HIV lecture 2
- Created by: bowmanca01
- Created on: 19-02-17 17:04
HIV molecular structure
HIV 1
Genome is 9.3kb
Has:
- 5' LTR to allow reverse transcription
- gag, codes p17 matrix antigen, p24 capsid antigen, p6/7 nucleocapsid.
- Pol, codes for reverse transcriptase, protease, intergrase
- env, codes for surface glycoprotin gp120 and transmembrane glycoprotein gp41
- Also has another 6 proteins codes for vif, vpr, vpu, rev, tar and nef
HIV 2
Same as 1, but vpu is replaced by vpx.
Why is HIV so complex
Normally, retroviruses on have LTR'S, Gag, Pol and Env.
HIV's extras enables replication and persistence in adult host who is immunocompetent.
Normally retrovirus' can only cause disease in neonatal animals
Enables cross species transmission
HIV life cycle
- The HIV virus binds to cell. The virus fuses with the cell and enters the cell.
- The ssRNA undergoes reverse transcription to produce dsDNA, which still inside the capsid.
- The dsDNA intergrates into the host DNA
- Transcription and translation occurs, there is assembly of components and budding into multi vesicular bodies (MVB)
- The viroins are then released and they mature. Until maturation it is not infectious
HIV pathogenesis
There is an initial primary phase illness'.
- There are lots of initial viral replications shown by rapid increase in viraemia
- Followed by 10+ years of asymptomatic
- Good immune response causing virus replication to drop
- It falls to set point, the lower the set point, the longer te asymptomatic phase
- High levels of antibodies and HIV specific CTL
- Finally a reduced level of AB and CTL causing AIDS
- There is a high level of viral replication
HIV latency
Originally thought that HIV was a true latent virus
Long clinical asymptomatic phase
Low levels of virus detected in peripheral blood of asymptomatic patients
Viral replication in vitro only detected in activated T-cells
There is clinical latency but not cellular latency
- Rapid turnover of virus and virus infected cells
- 10 to power of 10 viroins produced per day
- 1/2 life of infected cells in less than 2 days
- 1-2% of the total CD4 cells (2x109) destroyed everyday which is matched by the production of CD4 cells.
Virus vs Host
Virus
- CD4 cell destruction causing direct killing (cytopathology) and indirect killing (apoptosis)
- Loss of CD4 function
- Lymph node destruction
- Viral variation- mutation
Host
- Cytotoxic T cell response
- Antibody response
- LD8 antiviral factors
- Chemokines
- ALL BLOCK VIRAL REPLICATION
Clinical latency
During clinical latency the balance shifts
More CD4 cells are killed than produced
Lymph node destruction interferes with immune response
Loss of CD4 Th1 function (even before CD4 depletion)
Accumulation of viral variants overhelms the weakened immune system
Primary infection
Primary infection
Mononucleosis like syndromes
Fever, malaise, rash, diarrhoea, lymphadenopathy
Clinical latency
Often no symptoms but sometimes: Fatigue, weight loss, thrush or shingles
Normal levels of CD4 cells- 2000/mm3
200-500/mm3
Generalised lymphoadenopathy
Oral lesions, especially candidiasis
Reactivation of herpes zoster (shingles)
Reactivation of latent Mycebacterium tuberculosis
Basal cell carcinoma of skin
More aggresive pox virus and papillomavirus, not as well controlled
Continued
Less than 200 CD4 cells per mm3
Protozoal infections:
- Pneumocystis carini, Toxoplasma gondi,
- Cryptosporidia, Microsporidia
Bacterial infections
- Treponema pallidum, Mycobacterium avium intracellulare
Fungal infections
- Candida albicans, Cryptococcus neoformans
Viral infections
- CMV, HSV, EBV lymphoma, Kaposi's sarcoma (KSHV), anogenital carcinoma (HPV)
Direct pathogenicity of HIV
AIDS dementia complex (ADS): Infection of brain macrophages and glial cells
2/3 of all AIDS patients
Dementia, motor and behavioural abnormalities seizures
Developmental problems in children
Weight loss due to infection of the gut epithelial macrophages
Diarrhoea, malabsorption- Blunting of intestinal villae
Dont know the cause properly, could be due to toxic effects of viral proteins, indirect effects on cytokin regulation
Pathogenic effects in lungs due to replication in lung macrophages
AIDS
HIV type 1 and 2
Virus infects CD4 cells
T lymphocyes- Monocyte derived APC's (DC)
Targets of HIV
Target cell types of HIV infection:
- Monocytes (mononuclear phagocytes)
- Precuror to APC's
- Macrophages
Ingest foreign material e.g. bacterial, cell debris
Kills virus infected/tumour cells
Present peptides to T cells by MHC I+II
- Dendritic cells
Obtain antigen in tissues (e.g skin , peripheral blood)
Migrate to lymphoid organs and activate T-cells
Large amount of extracellular virus found trapped on surface of follicular DC's.
How does HIV get into cells?
High affinity interations between gp120 and cell surface glycoprotein CD4. Conformational change in the gp120 allows binding to co-receptor
Further conformation change gp41 exposes fusion domain
Fusion between viral and cellular membranes allows enry of viral core
HIV receptors
CD4: Primary receptor - 4 Inracellular IgG like domains, short cytoplasmic tail
Normal function: Binds to class 2 MHC on antigen presenting cells.
Chemokine receptors- 7 transmembrane helices
Normal function- binds chemokines to attract lymphocytes and macrophages
Categories HIV into 2 groups
Early in infection- Acute phase and asymptomatic
- R5 viruses use CCR5 (recognise beta chemokine receptor)
- Non syncytium inducing- Not very toxic
- Replicate in primary T cells and macrophages, not in transformed T cells
Later in infection
- X4 viruses, use CXCR4 ( alpha chemokine receptor)
- Also able to replicate in transformed T cells and fuse cells (S1)
- Mutation in V3 loop of gp120
- AA 306/320 change from negative to positive
Tropism of HIV
R5 virus (M-tropic, NS1)
- Macrophages, T cells
X4 virus (T tropic, S1)
- T cells, especially memory T cells
Genetic resistance to HIV
Exposed but uninfected individuals were homozygous for a 32bp deletion in CCR5 gene
1% of the white population homozygous, 15% heterozygous, not found in Africa/Asian population
Heterozygous individuals partially protected
No other clinical effects of this deletion by loss of CCR5
These individuals still have intact CXCR4 genes
- Why not infected with X4 virus?
Role of CCR5 tropism during transmission and asymp
Virus population in recently infected individuals highly homogenous and preferentially macrophage- tropic
Macrophage in urogenital/ anal mucosa are the port of entry for HIV.
CCR5 is highly expressed in the mucosal macrophages, however the R5 (M-tropic) viruses also selected after parental transmission
Escape mechanism to enable virus to survive in the presence of uncompromised immune system
Role of DC's
Sexual transmission leads to virus entry into mucosal epithelium
Immature DC's take up virus as they associate
Migration to lymphoid tissue
mDC enters lymph node and present virus
Virus trasmitted to T-cells
Comments
No comments have yet been made