HIV Flashcards
(36 cards)
Discuss the extent of the HIV epidemic on a global scale
HIV & AIDS has been responsible for the death of 42.5 million people since the beginning of the epidemic
In 2012, there were 35.5 million people living with HIV -> estimated new infection rate of 2.3 million per year
The majority of HIV cases occur in sub-saharan Africa -> contributing to severely shortened life-spans in these areas without proper healthcare systems. The disease burden in such areas retards economic growth which, in itself, perpetuates poverty and the poor HIV outcomes associated with that state.
Illustrate the extent of HIV and AIDS diagnoses in Australia over the last 30 years
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Compare the HIV modes of transmission between Australia and the world collectively
In Australia, the majority of HIV/AIDS cases are aquired by males-who -have-sex-with-males (M2M) transmission (70+%)
This differs from world trends where the main mode of transmission is via heterosexual intercourse (80-85%)
Other modes of acquiring HIV/AIDS includes:
- IV drug use
- Blood transfusions
- Unknown
What factors promote heterosexually transmitted HIV epidemic?
Little of no condom use
Multiple sexual partners
Overlapping sexual partners
Large sexual networks
Age mixing: old men with young girls
Women dependent om marriage/prostitution
High STD rates (esp. HSV-2)
Populations with high viral loads due to lack or anti-retrovirus therapy
Low rates of male circumcision
Characterise and classify the virology of the HIV virus
HIV is a retroviridie family virus
It is a + sense ssRNA virus with an icosahedral capsid and envelope
It’s genome is replicated in the host cell nucleus before viral assembly in the cytoplasm
There are two core HIV viruses that both developed as zoonoses: HIV-1 and HIV-2
HIV-1 is from the chimpanzee; HIV-2 is from the simian monkey
Discuss the genes that comprise the genome of the HIV-1 Genome
The HIV-1 genome contains three core genes: gag,pol and env.
gag gene
Encodes the structural proteins of the capsid, matrix, core and nucleocapsid of the virus
pol gene
Encodes a range of viral enzymes important to the replicative process: reverse transcriptase, integrase and protease
env gene
Encodes the envelope glycoproteins important for viral virulence: gp 120 and gp 40
Outline the replication cycle of HIV
- HIV virus binds cells that express CD4 surface protein: CD4+ T-cells and macrophages
- Membrane fusion of virus and host cell
- Localisation to the HIV genome to the cytoplasm
- Reverse transcription of +ss RNA genome to cDNA
- cDNA modified to become provirus that migrates into the nucleus
- Transcription of the provirus occurs
- Translation of viral proteins by host ER/ribosomes ( become virion structural proteins in cytoplasm or envelope glycoproteins expressed on host cell surface)
- Transcribed genomic RNA + viral proteins form virion
- Virion buds off host cell, encapsulating itself in an envelope composed of the host cell membrane and viral envelope proteins
- Maturation of virus particle via protase activity
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Explain in detail the mechanism of membrane fusion of the HIV virus
- HIV surface ligand gp120 binds to host cell **CD4 receptor **
- This leads to a conformational change allowing the gp120-CD4 complex to bind host chemokine co-receptors CCR5 or CXCR4
- **CCR5/CXCR4 **binding promotes gp41 fusion peptide insertion into host cell.
- Structural rearrangement of the gp41 trimers drives membrane fusion
- Membranes fuse and viral ssRNA genome is deposited in the host cell cytoplasm
Compare the tropism of R5 and X4 HIV viruses
HIV viral strains can be differentiated by their use of co-receptor for host cell invasion: CCR5 or CXCR4
CCR5 account for 95% of infections and are associated to early HIV/AIDs disease course. They are less pathogenic (less T-cell destruction).
CXCR4 HIV is rarely transmitted but emerges late in the course of infection. They are highly pathogenic and destroy T-cells more effectively. 50% of AIDS patients carry CXCR4 HIV.
The specific differences between them can be found in the table attached
Describe the route of infection and subsequent spread of HIV virus throughout the body
There is normally only one strain of HIV that infects an individual despite exposure to many strains
Exposure to HIV-1 is typically incurred through mucosal surfaces. These viruses generally display R5/M tropism.
HIV binds and infects dendritic APC cells that also express the CD4/CCR5 surface proteins.
APC’s transport the virus to regional lymph nodes where the spread of infection occurs to **activated CD4+ T lymphocytes **
Entry of virus infected cells to blood stream results in widespread dissemination of the virus to active CD4+ T cells
Discuss the importance of **reverse transcriptase **to the virulence of HIV
Reverse transcriptase converts the viral genomic +sense ssRNA to proviral double stranded cDNA
It has a high error rate (1 in 10,000 nucleotides) - introducing novel mutations into the genome that particularly alters the human body’s ability to develop an adaptive immune response.
It is seen as the most important drug target
It also duplicates the sequences at the ends of cDNA to produce long terminal repeats (LTR)
Discuss the process of integration and the role of integrase
The HIV enzyme **integrase **catalyses the random integration of the HIV provirus cDNA into the host cell genome.
This integration is required for the production of new viruses
The 5’ LTR acts as the HIV gene promotor where **integrase **integrates the provirus cDNA into the host cell.
Integration occurs in resting and terminally differentiated cells - but the actual translation and formation of new virus particles occurs when active CD4+ T cells are transcribing proteins -> these cells are activated in response to HIV infections
Why is HIV particular replicative in active CD4+ T-cells?
Activation of T cells by antigens or cytokines upregulates several transcription factors, including NF- κB, which stimulate transcription of genes
The long-terminal-repeat sequences that flank the HIV genome also contain NF- κ B–binding sites that can be triggered by the same transcription factors that transcribe endogenous host NF-k B genes.
In latently infected CD4+ cells that encounters an environmental antigen induction of NF- κ B in the LTR occurs as a physiologic response and activates the transcription of HIV proviral DNA (a pathologic outcome) and leads ultimately to the production of virions and to cell lysis.
Furthermore, TNF and other cytokines produced by activated macrophages also stimulate NF- κ B activity and thus lead to production of HIV RNA.
Thus, it seems that HIV thrives when the host T cells and macrophages are physiologically activated, an act that can be best described as “subversion from within.
What is the importance of HIV regulatory proteins?
HIV regulatory proteins Tat and Rev are essential for HIV replication
Tat enhances RNA polymerase II elongation of integrated viral DNA
**Rev **stabilises and transports unspliced and partially spliced RNA to the cytoplasm following transcription in the host cell nucleus.
Other regulatory proteins Vif, Vpu, Vpr and Nef are **not essential for HIV replication but are important for in vivo pathogenesis **
What are the functions of HIV regulatory proteins Nef, Vpu and Tat?
These regulatory proteins are important for in vivo pathogenesis by preventing MHC-1 proteins presenting HIV peptides to cytotoxic T lymphocytes
Vpu
- Inhibits tetherin to facilitate release of fully infectious virions
- direct MHC-1 from the cell surface to lysosomes for lysosomal destruction
- directs MHC-1 from cytoplasmic modifying organelles to the proteosome for destruction
Vif
- Degrades host APOBEC3G
Nef
- Direct MHC-1 from the cell surface to lysosomes for lysosomal destruction
Tat
- Tat inhibits MHC-1 gene transcription
What are three host proteins that have developed as anti-viral factors to prevent HIV infections?
TRIM5a
TRIM5a destabilises and untimely alters the viral capsid upon membrane fusion which degenerate the virus
APOBEC3G
Edits foreign RNA through lethal hypermutations which destroys the virus
Tetherin
Inhibits the release of viruses from the cell surface to prevent the spread of infected CD4+ lymphocytes
What is involved in the maturation of HIV particles?
The icosahedral core of HIV matures to form a complex rod shape after budding as a result of the gag-pol precursor protein that cleaves polyproteins into individual proteins
Discuss HIV latency in CD4+ T cells
The main HIV latency reservoir is in central and transitional memory T-cells
Latency is established at the transcriptional level -> there is no transcription of integrated viral cDNA and thus no viral replication
The genomic expression of Tat is required for HIV transcription -> in latent HIV populations, Tat is suppressed
Latent populations of HIV are not cleared by HAART and retain the same viral load-> the cessation of HAART will result in the reactivation of active HIV from these latent populations
What are the three phases of untreated HIV/AIDS infections?
Primary infection, asymptomatic infection and symptomatic infection/AIDS
Discuss the acute infection phase* *of HIV/AIDS infection
The acute infection phase of HIV is characterised by a rapid and massive loss of the body’s CD4+ T cells
HIV infects and kills > 60% of mucosal CD4+ CCR5+ memory T-cells (both resting and active) **within days **
Incubation period = 2-4 weeks ; clinical illness lasts 1-4 weeks
The initial decline in HIV viral load is due to CD4 substrate exhaustion (reduced number of CD4+ cells to infect)
What signs and symptoms are observable in the acute phase of HIV infection?
- Fever
- Myalgia/arthralgia
- Nausea/vomiting/diarrhoea
- Weight loss
- Malaise/lethargy
- Rash
- Lymphadenopathy
- Pharyngitis
- Oral thrush
- Headache/retro-orbital pain
- Meningitis
- Transient CD4 depletion
What is meant by the HIV viral load?
Viral load is the amount of HIV RNA in the plasma
This doesn’t take into account the amount of virus in lymph nodes, brain or other sanctuary sites
What is the **seroconversion window **in HIV infections?
How does this compare to vRNA immunoassays?
Seroconversion window refers to the period of time from which HIV antibodies develop and are detectable by ELISA screening
Antibodies to HIV-1/HIV-2 EIA occurs 35 days post infection
vRNA assays are more sensitive than antibody assays:
* HIV RNA is detectable within the first 1-18 days of infection*
How does the immune system respond during the acute phase of HIV infection?
Proliferation of a single line of CD8+ CTL to a specific “immunodominant” HIV epitope -> CTL to this epitope = 5% of all CD8+ CTL
High titres of HIV specific antibody. 5% of of total IgG specific for HIV envelope antigens
- Most Abs to envelope do not neutralise HIV due to high levels of glycosylation
