HIV

Question 1

What is Africa’s most severe and costly epidemic?

Answer 1

HIV+Malaria+TB

Question 2

how are mothers with HIV infecting their babies?

Answer 2

pregnancy
childbirth
breast-feeding

Question 3

What strategies have been developed to combat and prevent this disease?

Answer 3

Research; ARVs treatment; prevent babies from getting HIV

Question 4

Long card (opinion-based)

HIV can be treated…

Answer 4

• We need to CHANGE our attitude and way of looking at HIV/AIDS
• We need to STOP seeing HIV/AIDS as a ‘death sentence’
  o Disease that we cannot treat
• We need to STOP viewing HIV as a hopeless situation
• We must approach HIV as a disease that we CAN TREAT
• We can ‘prevent’ HIV+ from getting sick
• We can PREVENT babies from getting HIV
  o HIV medication (ARVs) are now affordable and accessible in most areas
• The global fund: donates billions of dollars to treat HIV+ in Africa
  o Different types of medication are available to STOP HIV from multiplying
• There is HOPE for HIV+

Question 5

Who was patient zero and what did he refer to HIV as?

Answer 5

Gaëtan Dugas; “gay cancer”

Question 6

Define HIV

Answer 6

Human Immunodeficiency Virus - rapidly multiplying

Question 7

Why is HIV so lethal?

Answer 7

It attacks immune cells (specifically: CD4 cells/T helper cells)

Question 8

How does the virus survive?

Answer 8

• Virus uses these cells to make copies of itself
• As HIV destroys more and more CD4 cells and makes more copies of itself, it gradually weakens a person’s immune system
• Body finds it harder to fight off infection

Question 9

How long can the immune system go without taking toll, if HIV is left untreated?

Answer 9

10-15 years + (depends on age, general health and background)

Question 10

How much can the virsu mutliply each day?

Answer 10

> 1x10^6 times/day

Question 11

What happens during the multiplication process?

Answer 11

o Numerous genetic ‘mistakes’ that occur
o Resulting in different types and strains of HIV
o makes it difficult to cure

Question 12

Name and describe the types of HIV

Answer 12

o HIV-1 (worldwide):
Most common and pathogenic
has 4 sub-groups, each of them with many sub-types, but clinically identical
o HIV-2 (Localised in West-Africa):
has lower pathogenicity and lower Mother-To-Child-Transmission risk (MTCT)

Question 13

Is HIV treated differently depending on viral type?

Answer 13

No, however different types of viruses may be important in development and use of HIV vaccines in future

Question 14

Describe the structure of HIV

Answer 14

• Within this structure not only are they receptors and
  different types of glycoproteins, there is also a viral core
• Within this viral core, there is the enzyme reverse transcriptase which is error prone along with two
  RNA strands of the virus now

Question 15

Name the stages of the virus replication cycle

Answer 15

1. binding to cell
2. reverse transcription
3. integration into host’s dna
4. transcription
5. assembly and budding

Question 16

Explain step one in the replication cycle

binding to cells

Answer 16

• HIV can only multiply by entering host cell and by
  o using host cell to multiply itself
• Host cell = CD4 lymphocytes
  o HIV needs to bind to CD4 and fuse with surface
• HIV (gp120 + gp41 receptors) attaches to CD4 receptors
  o CD4 receptors: CCR5 and CCR4
  o only found on CD4 cells
  o binding depends on the type of the cell and the stage of the
  disease
  o leads to conformational change of gp120 which collapses on
  itself allowing fusion and entry in host cell

Question 17

Explain step two in the replication cycle

reverse transcription

Answer 17

• Following binding and fusion, capsid containing RNA strands and
  reverse transcriptase enzymes enters CD4 cells
• RNA strands converted to DNA
  o occurs in cytoplasm via retroversion
  o RETROVERSION
  Single-stranded RNA retroverted to doublestranded
  DNA
  o controlled by reverse transcriptase enzyme

Question 18

Explain step three in the replication cycle

integration into host’s dna

Answer 18

• Virus retroverts RNA to DNA so that viral DNA attaches to host DNA
  o occurs in nucleus of host
  o newly made HIV DNA moves to the nucleus
  o HIV DNA spliced (integrated) into the host DNA
  o Enzyme: integrase (responsible for integration of viral and host DNA)
  o integrated viral DNA = provirus

Question 19

Explain step four in the replication cycle

transcription

Answer 19

• Host cell nucleus now contains genetic information of HIV – provirus
• HIV uses the host cell to replicate itself
• DNA transcribed into mRNA + genomic RNA
  o using host’s enzymes
  o transported out of nucleus to the cytoplasm
  o mRNA is translated into new viral proteins
  o host’s enzymes and ribosomes used
• cytokines (secreted when immune reaction against opportunistic
  infection) may activate this step

Question 20

Explain step five in the replication cycle

assembly and budding

Answer 20

• Newly made HIV core proteins, enzymes, genomic RNA move towards
  surface of cell
  o new, immature viral particles (virions) assemble
  o YET TO BE INFECTIOUS
  o bud of from host cell, taking some cell membrane with it
  o not infectious outside host
• Protease enzyme starts processing proteins in newly formed virus
  o finishes by cutting HIV protein chains into individual proteins
  o combine to make a new working virus
  o process completed by formation of capsid core and lipid
  envelope
  o Virus is mature, escapes via budding
  o Budding = virus comes out of CD4 cells and takes a bit of cell
  membrane with it

Question 21

Long question

Targeting HIV replication

Answer 21

• The replication of HIV-1 is a multi-stage process
• Each step is crucial to successful replication and is therefore a potential target of antiretroviral drugs
• Step one is the infection of a suitable host cell such as a CD4 positive T lymphocyte.
• Entry of HIV into the cell requires the presence of certain receptors on the cell surface, CD4 receptors
  and coreceptors such as CCR5 or CXCR 4.
• These receptors interact with protein complexes which are embedded in the viral envelope.
• These complexes are composed of two glycoproteins and extracellular GP 120 and a transmembrane
  GP 41.
• When HIV approaches a target cell, GP 120 binds to the CD4 receptors, this process is termed
  attachment. It promotes further binding to a coreceptor.
• Coreceptor binding results in a conformational change in GP 120. This allows GP 41 to unfold and
  insert its hydrophobic terminus into the cell membrane. GP 41 then folds back on itself. This draws the
  virus towards the cell and facilitates the fusion of their membranes.
• The viral nucleocapsid enters the host cell and breaks open, releasing two viral RNA strands and 3
  essential replication enzymes: Integrase, protease and reverse transcriptase.
• Reverse transcriptase begins the reverse transcription of viral RNA. It has two catalytic domains: the
  ribonuclease H active site and the polymerase active site.
• Here single stranded viral RNA is transcribed into an RNA-DNA double Helix.
• Ribonuclease H breaks down the RNA. Polymerase then completes the remaining DNA strand to form a
  DNA double Helix.
• Now integrase goes into action; it cleaves a dinucleotide from each 􀏯’ end of the DNA creating two
  sticky ends.
• Integrase then transfers the DNA into the cell nucleus and facilitates its integration into the host cell
  genome. The host cell genome now contains the genetic information of HIV.
• Activation of the cell induces transcription of proviral DNA into messenger RNA.
• The viral messenger RNA migrates into the cytoplasm where building blocks for a new virus are
  synthesized.
• Some of them have to be some of them have to be processed by the viral protease.
• Protease cleaves longer proteins into smaller core proteins. This step is called crucial create an
  infectious virus.
• Two viral RNA strands and the replication enzymes then come together, and core proteins assemble
  around them forming the capsid.
• This immature viral particle leaves the cell acquiring a new envelope of host and viral proteins.
• The virus matures and becomes ready to infect other cells.
• HIV replicates billions of times per day destroying the host’s immune cells and eventually causing
  disease progression.
• Drugs which interfere with the key steps of viral replication can stop this fatal process. Entry into the
  host cell can be blocked by fusion inhibitors for example. Inhibition of reverse transcriptase by
  nucleoside inhibitors or by non-nucleoside reverse transcriptase inhibitors is part of standard
  antiretroviral regimens.
• The action of integrase can be blocked.
• Protease inhibitors are also part of standard antiretroviral therapy. Each blocked step in viral
  replication is a step towards better control of HIV disease.

Question 21

Draw a diagram illustrating the 5 steps in HIV replication

Answer 21

Question 22

List 6 HIV dynamics

Answer 22

1. Has extracellular half-life < 6 hours
2. Production cycle of ± 2.6 days
3. Infected CD4 cell: half-life ± 1.6 days
4. ± 4-10 billion virions produced per day
5. ± 37.6 trillion virions / 10 years of infection
6. Destruction of ± 1.8 billion CD4 cells per day

Question 23

How is HIV transmitted?

Answer 23

1. Blood or blood products
2. Semen
3. Vaginal secretions
4. Breast milk
5. Other body fluids that may contain blood

Question 24

What increases risk of transmission?

Answer 24

• Unprotected sex
• STI’s (particularly ulcerative STI’s)
• Anal sex
• Rape
• Sex during menstruation
• High viral load of HIV+ partner

Question 25

What makes HIV so novel?

Answer 25

1. binds to different types of cells
   o immune system: CD4 T cells, BUT also monocytes, macrophages and other white blood cells
   (blood + lymph nodes + lymphoid organs)
   o other cells: microglia, gastro-intestinal epithelium, lungs, heart and kidney
2. not the same effect in all cells:
   o virus kills CD4 T-cells (cytopathic effect)
   o Does not kill macrophages (= reservoirs of virus)
3. HIV escapes body’s immune response, because:
   o HIV mutates reverse-transcriptase is error-prone (about 10 bases change at each replication
   cycle, mainly in envelope genes and regulatory genes)
   some mutations are lethal to the virus
   some other results in more virulent virus, not anymore recognized by host’s antibodies
   or immune cells
4. immune cells become dysfunctional, or are killed
5. HIV genome hides in cell’s genome, where ARVs cannot destroy it
6. viral DNA is not permanently incorporated: cannot be inherited!
7. heterogeneity: different strains infect different persons, and different types of cells

Question 26

what are the SA estimates of HIV +?

Answer 26

5.6 million (23/34 million global cases are in africa)

Question 27

True or false: HIV causes immune deficiency and diseases

Answer 27

True

Question 28

Read through

Estimates provided by Actuarial society of South Africa:

Answer 28

• 1.8 million AIDS deaths had occurred in South Africa, since the start of the epidemic
• Around 740 000 deaths occurred in 2006, of which 350 000 were due to AIDS (950 AIDS- related
  deaths per day)
• 71% of all deaths in the 15-49 age group were due to AIDS
• 230 000 HIV-infected individuals were receiving ARV treatment, and a further 540 000 were sick with
  AIDS but not receiving ARV treatment
• 300 000 children under the age of 18 experienced the death of their mother
• New infections: 527 000
• Currently 5.6 million people living with HIV in SA

Question 29

Define the immune system

Answer 29

1. protects individuals by inter-related abilities to distinguish between self and foreign structures in body
2. responsible for defending the body against various infections
   * Viruses
   * Bacteria
   * Fungi etc.
   * Helps to destroy cancer cells
3. Responsible for mounting inflammatory response
   * To heal tissue following infection and wounds
   * Resists harmful invasions into body (infections, foreign bodies - splinters)

Question 30

Describe the 2 ways the immune system functions

Answer 30

1. Innate immunity - skin, phagocytic cells, NK cells, various blood-borne molecules, physical barriers
2. Acquired immunity - discriminatory (self vs foreign)