Lec34 HIV Pathogenesis Flashcards
(44 cards)
1
Q
How many people in the world currently have HIV?
A
35 million
2
Q
How many new HIV infections per day in the world
A
6,300 in 2012
3
Q
What are viral properties of retroviruses?
A
- genome = RNA
- encode for reverse transcriptase = RNA dependent DNA polymerase
- replicated via DNA intermediate that integrates into host cell genome
4
Q
What is reverse transcriptase?
A
RNA dependent DNA pol
5
Q
What are examples of retroviruses?
A
- HIV
- HTLV
6
Q
What family is HIV virus in?
A
its a type of lentivirus
7
Q
What are the two glycoproteins that cover HIV envelope?
A
gp120 and gp41
8
Q
What is structure of HIV virus?
A
- enveloped
- double strand RNA
- envelope covered by glycoproteins [gp120 and gp41]
- just inside envelope is matrix
- just inside matrix is capsid composed of p24 proteins
- inside capsid if virus dsRNA which contains 9 genes [3 main structural, 6 regulatory and accessory]
9
Q
What is the HIV capsid composed of?
A
p24 proteins
10
Q
What are the 3 most important viral enzymes of HIV?
A
- protease
- integrase
- reverse transcriptase
11
Q
What are the 3 main structural genes of HIV and what do they encode for?
A
Gag = matrix and capsid Pol = reverse transcriptase [RT], protease [PR], and integrase [IN] Env = envelope proteins
12
Q
What is the function of the 6 regulatory/accessory genes of HIV? Which are required?
A
- regulate viral replication
- help to overcome cellular restrictions
- enhance virulence
- only Tat and Rev required [Ltr, Vif, Vpu, Env, Nef are not required]
13
Q
What is the replication cycle of HIV-1?
A
- attachment via gp120 [attaches to CD4 and [in early stage] CCR5/ [later] CXCR4]
- fusion of viral envelope and host cell membrane mediated by gp41 and release of viral RNA
- RT reverse transcribes RNA to DNA
- DNA important into nucleus
- DNA integrated by IN into host cell genome
- transcription of proviral DNA by host RNA pol by host RNA pol + multiple splicing
- translation of RNA, assembly and budding of immature, non-infectious particles
- outside cell, cleavage of immature polyprotein by PR to generate infectious viral particles
14
Q
What is function of gp120 glycoprotein?
A
- sits on top of HIV envelope
- mediates attachment
- attaches CD4 and CCR5 or CXCR4
15
Q
What is function of gp41 glycoprotiein?
A
mediates virus-cell fusion
16
Q
What cells contain CD4 and thus are targets of HIV?
A
- CD4 tell cells
- macrophages
- monocytes
- microglia
17
Q
What is importance of CCR5 mutation?
A
- CCR5 is initial coreceptor of HIV then CXCR5 is later coreceptor
- if have homozygous mut for CCR5 you won’t get HIV
- if you are heterozygous, have milder disease with slow prgoression
- this info used to create CCR5 blocker [maraviroc] as treatment
18
Q
What is mech of maraviroc action? requirement for this drug to work?
A
- treats HIV but blocking CCR5 receptor
- need to do tropism test first in order to make sure that the pt is still using CCR5 because in later stages of disease uses CXCR5 instead in which case the drug won’t help
19
Q
What is significant about the high number of errors that occur in reverse transcription of HIV from RNA to DNA?
A
- this means you have a lots of mutations –> each day a virus is generated with a mutation at every single position
- lots of mutations leads to infection of many quasispecies
- allows for immune evasion and drug resistane
20
Q
What is the major barrier to curing HIV?
A
- HIV integrates into the host cell genome –> the pro-virus can remain latent for years in cells not actively replicating [memory T cells]
21
Q
What is multiple splicing?
A
- process of using multiple different ways to splice a single genome so you can generate many more proteins from a small genome
22
Q
What is function of Vif?
A
blocks activity of APOBEC3G = a host cell product that causes hypermutations during reverse transcription
23
Q
What is function of Vpu?
A
facilitates budding by blocking action of tetherin
24
Q
How is HIV transmitted?
A
- sexual contact [genital/colonic mucosa]
- exposure to blood or infected fluids
- mother to child
25
How is HIV transmitted sexually? what puts you more or less at risk of transmission?
- transmission related to viral load in vaginal secretions/semen --> higher in acute HIV and in advanced AIDS
- STI increase risk of HIV acquisition
- uncircumcised males have higher risk of acquiring HIV
- M --> M easier than M --> F easier than F --> M
26
How is HIV transmitted from mother to child?
- in utero
- at time of birth
- through breastfeeding
27
How is HIV transmitted across mucosal surfaces and become systemic?
- vaginal secretions and normal mucosa are strong barrier to HIV transmission
- breaches in mucosal integrity increase transmission risk
- HIV is transmitted across the epithelium
- dendritic cells then carry HIV to draining lymph nodes where it can infect CD4 lymphocytes
28
Why is rectal transmission easier than vaginal?
- rectal epithelium more susceptible to trauma and thus breach in mucosal integrity
- rectum contains lymphoid follicles with M cells that can facillitate transmission
29
How is HIV disseminated?
- within days of infection goes from epithelium --> dendritic cells --> draining lymph nodes --> CD4 lymphocytes
- within a few days to a few weeks:
- -- long-lasting infection established in lymphoid tissue including gut
- -- infections of CNS also happen early [introduced by macrophages/monocytes]
30
What are symptoms of acute HIV syndrome?
- similar to mono or flu: fever, sore throat, malaise
31
What is happening with immune system /viral load in acute HIV?
- host immune is able to partially contain HIV replication
- viral load reaches peak
- see drop in CD4 but doesn't go down to dangerous levels of AIDS
- increasing CTL response
32
In absence of treatment what happens with HIV
- have chronic latent HIV with no symptoms for ~10 years before immune system loses control of disease and get opportunistic infections etc
- slowly declining T cells
- very slowly increasing viral load
33
What is immune response to HIV?
- CTLs specific for HIV peptide
- anti-envelope antibody
- anti-p24 antibdoy
34
What is best way to detect acute HIV?
- HIV RNA PCR [viral load]
| allows you to detect sooner than HIV antibody test
35
When in course of infection do you start to develop antibodies to HIV?
~ 3 weeks, after you already have symptoms
36
How long does i take to eradicate virus from long-lived latently infected cells?
up to 70 days
37
Can you detect HIV virus in lymph node even when patient has undetectable viral load?
Yes -- you can always detect virus in lymph nodes because of reservoir of long-lived latently infected cells
38
What are 4 mech by which CD4 cells decline in number/function?
- virus can kill infected cell
- immune system [virus specific CTL] can kill infected cell
- HIV can activate uninfected CD4 cells and cause apoptosis
- abnormal signaling from gp120-CD4 interaction can cause anergy
39
What is chronic immune activation in HIV? what are problems with it?
- T and B cells activated by HIV make more antibodies and cytokines --> get high IgG levels
- activation allows uninfected cells to become more easily infected and increases replication of HIV in already infected cells
- activated immune cells have rapid-turnover --> get thymic dysfunction + fibrosis in lymph nodes which limits ability to replace the T cell pool
- chronic inflammation from immune activation implicated in pathogenesis of HIV associated complications
- immune activation independently predicts HIV disease progression risk
40
How does immune activation in brain lead to neuronal damage?
- HIV infects microglia --> release cytokines that affect neuronal function [inflammatory state in brain]
41
What are causes of immune activation in HIV?
1. direct effect of virus on infected CD4 T cells
2. intestine infected in first few days --> white cells in intestine dying off --> means bacteria/products [LPS] can enter circulation --> cause inflammation --> inflammation activates lymphocytes --> active lymphocytes more susceptible to HIV infection
42
What are the mech by which HIV evades immune system?
- effects on CD4 T cells and as a consequence on CTL
- glycosylates surface proteins [difficult for host immune to develope antibodies]
- high mutation rate [means variable seq or surface proteins so can escape antibodies that are formed]
- conserved regions of surface glycoproteins are recessed or hidden
- accessory proteins block specific arms of immune system [ex. Nef downregulates MHC1 and protects from CTL killing]
43
What characterizes acute HIV infection?
- very high viral load
- moderate decrease CD4 cells
- partially controlled by host
- mono-like illness
- infection established in lymphoid tissue throughout body
44
What characterizes clinical latent HIV?
- sate equilibrium with billions of viral particles produces every day that infects lots of T cells
- T cells die quickly but regenerate pretty quickly so vey gradual decrease in CD4
- plasma viral load at stable "set point"
