HIV Lecture 1

Question 1

what HIV is

Answer 1

a retrovirus that has the ability to insert its genetic material (RNA) into the genome of the cells

Question 2

how HIV is transmitted

Answer 2

• unprotected sex
• sharing of needles
• from HIV-infected mum to baby
• breast milk
• blood transfusion

Question 3

three effects of HIV

Answer 3

• Immunosuppressive
• Neurological
• Carcinogenic

Question 4

Immunosuppressive effects of HIV

Answer 4

• decrease in helper T-cell count
• give rise to opportunistic infections

Question 5

T cell count of healthy individual

Answer 5

800-1300 cells/cm2

Question 6

T cell count of HIV infected individual

Answer 6

<200 cells/cm2

Question 7

Neurological effects of HIV

Answer 7

• 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

Question 8

Carcinogenic effects of HIV

Answer 8

• relates to immune deficiency
• Kaposi’s sarcoma is a rare tumour of blood vessel tissue in skin
• B-cell lymphoma

Question 9

what life expectancy for HIV-positive patients depends on

Answer 9

timely initiation of medical treatment as well as access and committed adherence to long-term therapy and medical care

Question 10

HIV Structure

Answer 10

• HIV capsid
• HIV matrix proteins
• Viral envelope

Question 11

HIV capsid

Answer 11

• two single stranded RNA pieces
• contains the HIV enzymes

Question 12

what protein is the HIV capsid made out of

Answer 12

Protein p24

Question 13

HIV matrix proteins

Answer 13

ensure integrity of virion particle

Question 14

what protein surrounds the HIV capsid

Answer 14

protein p17 surrounds capsid, ensuring integrity

Question 15

viral envelope

Answer 15

• lipid bilayer
• made from budding
• contains proteins from host cell

Question 16

what protein is the viral envelope cap made out of

Answer 16

gp120

Question 17

what protein is the viral envelope stem made out of

Answer 17

gp41

Question 18

HIV genome

Answer 18

• contains 3 structural polyproteins and 6 non-structural proteins only found in infected cells
• polyproteins are Gag, Pol and Env

Question 19

what the structural protein Gag does

Answer 19

• contains matrix protein p17
• contains capsid protein p24
• contains nucleocapsid proteins

Question 20

what the structural protein Pol does

Answer 20

• contains reverse transcriptase
• contains RNAse H
• contains integrase and the viral protease

Question 21

what the structural protein Env does

Answer 21

• gives gp140 the precursors of gp120 and gp41

Question 22

how many steps in HIV life cycle

Answer 22

nine steps

Question 23

examples of opportunistic infections

Answer 23

• candidiasis
• pneumonia

Question 24

properties of HIV drug targets

Answer 24

• 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

Question 25

Rational Drug Design using knowledge of HIV function

Answer 25

1. Inhibitors of pretranscription phase 2. Inhibitors of transcription phase 3. Inhibitors of post transcription phase

Question 26

Inhibitors of pretranscription phase

Answer 26

- 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

Question 27

Inhibitors of transcription phase

Answer 27

- viral DNA is transcribed from viral RNA - this means main target for this phase is reverse transcriptase enzyme

Question 28

Inhibitors of post transcription phase

Answer 28

- viral DNA integration into the host cell genome - Integrase inhibitors - Protease inhibitors

Question 29

Combination Therapy and 90/90/90 programs

Answer 29

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

Question 30

reverse transcriptase

Answer 30

- 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

Question 31

RNA-Dependent DNA Polymerase

Answer 31

- 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

Question 32

nucleoside RT inhibitors (NTRIs)

Answer 32

- compete with normal substrates at enzyme catalytic site - examples include zidovudine - didanosine - they block the ability for RT to bind

Question 33

non-nucleoside RT inhibitors (NNRTIs)

Answer 33

bind to allosteric non-substrate binding sites (selective!)

Question 34

First generation non-nucleoside RT inhibitors

Answer 34

- 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

Question 35

First generation non-nucleoside RT inhibitors examples

Answer 35

- Nevirapine and delavirdine - Nevirapine does not need to be metabolised in order to be active

Question 36

Second and third generation non-nucleoside RT inhibitors

Answer 36

- 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

Question 37

Second generation non-nucleoside RT inhibitors

Answer 37

- Efavirenz - Capravirine