HIV Lecture 1 Flashcards
what HIV is
a retrovirus that has the ability to insert its genetic material (RNA) into the genome of the cells
how HIV is transmitted
- unprotected sex
- sharing of needles
- from HIV-infected mum to baby
- breast milk
- blood transfusion
three effects of HIV
- Immunosuppressive
- Neurological
- Carcinogenic
Immunosuppressive effects of HIV
- decrease in helper T-cell count
- give rise to opportunistic infections
T cell count of healthy individual
800-1300 cells/cm2
T cell count of HIV infected individual
<200 cells/cm2
Neurological effects of HIV
- effects brain and spinal cord
- abnormal proliferation of glial cells that surround neurons
- lesions resulting from loss of white matter
- can cause dementia and MS
Carcinogenic effects of HIV
- relates to immune deficiency
- Kaposi’s sarcoma is a rare tumour of blood vessel tissue in skin
- B-cell lymphoma
what life expectancy for HIV-positive patients depends on
timely initiation of medical treatment as well as access and committed adherence to long-term therapy and medical care
HIV Structure
- HIV capsid
- HIV matrix proteins
- Viral envelope
HIV capsid
- two single stranded RNA pieces
- contains the HIV enzymes
what protein is the HIV capsid made out of
Protein p24
HIV matrix proteins
ensure integrity of virion particle
what protein surrounds the HIV capsid
protein p17 surrounds capsid, ensuring integrity
viral envelope
- lipid bilayer
- made from budding
- contains proteins from host cell
what protein is the viral envelope cap made out of
gp120
what protein is the viral envelope stem made out of
gp41
HIV genome
- contains 3 structural polyproteins and 6 non-structural proteins only found in infected cells
- polyproteins are Gag, Pol and Env
what the structural protein Gag does
- contains matrix protein p17
- contains capsid protein p24
- contains nucleocapsid proteins
what the structural protein Pol does
- contains reverse transcriptase
- contains RNAse H
- contains integrase and the viral protease
what the structural protein Env does
- gives gp140 the precursors of gp120 and gp41
how many steps in HIV life cycle
nine steps
examples of opportunistic infections
- candidiasis
- pneumonia
properties of HIV drug targets
- have to be essential for pathogen reproduction
- must not have a close analogue in host cell
- must act early enough to stop progress of disease
Rational Drug Design using knowledge of HIV function
- Inhibitors of pretranscription phase
- Inhibitors of transcription phase
- Inhibitors of post transcription phase
Inhibitors of pretranscription phase
- blockage of viral entry into host cell
- inhibitors of gp120 binding to CD4
- inhibitors of gp120 binding to coreceptors
- inhibitors of viral fusion and uncoating
Inhibitors of transcription phase
- viral DNA is transcribed from viral RNA
- this means main target for this phase is reverse transcriptase enzyme
Inhibitors of post transcription phase
- viral DNA integration into the host cell genome
- Integrase inhibitors
- Protease inhibitors
Combination Therapy and 90/90/90 programs
HIV patients are now treated with anti-retroviral drugs at time of diagnosis
- Delaying treatment until CD4 levels drop no longer advised
- Patients treated with at least 3 drugs, like a nucleoside RT inhibitor, a non-nucleoside RT inhibitor and a protease inhibitor
- WHO HIV program aims to see 90% of HIV infected people diagnosed, 90% of diagnosed people on ART and 90% of people on ART to have viral loads <200/ml
reverse transcriptase
- converts single strand RNA to double stranded DNA
- has a catalytic unit for activating RNAse H enzyme, which liberates the proviral DNA from RNA after transcription
RNA-Dependent DNA Polymerase
- Hetrodimeric enzyme: p66 and p51
- 4 subdomains in p66: finger, palm, thumb and connection
- p66 palm domain contains polymerase active site
- 3 aspartic acid residues at positions 110, 185 and 186 constitute the catalytic triad
- p51 domain contains rubonuclease H active sites
nucleoside RT inhibitors (NTRIs)
- compete with normal substrates at enzyme catalytic site
- examples include zidovudine
- didanosine
- they block the ability for RT to bind
non-nucleoside RT inhibitors (NNRTIs)
bind to allosteric non-substrate binding sites
(selective!)
First generation non-nucleoside RT inhibitors
- hydrophobic molecules that bind to allosteric site
- binding of NNRTI to HIV-1 RT makes p66 domain hyper extended as it induces a rotamer conformation; changes in Tyr-191 and Tyr-188
First generation non-nucleoside RT inhibitors examples
- Nevirapine and delavirdine
- Nevirapine does not need to be metabolised in order to be active
Second and third generation non-nucleoside RT inhibitors
- structure-based drug discovery was used to develop these
- resistance to first generation was caused by a large amino acid being replaced by a smaller one
Second generation non-nucleoside RT inhibitors
- Efavirenz
- Capravirine
