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Flashcards in HIV/AIDS Deck (13)
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1

 

Describe HIV routes of transmission

Sexual-Anal or vaginal (hetero/homosexual transmission; semen, vaginal fluid) *oral sex - rare*

Blood-to-blood contact & Intravenous Drug User (IVDU)

Perinatally (maternal-child transmission, breast milk)

2

 

Understand pathogenesis of HIV

 

HIV is a retrovirus which invades CD4+ T-lymphocytes cells 

CD4+ = immune cells responsible for orchestrating and coordinating immune response 

Thus HIV patients cannot fight off infection as easily because the CD4+ has been hijacked 

HIV is a retrovirus (contains 2 single strands of RNA) and it LACKS machinery needed for self replication (obligatory PARASITES)

In order to replicate HIV virus needs to transcribe its RNA into DNA 

The enzyme employed for this process is called Reverse transcriptase = converts single stranded RNA into double stranded DNA

Retroviruses cannot self-replicate, they are intracellular parasites

Retroviruses carry genetic material in RNA rather than DNA

HIV targets CD4 T cells b/c the surface of the T cells provide an attachment point for HIV 

gp120 is the primary surface receptor (glycoprotein) on the HIV envelope and it attaches to the T cell

Infected CD4 cell reproduces, inadvertently producing more viral HIV copies

3 ENZYMES are needs for HIV to penetrate the T cell and replicate:

Reverse transcriptase (step 3, 4 in replication cycle)

Integrase (step 5 in replication cycle)

Protease (step 10 in replication cycle)

Once HIV infects a CD4 cell, it DIES within 2 days 

3

 

Understand replication cycle of HIV

1: Attachment: 

gp120 on the HIV envelope attaches to a CD4 host protein

Other host proteins (aka co-receptors) secure the attachment (ie. CCR5, CXCR4)

Drug class that works here: CCR5 Antagonist

2: Fusion of HIV lipid bilayer with host lipid bilayer, release of HIV RNA into host cell

Drug class that works here: Fusion Inhibitors 

3: DNA Synthesis/Reverse transcriptase 

4: Replication/Integration

5: Integration (DRUG TARGET)

6: Transcription 

7: Translation 

8: Migration & Assembly 

9: Budding off 

10: Processing by HIV protease (DRUG TARGET)

4

 

CDC Definition of AIDS

A syndrome in which the individual is HIV positive and has either:

1. CD4 counts below 200 cells/mL

2. AIDS-defining illness

Pneumocystis pneumonia

Cytomegalovirus retinitis 

Disseminated histoplasmosis

Tuberculosis 

Kaposi’s sarcoma 

5

 

Symptoms of HIV

Symptoms fall into 3 categories:

Immunodeficiency, Autoimmunity & Neurologic Dysfunction

Here is what to look for:

Fever

General malaise and achiness

Fatigue

Night sweats

Sore throat

Gastrointestinal symptoms––anorexia, nausea, vomiting, heartburn, diarrhea

Swollen lymph nodes

New rash

Headache

Decreased WBC and/or CD4+ counts

6

 

HART Treatments

HAART (highly active antiretroviral therapy) or CAR (combined retroviral therapy)

Decreases plasma HIV levels 

Delays or reverses loss of immune fxn

Decrease certain AIDS-related complications

Preserves health, prolongs life, decreases HIV transmission     

$$$$$$$, lifelong

NOT curative     

7

 

Patients who should receive HAART

Patients with advanced (symptomatic HIV)

Patients with a history of AIDS-defining illness

Pregnant women

Patients with HIV-associated nephropathy, active Hep B infection, active cardiovascular disease 

Patients with:

CD4 counts <500 cells/mm3 (or a rapid decline in CD4 count)

High viral load (>100,000 copies of HIV RNA)

8

  

Describe briefly the mechanism of action of HAART drugs

TWO MECHANISMS OF ACTION: 

INHIBIT HIV ENZYMES (reverse transcriptase, integrase, protease)

BLOCK HIV ENTRY INTO CELLS (fusion inhibitors, CCR5 antagonists)

9

 

5 categories of HAART drugs

1. Reverse transcriptase inhibitors (2 sub types)

1.1 NRTIs (nucleoside/nucleotide reverse transcriptase inhibitors)

Drug Examples: Zidovudine (Retrovir, ZDV), Tenofovir, Abacavir (Ziagen) 

MOA:  

chemical relatives of naturally occurring nucleosides and nucleotides (DNA building blocks) 

suppresses synthesis of viral DNA by reverse transcriptase (prematurely terminates growing DNA strand)

Needs intracellular conversion to be active  

Common SEs: RARE lactic acidosis, severe hepatomegaly (fatal)

*see STEPS 3 & 4 of replication cycle 

 

1.2 NNRTIs (non-nucleoside reverse transcriptase inhibitors)

Example. Efavirenz (Atripla)

NOT analogs of natural nucleosides

MOA: 

NO structural relationship with naturally occurring nucleosides (DNA building blocks) 

Cause DIRECT noncompetitive inhibition of reverse transcriptase by binding to its active center  

ACTIVE as administered 

SE: rash, hypersensitivity reactions, CNS effects, teratogenic

*see STEPS 3 & 4 of replication cycle

2. INSTIs (integrase strand transfer inhibitors)

Example. Raltegravir (Isentress) 

MOA: 

Prevents insertion of HIV-derived DNA into DNA of CD4 cellsblocks DNA replication (Integrase)

Active against HIV strains resistant to other drugs

SE: hypersensitivity reactions 

*see STEP 5 of replication cycle

 

3. PIs (protease inhibitors)

Example. Darunavir

Most effective

MOA: 

Bind to HIV protease and prevent enzyme from cleaving HIV polyproteins.  Enzymes and structural proteins are left nonfunctional and cannot construct new virus.

Metabolized by cytochrome P450 enzymes 

SE: hyperglycemia,  fat redistribution, hyperlipidemia, bone loss, elevated LFTs, increased bleeding risk for hemophilia, inhibit P450

*see STEP 10 of replication cycle

4. Fusion inhibitors

Example. Enfuvirtide (Fuzeon, T-20) 

MOA: 

binds with gp41 on the viral envelopeblocking entry of HIV into CD4 T cells 181

Indicated for HIV resistant to other viruses

SE: universal injection-site reactions, inconvenient 

*see STEP 2 of replication cycle

5. Chemokine Receptor 5 (CCR5) antagonists 

Example. Maraviroc (Celsentri) 

MOA: 

blocks HIV entry into CD4 cells, limited to specific HIV strains 

SE: cough, dizziness, rash, abdominal pain

*see STEP 1 of replication cycle

 

**Maraviroc and Enfuviritide (fusion inhibitors) 

are the only antiretroviral drugs that 

BLOCK HIV entry!!**

 

*Most patients take 2 NRTIs + INSTI, NNRTI or PI

10

 

Describe monitoring that should occur for patients on HAART

Plasma HIV RNA (viral load)*

Indicates magnitude of HIV replication 

Predicts rate of CD4 T-cell destruction

HIGH: untreated pt, recent infection, lapse in adherence

GOAL: 20-75 copies/mL

CD4 T-cell counts (800-1200 cells/mm3)

Indicates how MUCH damage the immune system has already suffered

HIV Drug Resistance 

2 resistance tests (assays)

$$$

Frequent false-negative results 

HLA-B*5071 Screening 

Tests for genetic variation (abacavir)

CCR5 Tropism 

Tests for presence of CCR5 co-receptor

Some strains of HIV need to bind with CCR5 receptors to enter CD4 cells

Assay needed if going on Maraviroc (CCR5 antagonist)

11

 

Discuss prophylactic therapy

Prophylactic therapy is a preventive measure. 

PrEP (pre-exposure): use of antiretroviral drugs to prevent HIV infection in an HIV-negative person  

Indication:

Men who have sex with men (based on current studies)

Those at high risk of HIV acquisition

PEP (post-exposure): 

Indication:

Accidental exposure (needle stick, splash with bodily fluids)

Start within 1-2 hours of exposure, take for 28 days 

12

 

Who is at greatest risk for opportunistic infections

Any patient with a CD4 count < 200

13

 

Opportunistic Infections

 

An infection caused by a pathogen that takes advantage of a weakened immune system

 

Categorized by type:

Bacterial

Mycobacterium TB

Fungal

Pneumocystis pneumonia (PCP), Candidiasis (thrush), Cryptococcal Meningitis 

Protozoa 

Toxoplasmosis

Viruses 

CMV retinitis, herpes simplex, zoster, HPV

Manifestations by System

Respiratory

Pneumonia, TB

GI

Diarrhea, gastroenteritis, esophagitis 

Nervous System

Asymptomatic neurocognitive impairment, toxoplasmosis 

Metabolic 

Lipid disorders, diabetes