HIV and AIDS pathogenesis and treatment

Question 1

What is the origin of the HIV-1 pandemic?

Answer 1

Originated in the Democratic Republic of Congo in the 1920s transmitted from chimpanzee to human. Epidemic across America, Africa, Europe and Australia began in the mid-1970s. First case in 1905

Question 2

When was HIV discovered?

Answer 2

183/1984, along with CD4 receptor

Question 3

What is the prevalence of HIV by country?

Answer 3

Highest prevalence by continent in Africa > Americas> Europe> Asia

Question 4

What is the structure of HIV?

Answer 4

It has an envelope with the glycoproteins gp120 and gp41. Below the envelope is the matrix protein 17. The capsid encloses 2 copes of the HIV genome consisting of a single stranded RNA positive sense strand. It contains enzymes in its capsid to assist in replication.

Question 5

What is the role of gp120?

Answer 5

Assists HIV in attachment to CD4+ T helper cell receptor and the attachment to co-receptor which is essential for endocytosis. It is heavily glycosylated for protection against neutralising antibodies.

Question 6

What is the role of gp41?

Answer 6

Stabilises HIV attachment post-binding by acting as a transmembrane anchor. It is heavily glycosylated for protection against neutralising antibodies.

Question 7

What is the role of the capsid surrounding HIV?

Answer 7

It contains the viral proteins essential for the entry of HIV into the cell, integration of the viral genome and replication of the virus. Capsid contains the protein p7 which condenses the viral RNA.

Question 8

What is the genome of HIV?

Answer 8

Retrovirus- single stranded positive sense RNA. It has a poly-adenosine tail on the 3’ end and guanine triphosphate/GTP cap on 5’ end. This is bound to the p7 on the capsid.

Question 9

What is the main structural protein of HIV virion?

Answer 9

Gag polyprotein which makes up half of the mass. It drives virus particle assembly, release and maturation. THey are activated by cleavage from protease enzymes on capsid.

Question 10

Which enzymes are present in HIV?

Answer 10

Integrase, ribonuclease, reverse transcriptase and protease

Question 11

Role of integrase?

Answer 11

Inserts proviral DNA into host cell chromosomes

Question 12

Role of protease?

Answer 12

Important for replication of HIV virus by cleaving precursor proteins into smaller proteins which combine with the genetic material to create a mature HIV virus post translation.

Question 13

Role of ribonuclease?

Answer 13

Selective hydrolysis of RNA strand which is essential for HIV replication

Question 14

What is the target of HIV?

Answer 14

CD4+ cells which must have a coreceptor

Question 15

What is proviral DNA?

Answer 15

Genes from a virus which can be inserted into a host cell’s genome.

Question 16

What are the co-receptors important for HIV attachment?

Answer 16

CCR4 and CXCR5 which are not specific to T cells but also found in macrophages and dendritic cells

Question 17

How does HIV infection occur?

Answer 17

HIV binds to CD4+ receptor and co-receptor via gp120. It fuses and taken in by endocytosis. Reverse transcriptase forms DNA strand of RNA genome and integrase inserts this into the nuclear DNA. This causes transcription of viral mRNA and translation of viral proteins. These are released by exocytosis and use viral proteases to form mature HIV.

Question 18

How is HIV transmitted?

Answer 18

Blood borne virus transmitted percutaneously from contaminated equipment or via sexual intercourse with a greater risk anally. It is present in breast milk so from mother to child during labour

Question 19

How does HIV replicate in the body quicklY?

Answer 19

Post transmission, it targets dendritic cells at the mucosal cell membrane which travels to the lymph node and exposes HIV to the immune cells, especially CD4+ T cells, allowing replication. This results in the acute infection and fever in the initial stage.

Question 20

What is vertical gene transfer?

Answer 20

From mother to offspring.

Question 21

What are the stages of HIV infection?

Answer 21

Acute phase which lasts 2-4 weeks with flu-like symptoms
Chronic phase which can last 2-10 years where CD4+ cell count slowly declines as HIV count increases
At the end of the chronic period when CD4+ count falls below 200, this is AIDS with high susceptibility to common infection

Question 22

What are the common bacterial diseases in AIDS patients?

Answer 22

Mycobacterium tuberculosis, Mycobacterium avium complex and pneumonia

Question 23

What are the common viral diseases in AIDS patients?

Answer 23

Cytomegalovirus which causes flu-like symptoms. It can cause retinitis and lead to vision loss.

Question 24

What are the common fungal diseases in AIDS patients?

Answer 24

Candiadis (thrush) of oesophagus

Question 25

What are the common parasitic diseases in AIDS patients?

Answer 25

Pneumocytosis jirovecci pneumonia and toxoplasmosis of the brain

Question 26

Pneumocytosis jirovecci pneumonia

Answer 26

Infection of the lung by the fungus through air that causes trouble breathing that is progressive, low oxygen saturation, dry cough which is non-productive, weight loss and fever. It attaches to the type 1 alveolar epithelium. Usually asymptomatic in healthy people.

Question 27

How is Pneumocytosis jirovecci pneumonia treated and managed?

Answer 27

Antibiotic cotrimoxazole, steroid drugs and anti-retrovirals

Question 28

What is toxoplasmosis?

Answer 28

Zoonoses from infeceted meat or cat faeces. It is an opportunistic parasitic protozoa animals that causes cysts to form in the brain and leads to encephalitis and cause cognitive impairment.

Question 29

What are the common cancers in AIDS patients?

Answer 29

Cervical cancer, Lymphoma and Kaposi's sarcoma

Question 30

What is Kaposi's sarcoma?

Answer 30

Cancer of the cells lining the GI tract from the mouth to the anus. It occurs because of the hijacking of the cell's genome which results in uncontrolled growth.

Question 31

What are the HIV related pathologies?

Answer 31

Encephalopathy and wasting syndrome (unwanted weight loss)

Question 32

Which conditions are associated with CD4 count of 400?

Answer 32

Skin and mucosal conditions such as thrush, herpes and the rash shingles

Question 33

Which conditions are associated with CD4 count of 50-150

Answer 33

Infections such as toxoplasmosis. Cancers associated with AIDS eg lymphoma, Kaposi's sarcoma

Question 34

Which conditions are associated with CD4 count of below 50?

Answer 34

Lymhoma, cytomegalovirus

Question 35

WHat are the nucleotide transcription inhibitors mechanism of action?

Answer 35

Includes both nucleoside and nucleotide RTI. Acts in the cell where it is converted into active 5' triphosphate which compete to be incorporated into viral DNA with other nucleotides. It lacks a 3' hydroxyl group and causes termination of viral DNA chain because it cannot form 5'3 phosphodiester bonds.

Question 36

Difference between nucleotide and nucleoside reverse transcriptase inhibitors?

Answer 36

Nucleoside: consist of sugar and base. Nucleotide: consist of sugar, base and phosphate group Nucleosides need to be phosphoryated by cellular kinases for reverse transcriptase to recognise it and integrate into viral DNA.

Question 37

How do non nucleotide reverse transcriptase inhibitors act?

Answer 37

Binds to the p66 allosteric site of reverse transcriptase enzyme, causing conformational change which prevents DNA polymerase enzyme activity.

Question 38

What was the first anti-retroviral drug?

Answer 38

AZT which most HIV strains are now resistant to

Question 39

How do protease inhibitors work?

Answer 39

Competitively inhibits the cleavage of Gag-polyprotein for virus protein assembly. It requires a pharmokinetic boost to enhance activity, such as preventing liver enzyme metabolism of drug.

Question 40

What are the principles of anti-retroviral therapy?

Answer 40

Offer treatment to HIV patients, regardless of CD4 count, achieve viral suppression to undetectable levels, involve patient at all stages for increased adherencen and monitor efficacy and tolerability by testing virus for resistance and checking CD4 count.

Question 41

How is viral suppression of HIV achieved?

Answer 41

Requires combination of 3 drugs from at least 2 different classes to prevent resistance

Question 42

How can adherence be encouraged?

Answer 42

Combination pills, fewest side effects, minimal number of tablets.