lecture 13 Flashcards

Question

What is the structure of a retrovirus?

Answer 1

- two single strands of RNA - lipid bilayer on outside - proteins in lipid bilayer = envelope proteins - sitting out on lipid bilayer is the gp120 = glycoprotein responsible for latching onto a human cell - embedded in the lipid bilayer by another glycoprotein: gp41 - env responsible for attachment to cell and fusion of the viral membrane to the plasma membrane (SU-surface; cell attachment, TM-transmembrane; fusion domain) - gag: MA-matrix, structural protein under envelope; CA-capsid, another protective layer for RNA; NC-nucleocapsid, sit along two strands of RNA - pol: enzyme that the virus needs to replicate; RT-reverse transcriptase, allows virus to copy from RNA to DNA; IN-integrase, allows virus to integrate into the host genome; PR-protease, allows virus to make the proteins it needs (important in drug development)

Answer 2

- clade B is dominant virus that we see in Australia, US, Canada, parts of south america and parts of europe - clade C is the predominant virus seen in Africa and India, - important for understanding the epidemiology and origins of HIV and how it is spread - important for vaccine development - defined by their genetic diversity from each other - within HIV-1 M group: sit separate to each other on a phylogenetic tree

Answer 3

- sits very closely to SIV-CPZ - this is what suggests the link - SIV-SM sits on the same branch as HIV-2

Answer 4

1. CD4 binding - gp120 2. Co-receptor binding - chemokine co-receptor (CCR5 or CXCR4) 3. fusion - reverse transcription of viral RNA genome - proviral DNA - integration - transcription - viral RNAs - translation - assembly 4. budding 5. maturation 6. new HIV virion

Answer 5

- rapid - error prone RT leads to rapid evolution of multiple quasispecies - 10 billion particles produced per day - impact on host cells - - CD4+ T-cells: activated = death, resting = latent - - monocyte/macrophages: long lived slow release of virus

Answer 6

- gp120 binds CD4 and a chemokine co-receptor - Attachment: viral gp120 protein binds to CD4 on host cell - results in a conformational change - Co-receptor binding: gp120-CD4 complex binds to CCR5 or CXCR4 on host cell - Fusion: virus fuses with host cell membrane, facilitating viral entry

Answer 7

- CCR5 and CXCR4 - different strains of the virus use different coreceptors - viruses that use CCR5 are called R5 - viruses that use CXCR4 are called X4 viruses - in some patients over time the develops the capacity to use both and is known as D/M - dual tropic - this is important because it determines which cells the virus predominantly enters - big impact on the natural history of the infection - most people are infected with R5, about 95% - virus populations containing a mixture of R5-tropic, X4-tropic, and/or dual-tropic HIV are called mixed tropic (D/M)

Answer 8

CCR5-using viruses (R5) - nearly all infections are caused by R5 viruses - R5 viruses cause less T-cell destruction - more easily transmitted but cause less T-cell destruction - probably an advantage for the virus CXCR4-using viruses (X4) - rarely transmitted (don't cross mucosal membranes as efficiently) - emerge late in the course of infection - 50% of patients with AIDS carry an X4 virus

Answer 9

- CCR5 mutations - the delta32 mutation leads to a deletion of 32bp and no expression of CCR5 - about 1% of people in the room will be CCR5 negative meaning they carry this delta 32 mutation - don't make CCR5 to be presented on the surface of their cells - 5 - 10% of people are heterozygous - discovered because some people who were very high risk (gay men in new york) just weren't getting it - rare normal wt/wt - normal CCR5 expression - progression of HIV over about 10 years - normal immune function heterozygotes - decreased CCR5 expression - delayed progression to AIDS/death - normal immune function homozygotes - no CCR5 expression - rare infection with X4 - normal immune function (v. rare infections that are worse because of it, but normally redundant)

Answer 10

- 5 - 14% of caucasians of european descent carry the mutation (1% are homozygous) - the origin the mutated allele has been traced to European geography ~1,000 years ago - possible selection by pandemic pathogen, likely smallpox or bubonic plague - rare in south america, africa, asia - up to around 14% in scandinavian countries - HIV probably kills you too efficiently to create a selection advantage in the host for a particular mutation

Answer 11

CD4+ T lymphocytes - activated T-cells - massive and early depletion in the GIT monocytes and macrophages - express CD4, CCR5 and low level CXCR4 - tissue macrophages in brain (glial cells), lung, gut, bone marrow monocyte precursors, lymphoid tissue macrophages - macrophages are chronically infected and serve as a reservoir Dendritic cells - allow HIV entry, but productive infection is rare Other cells - thymocytes - CD34+ progenitor cells

Answer 12

- APOBEC3G host protein has a function in editing RNA, inhibited by vif (HIV protein) - TRIM 5-alpha blocks uncoating of retroviruses, inactive against HIV because of capsid HIV protein - Tetherin normally blocks release of virus, vpu inhibits - LEDGF tethers HIV to host chromatin, integrase takes advantage of this to facilitate integration - intracellular evolution - HIV has evolved to overcome some of out natural defences to other retroviruses

Answer 13

- within hours: penetrates mucosal surface (e.g. vagina or rectum) - enters via a break in the epithelium (why it is transmitted more easily in people with previous STI) - first cell it comes in contact with is the dendritic cell - DCs pass on to activated T cells - within days you start to get release and infection of both activated CD4+ T cells (productive infection) and latent CD4+ T cells (latent infection) - virus carried to local lymphnode - replicates like mad - within 1 - 2 weeks start to see virus within plasma - weeks/months/years you see immune response

Answer 14

- we make a really good immune response to HIV, we just can never clear it - T and B cell response - CD4 presented antigen on MHC II - CD8/MHC I - w/i weeks start to measure virus in blood - w/o any treatment at all viral load declines because you are making an effective HIV-specific CD8+ t cell response - brings it down to set point - some people are able to really control the virus well and can bring it down by themselves without drugs to extremely low levels while others have very limited capability to control the virus - w/i about a month you start making antibodies - less effective doesn't seem to do much basically makes Abs that are non-neutralising or if they are neutralising, the virus rapidly escapes

Answer 15

Sequence variation - lack of recognition (both CTL and antibody) - antagonism ``` altered antigen presentation - down regulation of MHC class I molecules by Tat, Vpu and Nef ``` loss of effector cells - clonal exhaustion - loss of CD4 T cell help - replicative senescence latency - particularly in resting T-cells, macrophages and astrocytes privileged sites of viral replication - brain, testis, gastrointestinal tract

lecture 13 Flashcards

HIV-1 infection: virology, pathogenesis and treatment - epidemiology - virology: general, HIV entry - immunology