Virology - Retroviruses (HIV-1, HIV-2) Flashcards
Outline the Retroviridae family.
- Retro: backwards, so called as they possess the enzyme reverse transcriptase.
- Two subfamilies: Spumavirinae, Orthoretrovirinae.
- Spumavirinae not associated with human disease. Orthovirinae contain genuses: Beta-, Delta-, Epsilon-, Gamma-, and Lentivirus.
- HTLV-1 and HTLV-2 are Deltaretroviruses.
- HIV-1 and HIV-2 are Lentiviruses.
- First virus was isolated from T cells from a T cell leukaemia patient - human T-cell lymphotropic virus type 1 (HTLV-1), in 1980.
- AIDS is caused by HIV-1.
- HIV-2 is restricted largely to West Africa and is less pathogenic.
What are the HIV-1 variants?
HIV-1 variants are classified into three genetic groups: major (M), outlier (O), and non-M, non-O (N).
- Group M: domiate the pandemic, further subdivided into subtypes A-K.
The genome organisation is similar for all retroviruses as their genome contains the same order sructural and enzymatic genes, coding for the same proteins. What are these genes and what do they code for? Use HIV as an example.[3]
Their genomes contain the same order of the genes gag**, **pol, and env coding for three groups of structural and enzymatic proteins.
In HIV:
- gp120: spike ‘bulb’
- gp41: spike ‘stalk’
- p17: matrix protein
- p24: capsid protein
- p7: nucleocapsid
Outline the gene functions in HIV-1. [10]
- gag: virion proteins
- pol: enzymes
- env: envelope proteins (from gp160)
- tat: transactivating gene, stimulates viral protein synthesis
- rev: mediates viral mRNA transport from nucleus
- nef
- vif
- vpr
- vpu
- LTR
Outline HIV-1 replication. [7]
Retroviruses replicate and produce viral RNA from a DNA copy of the virion RNA.
- Initial attachment: envelope glycoprotein gp120 interacts with part of the CD4 molecule of T helper lymphocytes and other cells. The HIV envelope then interacts with a co-receptor (chemokine receptors: CCR5, CXRC4).
- Entry: fusion of the viral envelope with the cell membrane, which requires exposure of gp41 hydrophobic domiain.
- RNA is released into the cytoplasm and reverse transcriptase acts to form a dsDNA copy, which is transported and spliced into the host cell DNA, at which point it is a provirus.
- Infection is then permanent. May be latent or enter a productive cycle.
- Transcription of viral mRNA from the provirus using host Pol II.
- Virions are assembled at the host membrane where envelope and core proteins are located.
- Virion buds off to form complete virus. Completed in about 24 hours. Destroys host cell.
Outline the pathogenesis of AIDS.
- Initially there is a good cytotoxic T cell (Tc) response, which reduces the viraemia and produces antibodies.
- Functional changes in monocytes, macrophags, dendritic cells, and T helper cells (TH).
- Immune system is depressed.
- Failure to eliminate infection.
- Virus persists.
- Loss of control of latently carried microorganisms, leading to opportunistic infections.
- Disease AIDS.
What happens during the different stages of HIV infection?
Symptomatic primary HIV infection (PHI) occurs within 10-30 days of inital exposure to the virus and resolves in the majority of infected individuals within a month. Symptoms:
- fever
- pharyngitis
- headache malaise
- generalise lymphadenopathy
- non-pruritic maculopapular rash
Following the PHI stage a largely asymptomatic phase ensues. This may last as long as 10 years in which the virus continues to replicate, and damaging the immune system in untreated individuals.
The decline in immune function eventually predisposes the patient to the development of acquired immune deficiency syndrome (AIDS).
There are over 20 AIDS-defining illnesses, a diagnosis of AIDS is made if one or more of the conditions are present. Give some examples.
Main AIDS defining illnesses:
- Pneumocystis jirovecii pneumonia
- Toxoplasma gondii
- Kaposi’s sarcoma
- Mycobacterium tuberculosis (sub-Saharan Africa)
Describe the major immunological and virological changes during the stages of HIV infection.
- Inital control of the viral load by immune system
- Infection and dramatic loss of CD4 cells
- Clinical latency (up to 10 years)
- Gradual depletion of CD4 cells and increase in viral load
<200 CD4 cells/microlitre representative of AIDS.
What are the laboratory markers associated with progression of HIV infection?
- Decreasing number of CD4+ T lymphocytes
- Increasing proportion of infected CD4+ cells
- Increasing titre of HIV RNA in plasma (viral load)
- Detectable p24 antigen in plasma
- Isolation of virus in culture - rapid growth, syncitium formation (multinucleate cells)
What tests are used to test for HIV?
- Most use enzyme-linked immunoassays (ELISAs) using HIV antigens derived from cloned recombinant HIV gag, pol, and env genes, or synthetic peptides.
- Combination assays: highly sensitive to detect anti-HIV and p24 antigen in a singla ELISA
- PCR used during early acute stage and in infants carring maternal anti-HIV, and for monitoring progression
How are HIV-1 and opportunistic AIDS infections treated?
Currently used multiple drug regimens (previously referred to as HAART, now known as combination antiretroviral therapy, or cART) have achieved remarkable success in halting the progression to AIDS.
Outline HIV structure.
