HIV

Question 1

Recall the classification of HIV.

Answer 1

Question 2

Describe the property of lentiviruses

Answer 2

Question 3

Recall the HIV genome.

Answer 3

Question 4

A high degree of variability exists for ____ and _____ proteins of the HIV.

Answer 4

Question 5

Recall the structure of retroviruses

Answer 5

Question 6

Recall the key features of HIV replication.

Answer 6

Question 7

The main HIV chemokine receptors are _______ and _______. __________ and ____________ virus enters CD4+ T-cells via CCR5 and CXCR4 respectively.

Answer 7

Question 8

Recall about HIV co-receptors usage and natural history.

Answer 8

Question 9

Recall the natural resistance to HIV.

Answer 9

Question 10

Recall innate anti-viral cellular factors and how HIC counteracts these proteins.

Answer 10

Question 11

Recall the immune response to HIV.

Answer 11

Question 12

Recall the evasion of the immune response by HIV.

Answer 12

Question 13

Recall the timeline of HIV disease.

Answer 13

Question 14

Recall the CD4+ T cell homeostasis

Answer 14

Question 15

Recall the cause of CD4+ T cell decline.

Answer 15

Question 16

Recall the HLA type important for immune response.

Answer 16

Question 17

Recall the effects of the depletion or dysfunction of other cells.

Answer 17

Question 18

Recall the markers of immune activation that are elevated in HIV infection.

Answer 18

Question 19

Recall what causes immune activation in HIV infection.

Answer 19

TLR4 expressed in monocytes/macrophages

Question 20

Mention the different antiviral drugs for HIV

Answer 20

Question 21

_____ leads to rapid decline in HIV RNA and CD4 recovery.

Answer 21

ART

Question 22

According to the TART study, ____ now recommended for all patients.

Answer 22

Question 23

Recall the current challenges of ART.

Answer 23

Question 24

Recall the disease risk that increases with ATR.

Answer 24

Question 25

Recall the possible combination of prevention measures against HIV.

Answer 25

Question 26

Recall the different prevention modalities built on antiviral therapy.

Answer 26

Question 27

Recall the efficacy PREP.

Answer 27

Question 28

Recall dapivarine vaginal ring efficacy.

Answer 28

Question 29

Circumcision reduces the risk of HIV acquisition. True or False.

Answer 29

True

Question 30

Recall the various vaccine approaches.

Answer 30

Question 31

Recall prime-boost vaccine approaches.

Answer 31

Question 32

Describe bNAbs.

Answer 32

Question 33

Recall the future direction and challenges for bNAbs.

Answer 33

Question 34

Recall Ad26 virus + gp140 boost in monkeys and humans.

Answer 34

Question 35

Recall the lifecycle of HIV.

Answer 35

HIV first has to attach to a CD4 cell. The proteins on the outer surface of HIV (called gp41 and gp120) connect with receptors on the surface of the CD4 cell (usually the CD4 receptor and the CCR5
coreceptor).

After HIV attaches to the CD4 cell, it is absorbed into the main body of the cell. As this happens, HIV first loses its outer shell. This leaves viral capsid with HIV and three key enzymes (a type of protein) that HIV uses to replicate.

The first enzyme is called RT. This stands for reverse transcriptase. RT changes the single strand of HIV (called RNA) into a double strand to fit in with human DNA. The new double-stranded HIV crosses into the central nucleus of the CD4 cell. This is where HIV is integrated into human DNA. The CD4 nucleus then starts producing raw material to make new HIV. These long strands of new HIV particles need to be cut up and assembled as new virus. The enzyme involved in the cutting and assembling process is called protease. The newly formed virus then has to leave the cell.

Question 36

Recall barriers to curing HIV.

Answer 36

• latently infected T-cell
• Residual viral replication
• anatomical reservoirs

Question 37

Recall two forms of HIV infected T cells,

Answer 37

Question 38

How do infected cells survive on ART?

Answer 38

As long as the cell remains inactivated/naiive, the virus will remain latent. These latent T cells could also proliferation. This forms the largest barrier to HIV cure.

Active reservoirs can’t die, but can’t infect other cells during ART. Found usually in lymph nodes and guts (usually in B cell follicles - where no cytotoxic cells are present)

Question 39

Recall the process of latency reversal (shock and kill).

Answer 39

While HIV is in this latent state, the immune system cannot recognize the virus, and antiretroviral therapy (ART) has no effect on it. Latency-reversing agents reactivate latent HIV within CD4 cells, allowing ART and the body’s immune system to attack the virus.

Question 40

Recall clinical strategies being evaluated to achieve remission of ART.

Answer 40

Question 41

Recall the process of permanent silencing.

Answer 41

Question 42

Explain how antiretroviral therapy can be effective despite the high rate of HIV mutation.

Answer 42

HIV treatment is highly effective when 3 drugs are used simultaneously. The pressure from three different drugs means that it is highly unlikely for an HIV strain to simultaneously develop resistance to all three. This results in rapid decline in HIV RNA in plasma, recovery of CD4+ T cells, reduced morbidity and reduced mortality. Resistance does occur but is now rarely seen, particularly in patients who are compliant with all medications.

Question 43

What is CD38?

Answer 43

The CD38 protein is a marker of cell activation. It has been connected to HIV infection, leukemias, myelomas, solid tumours, type II diabetes mellitus and bone metabolism, as well as some genetically determined conditions.

Question 44

Briefly describe three potential barriers to a cure for HIV.

Answer 44

• The presence of latently infected cells, making elimination of the virus difficult.
  
  • Multiple factors maintain HIV latency including integration of the virus into the nuclear chromatin, defects in transcription, the low level of expression of transcription factors in resting T cells, defects in RNA export in the resting T cell, and a limiting of translation needed to produce viral proteins.
• Residual viral replication that forms a reservoir of active virus.
• Anatomical reservoirs of the virus.
  
  • There is HIV persistence on ART, with infected cells being sequestered in protected areas like the brain, lymphoid tissue and the gastrointestinal tract.

Question 45

In the epidemiology section, newly diagnosed HIV infections and newly acquired HIV infections in Australia were discussed. What is the major difference between them?

Answer 45

A newly acquired infection is defined as an infection diagnosed in a patient who has had a negative HIV test in the past 6 months. Newly diagnosed infection is a positive result in a patient whose time of acquiring the virus is not clear as there are no recent negative tests.

Question 46

Does viral replication only occur in replicating cells since HIV RNA would only be produced if the host cell’s genome was being transcribed?

Answer 46

Full blown HIV replication including release of viral particles mostly occurs in ACTIVATED T cells. However, there may still be RNA and even HIV protein produced in RESTING T cells. Remember, RESTING T cells still need to transcribe RNA to make proteins etc.

Question 47

Virus populations containing a mixture of R5-tropic, X4-tropic, and/or dual-tropic HIV are called mixed tropic (D/M)’. How do people get all 3? If only one HIV virus entered the body, and for example that one virus is R5, then doesn’t that mean all the new viruses produced after the integration with host cell DNA will be R5?

Answer 47

It is certainly true that the initial infection is caused by one or a couple of “founder” viruses. Usually this transmitted strain is an R5 strain. However, due to the error prone nature of reverse transcriptase and the massive turnover of virus particles, mutation begins to appear throughout the viral genome, in particular the env gene. The env gene encodes the Env protein, which is the virus surface protein that binds CD4 and the coreceptors. These mutations can be lethal as they can destroy the coding sequence of the env. However, some mutations lead to a functional Env that can cause a switch from using CCR5 for entry to CXCR4 or both. Thus, when you sample a population you can find R5-tropic, X4-tropic, dual-tropic or mixed strains. This is particularly evident in individuals with AIDS where the frequency of X4-tropic strains increases.

Question 48

CXCR4 is expressed on cells with a _____________ phenotype whilst CCR5 is expressed on cells with an ____________ phenotype

Answer 48

CXCR4 is expressed on cells with a resting/naïve phenotype whilst CCR5 is expressed on cells with an activated/memory phenotype

Question 49

Recall gene therapy to eliminate CCR5.

Answer 49

Question 50

Recall clonal exhaustion and replicative senescence.

Answer 50

One of the hallmarks of HIV infection is chronic immune activation, this leads to T cell exhaustion. T cell exhaustion is characterised by loss of effector functions, up-regulation of multiple inhibitory receptors, alterations in transcription and metabolism and loss of proliferative capacity (or “replicative senescence”). Therefore, replicative senescence is a characteristic of an exhausted T cell. So the CD8 T cells – through the persistence of antigen and inflammation – lose their ability to replicate and mount a response.

Question 51

Why is the GIT a privileged site for replication of the HIV virus? Is this because it has many Peyer’s patches and T cells or are there other reasons?

Answer 51

HIV preferentially replicates in the GIT because of the high frequency of activated T cells in that site. The GI tract is not an immunologically privileged site. It’s just that there are an abundance of target cells there.

Question 52

Why does ART only prevents new virions from infecting other cells? Should it not completely halt viral replication in all cells so that there aren’t any new virions released that could go on to infect other cells?

Answer 52

The second part of your sentence answers the first part. Aside from protease inhibitors, all other antiretroviral drugs work prior to viral integration. Thus if the virus is already integrated, ART has no effect on them. When ART is commenced, any virus that emerges from the already integrated forms of HIV is incapable of infecting other cells.

Question 53

How to distinguish between cured and remission?

Answer 53

Cured is really saying someone no longer has any HIV virus in their body whereas remission can be a delay in a rebound or having post-treatment control (viral load does come back but at an extremely low level) the only way to distinguish would be to stop the patient on ART to allow the chance for any virus to come back.

Question 54

Why can’t our immune system recognise and kill inactivated CD4 T cells that are infected with HIV (and is now silenced)? Wouldn’t the CD4 T cell still have foreign envelope proteins on its surface that the immune response can recognise from when the virus entered the cell?

Answer 54

Those envelope proteins are likely rapidly recycled from the cell surface post viral infection. There are typically 14 envelope spikes on any given virion, they would disappear quickly from the cell surface. To produce protein on an infected cell, the integrated virus must produce spliced and unspliced RNA first. In latently infected cells, transcription of integrated virus is silenced or occurs at a very low level.