 to CD4; interactions between virus and chemokine co-receptors.
2). Nucleocapsid enters the cell, unfolds, releasing viral RNA, which is reverse-transcribed to DS DNA.
3). The viral DNA integrates in the host genome, where it lies dormant as a provirus.
4). Following cell activation, viral DNA directs the transcription of viral RNA.
5). Viral proteins are translated from the RNA.
6) Viral proteins and single-stranded viral RNA assemble to form new viral particles.
7). Virus buds from the cell, picking up some of cell membrane, complete viral particles can infect other cells.
When gp120 binds to CD4+ what other co-receptor is involved?
Chemokine co-receptor
What is the virus called when its genetic material integrates with host genome?
Provirus
The provirus is said to be what before activated?
Dormant
What is the specific chemokine co-receptor associated with CD4+TCR?
CCR5
Hijacks immune cell- HIV circumvents normal Dendritic Cell -T cell inter
Explain the viral strategy for efficient transmission of viral particles upon dendritic infection?
- Dendritic shoot out thin appendages - filopodia
- Rearrangement of actin filaments
- Relatively fast
- Carries the viral particle to T cells
- Waving arc motion
- Efficient viral transmission
Old Model HIV Binding
Explain HIV binding
- gp120 binds to co-receptor CD4+ on TCR
- gp41 bind to a second protein = chemokine co-receptor on TCR
- 2 types of co-receptor depending on HIV Variant
Old model HIV bonding
M-tropic variant
M-tropic variant
* gp41 brinds to b-chemokine co-receptor = CCR5
* Present: CD4+ T cells, Monocytes and Dendritic cells
Old model HIV binding
T-tropic variant
T-tropic variant
* a-chemokine co-receptor= CXCR4
* Only on CD4 T cells
* Not expressed on monocytes
* Not expressed on Dendritic cells
HIV Binding (New model)
Explain the new model for HIV model in detail?
- gp160= precursor fusion glycoprotein
- > fuse viral and host membrane
- Spike formation - trimer (3 molecules) of gp120 come together
- Cleaved -> gp4(transmembrane) + gp120(surface)
- gp120: binds to CD4+ co-receptor
- > structural change, binds to chemokine receptor (CXCR4 or CCR5)
- > Acitvates gp41 (high energy state)
- > buried fusion peptide (linked amino acids) extends
- Bridges gap between viral membrane and host cell membrane
- For viral content to enter host cell
How can HIV entry be inhibited?
- Downregulating the expression of chemokine receptor expression
- > reduces entry points for the virus
- saturating chemokine receptors with their natural ligand-> chemokine
- > prevent HIV entry
Chemokine exression
M tropic HIV susceptibility
- Binds to CCR5 chemokine receptor
- Mutation -> CCR5(change)32
- > 32 base pair deletions
- Renders receptor non-functional
- Protection to individuals against M tropic HIV variants
- Virus difficulty entering cells that express mutated CCR5 receptor
- Prevelant Europe and North Amerca
- Rare in Indian populations
What is MIP-1a?
- Macrophage Inflammatory Protein 1alpha
- Ligand to CCR5
- 1 in 5 Indians
T-tropic HIV variant susceptibility
- Binds to CXCR4 chemokine receptor
- Ligand= SDF-1 (stromal cell derived factor-1)
- Mutation leads to: Guanine -> Adenine (point mutation)
- Present in 40% in Healthy Asian individuals
- Interfers ability for the HIV virus to bind
Why is mutated CCR-5 gene results in delayed progression to AIDS?
- CCR5 - 2 alleles
- > function/mutation
- 10% of Northern Europeans- mutation - non functionable
- delayed AIDs progression -ineffective binding M tropic variants
1% of caucasians have 2 copies of the CCR-5 gene mutated. What does this mean in terms of HIV infection? Consider expression of CXCR-4 in your answer.
- Resistant to HIV
- As CCR5 is primary viral entry
- But still express- CXCR4 (T tropic variant)
- Suggesting M tropic variant is initial infection entry
How can be rapid progression of AIDs be determined?
Emergence of T tropic variant
Explain the steps of HIV replication in detail?
- Upon HIV entry into T cell -> nucleocapsid removed
- Reverse transcriptase: Viral ssRNA -> dsDNA
- > error prone process, 10mistakes/replication
- > high mutation rate
- dsDNA integrated into host genome (integrase)
- > Provirus (dormant/latent) -inactive for long periods of time
- RNA template degraded by Rnase H enzyme
T cell activation
* upregulation of NF-kb
* >triggers initiation of virus production from provirus DNA
* Transcribes into viral RNA-> (translated) Viral proteins
* Assembled -> new virus particles that bud from the host cell
* >acquires portion of host cell membrane
* >Viral envelope
* Cycle repeats to infect other cells
What is the role of the endoplasmic reticulum in the T cell?
- Processing and packaging of proteins
- Glycosylation
- > add carbohydrated molecules to protens
- Significance to protein function, structure and stability
What are the 3 clinical course of HIV infection?
- Infection
- the ‘latent’ stage
- Development of AIDS
Development of AIDs graph
- progressive loss of CD4 T cell function
- severe immune supression
- susceptible to opportunistic infections
Infection
- Most people no symptoms immediately after infection
- 15% : symptoms of influenza
- > fever, malaise, aching muscles, soar throat, swollen lymph nodes
- Development of swollen lymph nodes - no other clinical symptom identified
- Production of antibodies against HIV antigen
- > process called seroconversion
- Detection of antibofies to HIV- test for infection
- asymptomatic
- 33% swollen lymph nodes
- 10 years (AIDs development)
- Extremely variable
Development of AIDs is clinically defined by?
appearance of major opportunistic infections or by a drop in the CD4 T cell count to** below 200 cells/µl of blood**
AIDs symptoms
weight loss, night sweats, fever and diarrhoea
Opportunistic infection in HIV (AIDs)
