HIV: Viral pathogen Flashcards
What is HIV
human immunodeficiency virus (HIV is the virus)
AIDS: acquired immunodeficiency syndome (the disease)
what type of virus is HIV
Retrovirus - major class of RNA viruses
- reverse the normal order of synthesis to cope/transcribe their RNA genome into dsDAN which if then integrated into host genome
- virus encodes for a reverse transcriptase
- HIV = lentivirus group of retroviruses: cause infections that progress slowly over many years, like AIDS
how can AIDS be transmitted
blood, genetal or oral gential contact, mother to child
what type of virus is influenza
negative strand RNA
How was HIV discovered
- french virologist Luc Montagnier and american virologist Robert Gallo both published discovery in same issue of Science in 1983
- Gallo was accused of fraud but that was not the case
- Montagnier won nobel prize for the discovery not Gallo
describe disease progression of HIV
- relation between CD+ T lymphocytes vs VIral RNA
- upon primary infection CD4 T lymphocyte numbers slowly decrease, will enter calssical latency (virus sits in body and T cells gradually decrease)
- once decrease enough then opportunisitc diseases can take advantage and may cause death
Main symptoms of AIDS
Neurological: encephalitis and meningitis
Eyes: retinitis
Lungs: pneumocystis pneumonia, tuberculosis, tumors
skin: tumors
GI: esophagitis, chronic diarrhea, tumors
*main symptom is susceptibiltiyto infections that are unusual in the healthy population
when does AIDS develop
when CD4+ counds are <200/mm3
*decuase in CD4+ T cells
how can AIDS be postponed
- postponed by HAART
- highly active anti-retroviral therapy
*not a cure
why isnt there a cure for aids
- replication of HIV is very complex
- large number of regulator proteins allow the virus to hide effectively within host cells
- retroviruses have a high mutation rate bc of high error rate of reverse transcriptase enzyme
- even within a single patient the virus evolves into many different quasispecies
- envelope antigens constantly change - immune response cant regognize
describe quasispecies development
- in one infected patient the high mutation rates generate a dynami population of diverse mutant strains with differing properties of replication, tissue tropism and resistance to antibiotics
Describe the HIV structure and genome
- HIV is an eveloped virus
- viral capsid has 2 copies of the (+)ssRNA genome, the reverse transcriptase enzyme and 6 accessory proteins
*unlike influenza each (+)ssRNA contains a complete map of HIV genes
- the 2 RNA genomes can have different mutations arising from distinct replication events - HIV genome can be considered diploid
- Spike proteins
- transmembrane domain anchor the envelope to the matrix
- surface subunit domainbinds host receptors
describe attachment and host cell entry of HIV
- primary receptor for HIV is CD4 surface protein on T lymphocytes
- CD4 proteins can also be found on the surface of other cell types, rendering them susceptible to HIV
ex: langerhans cells (skin) and microglia (brain) - second protein CCR5 (chemokine receptor 5) is also involved
- envelope spike protien gp120 is the virla binding partner
describe the HIV gp120/gp41 protein complex
- binds the host CD4 receptor of T lymphocytes together with the chemokine receptor CCR5
- conformational changes of the bound viral protein complex drives fusion of viral envelope and host membrane - the HIV core directly enters the cytoplasm
- HIV core then dissolved and releases contents
*Virus comes along bidns to receptor - causes conformational change, virus taken into host cell, then virus takes over cell
describe the HIV replicative cycle
- HIV virion attaches thoruhg CCR5 and CD5 and spike protien
- Fuses and protein and RNA released
- Core partly opens and RNA chromosomes copied/replaced to ds DNA
- dsDNA enters nucleus via a pore
- Viral DNA integrates in host chromosome
- Full length RNA transcripts are made
- Some RNA transcripts excit nucleus for tranlsationpf Gag and ag-pol
- RNA transcripts exit the nucleus to form RNA dimers for progeny virions
- Some RNA transcripts are spliced to translate Rnv proteins
- Env proteins (SU-TM) are translocated into the ER
- Env proteins are glycosylated and packed in the golgi
- Env proteins are exported to cell membrane
- Membrane embedded env proteins assist the packaging of RNA dimers plus GAG-pol peptides into the core
- Core particles assemble and are coated with envelope and then released from tetherins by Vpu
- As virus buds off the PR protease cleaves the GAG-pol peptide in order to complete maturationof the core and reverse transcriptase
what are the main steps in the HIV replicative cycle
- Reverse transcriptase copies the RNA genome to dsDNA which enters the nucleus and integrates into host chromosome
- Viral mRNAs are exported to cytoplasm for synthesis of viral proteins, viral mRNA also exported to golgi to make envelope proteins
- Virus particles are assembled at the cell membrane where a viral rptoein cleaves host tetherin protein to release virions without cell lysis
*doesnt actually kill host cell- if killed it would get self antigens circulating and triggering an immune response, if no kill then body doesnt really recognize the problem
**know virus encodes for polymerase and envelope proteins
what is a syncytia
- host cells can fuse to make syncytis - virus spreads without exposure to immune system
- occurs prior to budding, host cells studded with envelope protiens can bind to CD4 receptors in neighbouring cells
summary of replicative cycle of HIV (wht happens witht he RNA genome)
- retroviruses must integrate their genomes into the host cell genome in order to generate progeny virions
- RNA genome needs to serve as a template for DNA complement
- then RNA template needs to be replaced with NDA to give dsDNA for integration
- Reverse transcriptase accomplished all this but its error prone - 1-2 errors/virus cope leading to high mutation rate
*HIV has exceptionally large number of accessory proteins that govern the level of virus production and duration in quiescent phase and complexity of virla lifestyle
describe treatment and prevention of HIV
- vaccine research has ben unsuccessful bc HIV has extreamly high rates of mutation - envelope entigens are constantly changing allowing for immune escape
- today there are some same day diagnostic tests to detect HIV antibodies
- Anti-retroviral therapy is available by combination chemotherapy HAART (highly active anti-retroviral therapy), drugs against 2 or more targets that prevents mother to child transmission
HAART does NOT cure HIV, disease is chronic and chemotherapy is a lifetime commitment
describe the typical progression of untreated HIV infections
AIDS is diagnosed when TH cells (ie CD4+ T cells) fall below 200/uL of blood
- AIDS is double edged sword bc CD4 helper T cells are essential for induction of a protective cell mediated immune response agaonst intracellular pathogens - people die from these infections rather than the virus itself
what causes progression to AIDS?
- Transofrmation into Tumor cell: insertion of viral genome into hosts genome that can destroy host gene regulation/function - imparing TH cell function or leading to cell death
*if regulatory infected host cell is off then tumor cells can form
- Lysis: virus infects cell causing cell death and release of virus
- Slow release of virus without cell death (persisent infection)
- Latent infection: virus is present but not replications
*HIV can eb inactive for short period fo time
- HIV syncytia: cell fusion giving dysfunctional mega cells
what may potential HIV drugs target?
- block attachemnt to host cell: involves spike protein in CD4 or CCR5, or antibodies that can neutralize spike
- Prevent fusion of virus and host membranes
- inhibit reverse transcriptase- if cell had a protease that could degreade that enzyme
- inhibit integrase
- inhibit HIV protease
what antivirals are available against HIV?
AZT: Zidovudine, a nucleoside analogue -> regonizedby an blocks reverse transcriptase activity
FuzeonL fusion inhibitor -> blocks fusion of HIV envelope with host cell plasma membrane
Truvada (new 2014): combination of 2 RT-inhibitor drugs tenofovir and emtricitabine, was approved for Pre-Exposure Prophylaxis or PrEP as a way to prevent HIV infection in HIV uninfected people who are at high risk of infection
