Week 3 Flashcards
(46 cards)
Human immunodeficiency virus at risk groups
WHO defined key populations:
-men who have sex with men 21%
-IV drug users 13%
- sex workers and their clients
-mother to child 0.7%
- heterosexual contact is main transmission route for HIV; 49% of new infections
HIV infection and AIDS
Incubation period: 2-4 weeks
Acute infection: most people unaware they have been infected, fever, headache, rash, sore throat
Chronic infection: asymptomatic/latent, HIV replicating at low levels, can last for a decade or longer (some progress faster), transmission, eventually virus load greatly increases and CD4 T cell count drops
Acquired immunodeficiency syndrome: CD4 T cell count drops below 200 cells/mm, increased susceptibility to opportunistic infections, maximum survival approx. 3 years
HIV transmission
Bodily fluids; blood, breast milk, semen, vaginal secretions
Mother to child during pregnancy and delivery
HIV risk factors
Unprotected anal or vaginal sex
Another sexually transmitted infection STI such as syphilis, herpes, chlamydia, gonorrhoea, bacterial vaginosis. Inflammation and destruction of cells in region
Sharing contaminated needles, syringes, and other injecting equipment and drug solutions
Receiving unsafe injections, blood transfusions, and tissue transplantation and medical procedures that involve unsterile cutting or piercing
Accidental needle stick injuries
HIV lab testing and diagnosis
HIV antibody test: blood or oral fluids, routine
Nucleic acid test: blood, virus load, only used for high risk exposures
Antigen/antibody test: p24 antigen is made by infected cells, detected before antibodies
HIV types and strains
HIV-1 and HIV-2 are 2 distinct viruses
HIV-1 accounts for 95% of all infections worldwide
HIV-1 derived from gorillas and chimpanzees
HIV-2 more than 55% genetically distinct from HIV-1, concentrated in west Africa, less infectious than HIV-1 progresses more slowly than HIV-1 resulting in fewer deaths. NNRTI drugs ineffective against HIV-2. 8 known HIV-2 groups only A&B pandemic, derived from SIV from sooty mangabeys
HIV-1 group m most prevalent
Most ART drugs are tested in subtype B effective against wide range of subtypes
Human immunodeficiency virus
Theres no cure, no vaccine
Infected individuals have to take antiviral drugs for life
Drug resistant virus, drugs are expensive
Enveloped positive sense ssRNA virus
Contains two +ssRNA virus per virus particle
HIV is lentivirus (subgroup of retrovirus)
Two subtypes HIV-1 HIV-2
HIV lifecycle
Attachment and fusion
Viral RNA used to synthesise dsDNA by reverse transcriptase (RNA dependent DNA polymerase)
DsDNA circularises
- Attachment to host cell
2 binding to CD4 membrane fusion - Release of virion contents into the cell
- Reverse transcriptase transforms RNA into DNA
- Viral DNA integration in cell genome. Integrate enables viral DNA to integrate into human genome
- Production or viral RNA and proteins. Protease
- Production of integral membrane proteins gp41 gp120
- Budding of virus particles
HIV receptor and co receptors
Trimer: gp41, gp120, V3
CD4 binds and changes shape of gp120
Gp120 binds to coreceptor CCR4
Membrane fusion. 6 helix bundle formation
HIV lifecycle replication
1) dsDNA circularised and enters nucleus
2) dsDNA integrated into host genome, catalysed by enzyme integrase
3) HIV infection now permanent
4) HIV can either enter latency or enter into productive cycle
5) productive cycle
6) Pro-virus DNA transcribed into mRNA by host RNA polymerase and exported from nucleus
7) mRNA translated into proteins
8) viral proteins are assembled into virions
9) new progeny virus released by budding
10) virus particle matures and becomes infectious
HIV lifecycle; key stages where interruption is possible
- Binding
- Fusion
- Reverse transcriptase
- Integration
- Maturation
HIV - Highly active anti-retro-viral therapy HAART
The total failure of single drug therapy led to the adoption of multi drug combinations where 3 or more drugs with distinct resistance profiles and differing target genes are Co administered . Target different part of virus lifecycle
Typically:
- 2 different NRTIs and 1NNTRI
-2 different NRTIs and 1 protease inhibitor
NRTIs: nucleoside reverse transcriptase inhibitors
NNRTIs: non-nucleoside reverse transcriptase inhibitors
PIs: Protease inhibitors
FIs: fusion inhibitors also known as entry inhibitors
CCR5 antagonists also known as entry inhibitors
IIs: integrase inhibitors
Advantages and disadvantages of HAART
Advantages:
- highly specific- safe
- defined specificity
- relatively rapid to develop
Disadvantages:
-highly specific - limited utility for diverse viruses
-defined specificity - resistance mutation occurs rapidly
- relatively costly to manufacture
Nucleoside reverse transcriptase inhibitors NRTIs
Eg. Zidovudine, stavudine, lamivudine, abacavir, zalcitabine, emtricitabine, didanosine
Mechanism of action:
- incorporate into the DNA of the virus. Nucleoside phosphorylation. DNA polymerase
- compete with natural nucleosides
-obligate chain terminators
-inhibit transcription from RNA to DNA
-ultimately inhibits HIV replication
No effect on already infected cells
Zidovudine
Zidovudine AZT is a thymidine nucleoside analogue
OH group replaced with azido N3
Terminates incorporation of new nucleotides
Non-nucleoside reverse transcriptase inhibitors NNRTIs
Eg efavirenz, nevirapine, delaviridine
Mechanism of action:
- bind directly to reverse transcriptase near, but not at the polymerase active site
-distorts the RT enzyme and blocks conversion of RNA into DNA
-does not require activation by phosphorylation
Protease inhibitors PIs
Eg saquniavir, Indinavir, nelfinavir, amprenavir, fosamprenavir, ritonavir, lopinavir, atzanavir
Mechanism of action:
- HIV protease cleaves HIV polyproteins into structural proteins and enzymes required for assembly of new infectious virions
-protease inhibitors bind the protease and inhibit correct cleavage of viral proteins
-prevent HIV from being assembled and released from infected cells
Primary HIV infection
Virus infects immune cells at site of infection (CD4 and T cells, dendritic cells etc)
Virus is delivered to lymph nodes- congregation of immune cells infects loads
Active virus replication
High levels of viraemia and dissemination
Down regulation of virus replication by immune response
Virus set point reached after about 6 months
HIV infection and AIDS
Incubation period: 2-4weeks
Acute infection: most people unaware they’ve been infected swollen lymph nodes, fever, headache, rash and sore throat
CD4+ T cells decline temporarily CD8+ T cells increase temporarily, anti HIV 1 antibodies appear
Chronic infection: asymptomatic/latent, HIV replicating at low levels -transmission, can last for a decade or longer some progress faster, CD4+ cells gradually decline, CD8+ cells largely unaffected, CTL responses evolve, antibodies evolve. Acquisition of macrophage tropism
AIDS
Acquired immunodeficiency syndrome
CD4 T cell count drops below 200 cells/ml
Increased susceptibility to opportunistic infections
Weight loss
Malignancies
Neurological symptoms
Maximum survival approx. 3 years
CD4 +T cell depletion, loss of helper function
HIV-specific CD4+/CD8+ T cell exhaustion
B cells decrease/ dysregulation
NK cell impairment of function
AIDS-defining opportunistic infections
Cryptococcal meningitis
Toxoplasmosis
Pneumocystis pneumonia PCP; pneumocystis jirovecii
Oesophageal candidiasis (yeast)
Certain cancers, including Kaposi’s sarcoma
HIV replication is error prone
Error rate approx. 1 per genome per replication cycle
In vivo an HIV infected person may produce 10^9 virus particles/day
The rapid replication of the virus together with the error rate and high viral load causes the virus to evolve rapidly
The rapid evolution of the virus makes problems with:
-drug resistance
-vaccine design
Cross resistance
Mutations in resistance to HIV protease inhibitors often occur in and around the active site at codon 82 changing the shape of the molecule
Mutations to resistance to one drug often leads to resistance to many members of the same drug family
Drug resistance
Drugs do not cure HIV, they suppress replication
Drug need to be taken for the life of the patient
For drugs to be effective replication must be blocked completely
At least 3 drugs in combination must be employed to block viral replication/evolution
HIV is sequenced and for each mutation:
-fold decreased susceptibility is compared to wild type virus
-mutations in drug resistance positions are mapped
-new mutations are compared to most common mutations at drug resistance positions
-thousands of sequences and multiple ARV drugs available
