Case 17- HIV Flashcards

Question

CNS disease in AIDs

Answer 1

* Opportunistic infections Cryptococcus, CMV, MAC, PML, Toxoplasmosis * Primary cerebral lymphoma * HIV dementia complex * Spinal cord disease * Peripheral and autonomic neuropathy

Answer 2

54% are gay men 22% in heterosexual women 15% in heterosexual men 3% in IVDU

Answer 3

HIV replicates significantly Reaches very high viral load Results in acute HIV syndrome Might get non specific flu like symptoms

Answer 4

After acute HIV syndrome, virus enters clinical latency Resulting in a balance between HIV replication and CD4 cell stability Tends to be around for 10 years Very rarely any symptoms during this time

Answer 5

Dementia that occurs due to cortical atrophy, inflammation and demyelination caused by direct infection with HIV

Answer 6

ELISA | HIV antibody test

Answer 7

A lectin on the dendritic cell surface HIV can bind to this - becoming attached to dendritic cell Transported to the lymph nodes with the dendritic cell - ends up in close proximity to CD4 cells that it wants to attack

Answer 8

Primary receptor- CD4 | Secondary receptor- CCR5 or CXCR4, these are chemokine co-receptors which help HIV to fuse and enter the cell

Answer 9

Chemokine co-receptor that allows HIV virus to enter T cells Macrophage tropic Implicated in M-tropic/R5- tropic HIV R5 strains usually indicate early infection

Answer 10

Maraviroc Prevents HIV from binding to CCR5 Prevents HIV from entering the host cell

Answer 11

Chemokine receptor that allows HIV to enter T cells T cell tropism Implicated in T-tropic/R4-tropic HIV HIV infection typically switches to this strain from M tropic Associated with faster T cell clearance and more severe immunodeficiency

Answer 12

Viral and cellular membrane fuse Gp120 complex on HIV attaches with CD4 receptor Conformational shape change in the virus Exposing Gp41 complex on HIV This complex promotes fusion of viral and cellular membrane - co-membrane and viral genome and proteins are in host cell

Answer 13

Fusion inhibitor

Answer 14

Fusion inhibitor

Answer 15

Fusion inhibitor T20. Prevents fusion of HIV virus to CD4 cell. By preventing hair pining of the gp41 molecule thereby preventing erasure of the HIV virion and CD4 cells

Answer 16

Integrate enzyme allows movement of viral DNA in to the host nucleus - inserted into the chromosome The virus lives in the host

Answer 17

HIV DNA is now in the hosts genome - transcription and translation New viral proteins can be made - new HIV virion Proteins get cleaved by viral proteases to become mature Now the virion is infectious Virus buds off from the hosts membrane

Answer 18

* Virucides- direct effect against virions (too toxic for use) * Antivirals- have virus specific effects i.e. cell attachment or virus detected macromolecular synthesis * Immunomodulators- may either replace deficient immune system (i.e. immunoglobulins) or augment host response to pathogens (i.e. interferon)

Answer 19

Maximum tolerable dose per kilogram of body weight / Minimum dose per kilogram body weight that will cure the disease. The higher the CI the better, it will be specific to the virus and not attack cellular function

Answer 20

• High viral replication (RNA>DNA viruses) • Adherence to medication • Effectiveness of drugs • Mutations in virus that lead to resistance and don’t effect fitness In the virus point mutations occur at every point along the genome at least once a day.

Answer 21

* 1987: AZT approved by FDA. * 1992: multiple drugs attempted * 1995: protease inhibitors discovered * 1996: NNRTIs discovered; HAART used for first time.

Answer 22

Determine the structure of your target in a complex with a known inhibitor. Use this and other knowledge to design a better inhibitor, make it and test it

Answer 23

Use robotic techniques to make an enormous number of different compounds from a limited number of subunits. The individual components are then assayed for bioactivity, any active compounds identified can be used as a lead compound.

Answer 24

* Reverse transcriptase is used to convert viral RNA into DNA * NRTI’s look like nucleotides that are used to form DNA * Once an NRTI is mistaken for a nucleotide and is placed in the growing chain, further growth stops.

Answer 25

Also inhibits mitochondrial replication. Potent inhibitors of DNA polymerase which is essential for mitochondrial replication: Lactic acidosis, Steatosis, Lipoatrophy, metabolic syndrome.

Answer 26

The process of adding a new building block involves 3 steps: • Binding of the next nucleoside or nucleoside analogue (NRTI) triphosphate • Incorporation onto the end of the growing viral DNA chain and release of pyrophosphate • Translocation of the incorporated nucleoside to a different position to allow room for addition of the next nucleoside residue Nucleoside analogues are removed by mutant reverse transcriptase by a cleavage process called pyrophosphorylysis (PPi), translocation cannot happen, and the analogue is removed. No binding of reverse transcriptase to analogue.

Answer 27

NNRTI's bind directlty to reverse transcriptase | The binding stops the ability of the reverse transcriptase to add new nucleotides to the growing DNA chain

Answer 28

* Protease is an enzyme that breaks up the proteins made by mRNA * These proteins are used to assemble new viruses * By blocking the breakup of these proteins the necessary building blocks of new viruses are not available * Resistance is through confirmational change in the Protease

Answer 29

* Homozygous CCR5 Δ32 mutation is associated with lack of infection. * CCR5 tropic virus require CCR5 for cell entry- it is a co-receptor. * CCR5 inhibitors therefore prevent virion entry. * Resistance occurs when virus switches to be CXCR4 tropic.

Answer 30

1) Unknown exact mode of action | 2) Prevents integration of viral DNA into the human genome

Answer 31

* Dual NRTI and single Integrase * Dual NRTI and single PI * Dual NRTI and single NNRTI

Answer 32

1) Suspected when viral load increases or lack of virology suppression. 2) Resistance testing may be carried out. 3) However, patients need to be taking drugs as scheduled. 3) Resistance can be archived, cross resistance may occur. 4) Transmitted or prior resistance may reduce how effective future treatment is. 5) Monotherapy does not work due to resistance.

Answer 33

All PI and NNRTI are metabolised through CYP P450 in liver. Ritonavir is a major inhibitor of CYP P450. There are intra-retroviral interactions as well as with TB medication, sedatives and statins.

Answer 34

Poor adherence and drug interactions

Answer 35

``` Needle stick injury = 1 in 300 Mucous membranes = 1 in 111 Vaginal receptive = 1 in 500 Vaginal insertive - 1 in 1111-3333 Anal receptive = 1 in 33-1000 Anal insertive = 1 in 1666 Mother to foetus ```

Answer 36

Raltegravir (integrase) and Truvada (2 NRTI- tenofovir and emtricictabine). Test for HIV needs to be done post exposure. If the partner has an undetectable load then it will be untransmissible.

Answer 37

* Truvada (2NRTI Tenofovir and Emtricitabine) reduces risk of transmission in high risk population such as men who have sex with men and partners of positive patients who have a detectable virus. * Daily or Event based dosing * Reduces incidence of new HIV diagnosis significantly