HIV and anti-retrovirals (9.1)

Question 1

Describe the replicative cycle of HIV

Answer 1

Question 2

Describe the pathogenesis and different stages of HIV infection

Answer 2

Pathogenesis:

• Continual loss of CD4⁺ T cells
• The ultimate failure to replace the cells leads to a drop in peripheral CD4⁺ cell count
• Host is left susceptible to oppotunist infection and malignancies = AIDS
  
  • AIDS: Not all HIV patients have AIDS. Certain diseases that are ‘AIDS-defining’ in a patient with known HIV infection

Different stages of HIV infection

Acute phase (window) → Asymptomatic → Symptomatic

Acute phase: Flu-like symptoms. Lots of viral replication until brought under immune control

Asymptomatic: No outward sign of infection but gradual loss of CD4⁺ T cells. Very active viral replication. May persist for 10 years +

Symptomatic: Immune system ceases to function and diseae progresses

REMEMBER: Viral load (‘set point’) determines the speed and severity of the disease. Progression is also influenced by host (CCR5) and viral factors

Question 3

Describe the management of HIV infection

Answer 3

Diagnosis: Detection of anti-HIV antibodies indicates infection (due to 100 % chronicity of the disease)

Treatment:

2 NRTIs and a NNRTI

Monitoring:

Viral load assays

Question 4

Provide a basic summary of HIV

Family (→ replication), types, origin

Answer 4

Question 5

Draw the basic structure of HIV

Answer 5

Question 6

Anti-retrovirals: NRTIs

(Nucleotide reverse transcriptase inhibitors)

Answer 6

Nucleoside analogues lacking a 3^’ OH group which act to inhibit reverse transcriptase. Require phosphorylation by CELLULAR kinases for activation.

Inhibit RNA → cDNA

HOWEVER: May inhibit cellular DNA polymerases AND CYP metabolism leads to drug interactions

Example: AZT (azidothymidine)

• 2’3’ dideoxynucleoside analogue which inhibits RT, preventing chain elongation
• Phosphorylated by HOST cells

Disadvantages:

• Mutations → resistance
• Toxicity e.g. bone marrow (macrocytic anaemia)

Question 7

Anti-retrovirals: NNRTIs

(Non-nucleotide reverse transcriptase inhibitors)

Answer 7

Act through binding to reverse transcriptase to cause a conformational change which inhibits the synthesis of cDNA

Uses: May be used in combination with NRTIs - select medications for which codon mutations are different

Disadvantages: Substrate for CYP →drug interactions

Question 8

Anti-retrovirals: Protease inhibitors

Answer 8

HIV aspartyl protease cleaves gag and gag-pol polyproteins into individual viral proteins.

MoA: Inhibit protease mediated cleavage of polyproteins. Viral particles are still synthesised but are non-infectious

Disadvantages:

• Protease mutations cause resistance
• Dyslipidaemia
• Insulin resistance
• Metabolised by CYP → drug interactions

Use as boosters: Ritonavir is used in low doses as a booster. It’s inhibition of CYP allows other drugs to be used in smaller doses, reducing their toxicity

Question 9

Anti-retrovirals: Viral entry inhibitors

Answer 9

CCR5 antagonists: Prevents binding to host cell co-receptor

Enfuvirtide: Structural analogue of gp41. Prevents ‘hinge’ action of gp41 which subsequently prevents fusion of the virus and cell

Question 10

Anti-retrovirals: INSTI

(Integrase strand transfer inhibitors)

Answer 10

MoA: Block the strand transfer reaction (integration of viral DNA into host genome) of both HIV 1 and HIV 2

Very potent but very low barrier to resistance (1/2 mutations only)

Question 11

When should anti-viral treatment be started?

Answer 11

CURRENT: As soon as HIV infection is confirmed. Helps keep the viral load low, decreasing the progression of the condition

Previously:

• Symptomatic HIV infection
• AIDs defining illness
• HIV positive pregnant women
• CD4⁺ T cell count < 350/micro litre

Question 12

Learning objectives:

• Describe the replicative cycle of HIV
• Describe the pathogenesis and different stages of HIV infection
• Describe the mechanism of action of the main classes of drugs used to treat HIV infection ie nucleoside reverse transcriptase inhibitors, non-nucleoside RTIs, protease inhibitors, fusion inhibitors, integrase inhibitors.
• Describe the process whereby HIV acquires resistance to each of these classes of drugs.
• Indicate the reasons for using multidrug antiretroviral therapy regimes, and describe the principles involved in choosing such a multidrug regimen.
• Delineate potential targets within the HIV replication cycle which may be exploited in the development of new antiretroviral drugs.