HIV infection Flashcards
what is HIV?
HIV is a retrovirus, an RNA virus which uses reverse transcriptase (RT) to make a DNA copy that becomes integrated into the DNA of the infected cell
outline the characteritics of the HIV Genome Structure.
- Small RNA virus (~ 10KB): expresses just 10 genes
- Member of retrovirus family (uses reverse transcriptase to make DNA copy of itself)
- Lentivirus - means its slow and characterized by long incubation period
- has regulatory, structural and accessory genes
- accessory genes help it t o overcome herd immunity
- structural gene creates the viral capsid
outline the Mechanism of viral replication of HIV.
Glycoproteins on the HIV molecule (gP160 made of gP120 and gP 41) allow it to dock and fuse onto the CD4 and CCR5 receptors
The viral capsid the enters the cell and enzymes and nucleic acid are released
Using reverse transcriptase single stranded RNA is converted into double stranded DNA
Viral DNA then is integrated into the cells own DNA by integrase enzyme
When the infected cell divides the viral DNA is read and long chains of viral proteins are made
Assembly the viral protein chains are cleaved and reassembled
Budding here immature virus pushes out of the cell taking with it some cell membrane
Immature virus breaks free to undergo more maturation
Maturation protein chains in the new viral particle are cut by the protease enzyme into individual proteins that combine to form a working virus
outline genetic resistance to HIV-1.
1% of Caucasians are homozygous for a 32bp deletion in the CCR5 gene (CCR5D32) necessary for primary HIV-1 infection
People with only one copy of the mutant gene can be infected with HIV but show delayed disease progression
It has been hypothesised that the origin in Caucasians could be related to protection from the Plague
what HIV gene is most targetted for treatments?
pol - this encodes reverse transcriptase, integrase and protease
name the HIV primary and co-receptors.
primary = CD4
co-receptors = CCR5 and CXCR4 chemokine receptors
CCR5 is prominant in early infection - it can change to CXCR4 later in infection
what are the anti-retroviral therapy targets to target HIV replication?
- integrase inhibitors
- protease inhibitors
- reverse transcriptase inhibitors
- fusion / entry inhibitors
what are the characteristics of HIV which allows it to mutate rapidly?
- Error-prone replication (the enzyme reverse transcriptase makes at least 1 error in every replication cycle)
- Rapid viral replication (generation time ~2.5 days)
- Large population sizes (~1010 new virus particles produced each day)
why is there a large diversity of HIV-1?
- HIV-1 subtypes differ by >20% in amino acid sequence
- recombination occurs
what are the clinical features of untreated HIV-1?
Vaginal/oral candidiasis
skin disease
fatigue
bacterial pneumonia
herpes zoster
oral hairy leukemia, thrush, fever, diarrhoea, weight loss
Kaposi’s sarcoma, non-Hodgkin’s lymphoma
Pneumocystis carinii pneumonia
Toxoplasmosis, oesophageal candidiasis, cryptococcosis
cns lymphoma
outline HIV pathogenesis
- HIV is integrated into the DNA of the infected CD4-expressing cells
- HIV infects a range of CD4 + immune cells in addition to helper T-cells, (including regulatory T-cells, T follicular helper cells, dendritic cells, macrophages and thymocytes)
- However, the number of HIV-infected CD4+ T-cells in the blood does not explain the extent of immune suppression
- HIV can pass directly from cell to cell, and so it is relatively inaccessible to antibodies in the blood
- The small HIV genome encodes a range of genes that enable the virus to evade human immune system responses
Why does the immune response to HIV-1 fail to clear the virus?
- The immune system generates a massive immune response to HIV infection, involving up to 20% of all circulating T and B lymphocytes
- Antibodies develop against most viral proteins, but neutralising antibodies take months to develop and rarely neutralise the primary HIV strains that are transmitted from person to person
- One of the key immune responses to HIV-1, from CD4+ T-helper cells, is lost from very early in infection, because these are the cells HIV infects first
- There is a very vigorous response from cytotoxic CD8+ T-cells which provide the major force controlling viral replication but ultimately fail when “immune exhaustion” sets in
when antibodies are created for HIV antigens, why do these not completely neutrilise the virus?
- The viral particle has a surface derived from the host cell membrane and contains only a few (6 – 10) envelope spikes
- The HIV-1 envelope spike is heavily glycosylated (with sugars resembling human types), which makes it difficult for antibodies to bind to the surface
- The really critical parts of the viral envelope that are needed to enter CD4+ T-cells are either in deep pockets overhung by sugar molecules or only revealed when the virus docks onto the CD4 molecule
- The envelope (gp120/41) proteins can change substantially without affecting virus function
- The virus can evolve very quickly to avoid antibody recognition (including by the addition of more sugar molecules)
- In infected people the circulating neutralising antibodies rarely recognise their own prevailing viral envelope variants
outline how cytotoxic T-cells clear infected cells after invasion of virus.
- CD8+ cytotoxic T-cells identify cells expressing foreign material (from pathogens or tumours), processed as small fragments of protein (8-11 amino acids in length), presented on the surface of the infected cell by HLA class I molecules
- Different HLA class I molecules are able to present peptides with different characteristics: a set of three distinct HLA class I molecules (A, B & C) are inherited from each parent
- These peptides can come from any part of a pathogen, so include more conserved structural and functional internal proteins (whereas antibody recognition is largely limited to surface proteins)
cytotoxic t-cell role in the control of HIV-1
- Cytotoxic T-Lymphocytes (CTL) appear early in HIV infection, coincident with a rapid drop in viral load
- Depletion of CD8+ T-cells in SIV-infected macaques leads to marked rise in viral load in both acute and chronic infection
- CTL exert sufficient selection pressure on the virus for variants which escape CTL recognition to emerge
- CTL selection leads to HLA-class I associated “foot-prints” on viral evolution
- HLA class I molecules are significantly associated with good outcome (HLA B27, B57, B51), heterozygote advantage
- GWAS of viral controllers: the sole association was with class I HLA (3 amino acid positions in peptide-binding groove of HLA molecule)
How does HIV-1 evade the CTL response ?
- HIV can evolve to escape T-cell recognition at several points on the antigen processing and presentation pathway
- Mutant HIV variants that evade the T-cell response appear within weeks of primary HIV infection
- Initially responses develop to the new variants, but these are progressively undermined by the failure of CD4+ cell help and dendritic cell function
- The HIV-1 nef protein reduces cell-surface expression of HLA class I molecules needed for CTL recognition, whilst at the same time upregulating the “death” molecule Fas that can kill virus-specific CTL before they can kill the virus-infected cell
- HLA- A and B molecules are down-regulated to undermine CTL killing of infected cells but HLA-C expression is maintained to prevent NK cell killing
- Ultimately CTLs develop functional “exhaustion”, associated with expression of inhibitory molecules such as PD-1: levels of expression correlate with viral load
Could HIV-1-specific T-cells provide immunity to HIV-1 infection?
- HIV-1-specific CD8+ T-cells detected in some highly-exposed persistently seronegative individuals Rowland-Jones, Nature Medicine 1995, & JCI 1998, Kaul JCI 2001
- Magnitude of HIV-1-specific CD8+ T-cell response in uninfected infants born to mothers with HIV-1 infection correlates with protection from late breastmilk HIV-1 transmission John-Stewart, JID, 2009
- SIV-specific CD8+ T-cells can confer protection from experimental challenge in some studies Barouch, Science 2015, Hansen, Nature 2011
- No protection seen in T-cell vaccine clinical trials to date
