9 - AIDs

Question 1

What is PrEP?

Answer 1

Pre-exposure prophylaxis

• Daily oral antiretroviral with a fixed-doce combo of tenofovir disproxil fumarate (TDF) and emtricitabine
• Shown to be safe and highly effective in reducing risk of HIV aquisition (IF YOU TAKE IT)

Question 2

What is the physiology behind why a Ag/Ab test and RNA NEET are effective at detecting HIV at days 14 and 10 respectively?

Answer 2

HIV specific antibodies don’t come up until 30 days or beyond; therefore, just an Ab test may miss an infection if it’s before this point.

P24 antigen can sometimes be seen by day 14 and is detected by the Ag/Ab test.

If you’re really worried about an acute infection, viral RNA present around 10 days and may be detected by the RNA NAAT.

Question 3

What does the CDC recommend to detect HIV early? How quickly does this work? What else can be used to detect it?

Answer 3

4th/5th generation HIV Ag/Ab combination test to detect buth the p24 antigen and HIV antibody

• can be positive as early as 14 days post infection

However, an HIV RNA NAAT may detect HIV as early as 10 days post infection.

Question 4

How is HIV transmitted?

Answer 4

Usually at mucosal surface of vagina or rectum - virus crosses the mucosal surfae and infects activated C_D4+ T cells, dentritic cells, and macrophages._

Small foci of infection are established locally and then expand and disseminate infection through the draining lymph node and to the blood.

Question 5

What cells of the innate, intrinsic, and adaptive immune system mount a counter attack to HIV infection?

Answer 5

Innate: Dendritic cells (DCs) and NK cells

Intrinsic: Antiviral restriction factors

Adaptive: B and T cells

Question 6

How do dendritic cells mount an immune resposne to HIV infection?

Answer 6

They cause an initial surge of IL-15 and IFNs - these are involved in the initial anti-viral response

• Promote immune activation and apoptosis of infected cells
• Recruitment of other cells for help.
• Backfires in HIV because they recruit CD4+ cells which are the ones infected in HI

Question 7

What stimulates NK cell activation?

Answer 7

Innate cytokines including IFN-1, IL-15, and IL-18

NK activation is also regulated by receptor-ligand interactions

Question 8

What is the role of NK cells in an innate immune respone to HIV infection?

Answer 8

Lyse malignant or infected cells.

• combat HIV1 replication by killing cells with perforin/granzyme, Fas-ligand apoptosis, and ADCC
• Make antiviral factors IFNY, TNFa, and B-chemokines

Question 9

What are the restriction factors involved in the intrinsic immune resposne to HIV? What are they encoded by?

Answer 9

• APOBEC3G
• TRIM5a
• Tetherin (BST-2)
• SAMHD1

Inhibit viral replication directly; encoded by interferon stimulated genes (ISGs). HIV counteracts some of these via accessory proteins.

Question 10

What is the adaptive B cell response to HIV?

Answer 10

Initial Ab resposne to Env, but it’s non-neutralizing

Neutralizing Ab response developes slowly (~12 weeks post infection–too late)

HIV can also induce the lysis of follicular B cells and lead to the loss of germinal centers which results in problems rapidly generating Abs

Question 11

What is the adaptive T cell response to HIV?

Answer 11

HIV-specific CD8+ response is seem as viremia peaks, initially specific for Env and Nef

Virus sequences begins to change with rapid selection of escape mutants

Eventually T cells because more targeted with conserved epitopes

Question 12

How doesthe hosts immune resposne have clinical implication in HIV infection?

Answer 12

• Those with MHC class I alleles HLAB57 and HLA27 are associated with control of viremia.
• Combo of NK receptors KIR3DS1, KIR3DL1, with HLAB57 are associated with delayed progression to AIDs
• “Elite controllers” (<1% people with HIV) spontaneously control HIV and may have more functional CD8+ T cells.

Question 13

What is the pathogenesis of untreated HIV?

Answer 13

Immune system doesn’t abort the infection, but it eventually gets ahold of it and reaches a steady state.

The disesase will progress over time and opportunistic infections will occur and eventually lead to death.

Question 14

What is the pathogensis of chronic HIV infection (when treated)? What are causes/consequences of chronic HIV infection?

Answer 14

Persistent inflammation and immune dysfunction, even when pts are suppressed on ART.

• Ongoing HIV replication
• Infection with co-pathogens (CMV)
• Dysfunctional immunoregulatory factors
• Microbial translocation
• Lymphoid fibrosis

Question 15

What is microbial translocation (occurs with chronic HIV infection)?

Answer 15

Breakdown in tight junctions, loss of immune cells, and alteration of gut flora leading to microbial translocation.

Widespread exposure to LPS, microbial products resulting in increased immune activation and inflammation.

Loss of Th17 cells leads to a shift to Treg phenotype and increased translocation.

Question 16

What are some ways that HIV can be prevented if someone is engaging in sexual activity with someone infected with HIV?

Answer 16

• Condom use
• Antiretroviral treatment of partner
• Patient takes HIV drug (PREP)
• Circumcision of her partner (been shown to reduce HIV infection of male from female partner).

Question 17

What cell type is the most infected by HIV?

Answer 17

Activated CD4+ T cells

Question 18

Immune activation and inflammation leads to ____ deposition in ______ tissue.

Answer 18

Collagen deposition (fibrosis) in lymphatic tissue.

Even treated HIV does not allow levels of fibrosis to go down to levels associated with HIV- individuals.

Question 19

During antiretroviral therapy, what contributes to disease?

Answer 19

Ongoing inflammation and immune dysfunction

• Mucosal damage
• CD4+ depletion
• Immune activation
• oss of CD4+ T cells from recruitment and infection

Question 20

Does ART fully restore health and normal immune function?

Answer 20

NO! Treated individuals with suppressed HIV replication are still at risk for developing several non-AIDs disorders:

• CV disease
• Cancer
• Kidney disease
• Liver disease

Question 21

Why isn’t there a cute for HIV?

Answer 21

Because it integrates into the host DNA of CD4+ T cells.

Question 22

How is a latent HIV reservoir established?

Answer 22

HIV integrated into our DNA persists in long-lived memory CD4+ T cells that can divide to make more infected T cells.

This creates a reservoir of infected T cells that can become activated and produce infectious virus if someone stops their treatment.

Question 23

What is a latent reservoir established? Can it be decreased in size with ART? What happens if they stop ART?

Answer 23

Very early in the infection (first few weeks)

Decay of latent reservoir is VERY slow (60+ yrs to eradicate 10^5 cells)

With cessation of ART, latently infected cells become activated and product infectious virus.

Question 24

What is the important of early treatment?

Answer 24

• Early treatment limits the size of latent reservoir
• Limits development of viral escape mutants
• Increases number of plasma and memory B cells and improves B cell function
• Preserves mucosal immune function (maintainance of Th17 cells)

Question 25

What is HIV resistance? What can happen as a result?

Answer 25

Mutations that arise in the viral genome; this can occur in regions that encode molecular targets of therapy.

May result in failure to respond to certain treatments.

Question 26

Why does HIV acquire so many mutations?

Answer 26

HIV reverse transcriptase makes spontaneous errors (1 in 10^4) and the HIV-1 genome is 10^4.

This means there’s one error every time the genome is replicated

Question 27

What can cause HIV resistance?

Answer 27

Skipping or misses a doses of ART increases viral load and can allow HIV virus to mutate in such a way that promotes resistance.

Question 28

What are two types of resistance testing? How does each work?

Answer 28

HIV genotype: assays assess the genetic composition of HIV variants to deremine resistance mutations

HIV phenotype: assesses the ability of drugs to inhibit viral replication in cultered cells

Question 29

What are some guidelines for resistance testing?

Answer 29

HIV genotype at entry into care to guide therapy at time of medication initiation.

Resistance testing should be completed with HIV RNA >1000 copies/mL or suboptimal viral load redution after treatment initiation

Phenotype testing may be needed when known to have complex drug-resistance mutation

Question 30

Can resistant viruses be transmitted to others? How is this treated?

Answer 30

Yes! A regimen can be developed if someone has multiple resistances, but it may mean that they have to take a pill more than once a day.

Question 31

What is immune reconstitution inflammatory syndrome (IRIS)?

Answer 31

Paradoxical worsening of preexisting infection following the initiation of ART.

• may be an infection that is known and prev. diagnosed OR
• unmasking of previously subclinical and undiagnosed infection

Question 32

What is the diagnostic criteria for immune reconstitution inflammatory syndrome (IRIS)?

Answer 32

• Low pre-treatment CD4 (<100)
• Virologic and immunologic response to ART
• Temporal associated with starting ART
• Excluding other new infections

Question 33

What is the treatment for immune reconstitution inflammatory syndrome (IRIS)?

Answer 33

Usually supportive; may need a course of steroids.

They should continue ART in almost all cases.

Question 34

Current HIV testing strategy uses immunoassay to detect _____ and _____ in order to facilitate early detection. _____ can also be sent if you are worried about acute infection.

Answer 34

p24 Ag and HIV Abs

An HIV viral load can also be sent if you’re worried about acute infection.

Question 35

HIV uses ____ ____ to overcome the intrinsic antiviral mechanisms.

Answer 35

Accessory proteins

Question 36

The hallmark of chronic HIV pathogenesis is persistent _____ _____ and ____ _______. This likely leads to non-AIDs defining illnesses, even in pts on effective ART.

Answer 36

Immune activation and immune dysfunction