AIDS/HIV

Question 1

AIDS (Hallmark Features)

Answer 1

Pneumocystis carninii
Kaposi’s Sarcoma
Marked reduction in CD4+ T-Lymphocytes (less than 200/uL or HIV infected individual with “indicator infections” to be considered AIDS)
Increased susceptibility to opportunistic infections

Question 2

HIV (Characteristics)

Answer 2

Retroviridae family
+ssRNA
Enveloped
Two types: HIV-1 and HIV-2

Question 3

HIV-2 (Characteristics)

Answer 3

Primarily found in Western Africa
SLOWER declined in CD4+ T-cells
LONGER asymptomatic period
LOWER mortality

Question 4

gp120

Answer 4

Attachment Protein

Question 5

gp41

Answer 5

Fusion Protein

Question 6

pol

Answer 6

Reverse Transcriptase

Question 7

p17

Answer 7

Matrix protein

Question 8

p24

Answer 8

Capsid protein

Question 9

Retrovirus Life Cycle (General Overview)

Answer 9

Attachment –> Fusion –> Reverse Transcription –> Integration (of dsDNA)forming a Provirus –> Genome replication/Transcription –> Budding –> Protein Cleavage (Activates) –> Mature Virion

Question 10

HIV Life Cycle (Attachment)

Answer 10

gp120 binds to CD4 on T-lymphocyte, monocyte, or macrophage

Conformational change in gp120 allows binding to a co-receptor (CCR5 or CXR4)

Question 11

R5-tropic HIV

Answer 11

CCR5 is used as coreceptor
Transmitted from PERSON-TO-PERSON
Predominant EARLY IN DISEASE
Efficiently infects monocytes/macrophages and microglia

Question 12

X4-tropic HIV

Answer 12

CXCR4 is used as a coreceptor
Approximately 40% of patients TRANSITION from R5 to X4 viruses during course of disease
This is associated with Rapid progression to AIDS

Question 13

CCR5 gene (delta 32) Deletion (Hetero- vs. Homozygous)

Answer 13

Deletion affects binding to gp120

Heterozygous Deletion = LONGER ASYMPTOMATIC PERIOD before onset of AIDS

Homozygous Deletio = NO INFECTION with R5-tropic viruses
***X4-tropic can still infect

Question 14

HIV Life Cycle (Fusion)

Answer 14

gp41 mediates fusion between the viral envelope and plasma membrane

Question 15

HIV Life Cycle (Reverse Transcription)

Answer 15

Virally-encoded enzyme (pol gene)
Found within the virion
Produces a linear dsDNA copy of the RNA HIV genome
MOST ERROR PRONE of all retroviruses (1/2000 nucleotides)
High error rate –> Rapid evolution during course of disease

Question 16

HIV Life Cycle (Integration)

Answer 16

dsDNA copy of the genome moves into the nucleus of the cell
VIRAL INTEGRASE incorporates DNA copy of genome into host DNA
Now called a PROVIRUS, which is replicated with the regular cellular genes

PROVIRUS will remain in the cell for AS LONG AS IT SURVIVES (i.e. it is PERMANENT)

Question 17

HIV Life Cycle (Egress)

Answer 17

Progeny HIV virions exit the infected cell by BUDDING through the plasma membrane at LIPID RAFTS

Question 18

HIV Life Cycle (Maturation)

Answer 18

VIRAL PROTEASE cleaves the gag and gag-pol viral polyproteins in a process called VIRION MATURATION

Cleavage is essential for INFECTIVITY of the virion

Mature –> Dark, dense nuclear capsid

Question 19

HIV (Transmission: 3 types)

Answer 19

Sexual
Perinatal
Blood or body fluid exposure

NO casual contact or insect vector transfer

Question 20

HIV (Sexual Transmission)

Answer 20

• More efficient from MALE-TO-FEMALE than female-to-male
• MOST COMMON ROUTE worldwide is HETEROSEXUAL transmission
• Presence of other STDs, especially those that generate lesions (e.g. Herpes Simplex Virus or Syphilis), INCREASE the risk for transmission

Question 21

HIV (Mother-to-Child Transmission)

Answer 21

Overall Risk = 1/4

20-30% before birth
50-65% at birth
12-20% after birth (nursing)

Question 22

HIV (Accidental Exposure of Healthcare Workers)

Answer 22

Skin puncture from needle contaminated with blood from HIV patient = ~0.3%

Due to mucous membrane exposure = ~0.09%

Risks are reduced with prophylactic antiviral regimens

Question 23

HIV (Acute HIV Syndrome)

Answer 23

Approximately 3-6 weeks following infection
Symptoms (similar to MONONUCLEOSIS)
-Fever, malaise, arthralgia, lymphadenopathy, sore throat
Rash (usually faint)
Burst of viremia
May NOT have detectable levels of anti-HIV antibodies at this time

Question 24

HIV (Immune Response)

Answer 24

Following initial burst of viremia, an immune response is mounted that curtails the levels of virus in the blood

Question 25

HIV (Chronic Phase)

Answer 25

Chronic Infection: - A low level of viremia (NOT LATENT) is present during this time due to viral replication - HIV escape from immune system includes: 1) Antigenic Drift of gp120 2) Inactivation of key elements of the immune response 3) Cell-to-cell fusion ***Patients often ASYMPTOMATIC*** Median time of clinical latency in untreated patients is 10 years

Question 26

HIV (Set Point)

Answer 26

Predicts PROGRESSION RATE in untreated patients ***Amount of virus in the system one year following initial infection***

Question 27

HIV (Progression to AIDS)

Answer 27

Reduction in CD4+ T-cell numbers - Copius BUDDING of virions budding off T-cells - Interference with cellular processes - Other mechanisms Reduced ability to fight other microbial infections

Question 28

HIV (Associated Infections: Oral Hairy Leukoplakia and Pneumonia)

Answer 28

1) Oral Hairy Leukoplakia (***Epstein Barr Virus***) - White, plaques (wart-like) found on the LATERAL SURFACE of the tongue; concerning because indicative of immune suppression 2) Pneumonia - Pneumocystitis carinii - Mycobacterium tuberculosis * **More severe in HIV infection***

Question 29

HIV (Associated Infections: Thrush and CMV Retinitis)

Answer 29

3) Thrush -Candida albicans Slightly reduced immune capacity --> oral thrush Severely reduced immune capacity --> spread to lungs or other parts 4) CMV Retinitis - Cytomegalovirus (Herpes Virus) * **Seen when the CD4 counts are VERY LOW (~50/uL)

Question 30

HIV (Associated Infections: Neoplasms and Diarrhea)

Answer 30

5) Neoplasms ***Kaposi's Sarcoma (HHV-8)*** B-ell lymphomas 6) Diarrhea - Cryptosporidium - Isospora belli

Question 31

HIV-1 Infection Laboratory Marker Detection Order

Answer 31

1) Nucleic acid test (Viral RNA) | 2) p24 antigen (3rd generation immunoassay > 2nd generation > 1st generation)

Question 32

Recommended Laboratory HIV Testing for Serum or Plasma Specimens

Answer 32

HIV-1/2 antigen/antibody combination immunoassay ---> If POSITIVE, then undergose HIV-1/HIV-2 antibody differentiation immunoassay ---> if NEGATIVE for both, then undergoes HIV-1 NAT (nucleic acid test) ---> if this is NEGATIVE, then probably had a FALSE positive in the first place

Question 33

What does the HIV-1/2 antigen/antibody combination immunoassay look for and what is its purpose?

Answer 33

HIV p24 antigens (viral protein) HIV-1 antibodies HIV-2 antibodies Purpose: SCREENING TEST for HIV diagnosis

Question 34

What does the HIV-1/2 antibody differentiation immunoassay look for and what is its purpose?

Answer 34

HIV-1 antibodies HIV-2 antibodies Purpose: DIFFERENTIATES between HIV-1 and HIV-2 infections

Question 35

What does the HIV nucleic acid test look for and what is its purpose?

Answer 35

HIV RNA genomes Purpose: Detects RNA GENOMES. These genomes are detectable at EARLIER times of the infection than antibodies

Question 36

HIV (Other Detection Tests)

Answer 36

HIV NAT PCR Rapid tests for in-office (~20 mins; requires subsequent confirmatory testing)

Question 37

HIV Treatment (Entry Inhibitors)

Answer 37

***NOT recommended for initiation of treatment to newly-diagnosed patients*** 1) Chemokine coreceptor antagonists - Bind to CO-RECEPTOR and prevent its interaction with gp120 - MARAVIROC is a CCR5 antagonist and is limited to use in patients that possess ONLY R5-tropic HIV R5 2) Fusion inhibitors (FI) - Binds to gp41 and prevents conformation change needed for fusion of the viral envelope with the cellular plasma membrane e. g. ENFUVIRTIDE

Question 38

HIV Treatment (Reverse Transcriptase Inhibitors)

Answer 38

1) Nucleoside Inhibitors (NRTIs) - Incorporated into growing DNA chain during provirus synthesis and cause chain termination e. g. AZIDOTHYMIDINE (AZT) 2) Nonnucleoside Inhibitors (NNRTIs) - Bind to reverse transcriptase and inhibit its activity e. g. NEVIRAPINE

Question 39

HIV Treatment (Integrase Inhibitor)

Answer 39

Blocks the integration of the DNA copy of the viral genome into the cellular genome e.g. RALTEGRAVIR

Question 40

HIV Treatment (Protease Inhibitors (PIs))

Answer 40

- Peptidomimetic inhibitors of the viral protease - Protease inhibition leads to the production of immature, defective HIV particles e. g. SAQUINAVIR

Question 41

General Features of ARV Therapy (Goal and Recommendation)

Answer 41

Goal: Reduce viral load as low as possible for as long as possible Current recommendation for starting ARV therapy: >500 cells/uL CD4 count (BIII) 350-500 cells/uL CD4 count (AII) <350 cells/uL CD4 count (AI) ***Strongest Recommendation***

Question 42

HIV (General Features)

Answer 42

- Rapid resistance to monotherapy; ineffective - Highly Active Antiretroviral Therapy (HAART): 1) Combination therapies 2) Greatly increased the lifespan of HIV infected patients 3) Issues: toxicity, compliance, resistance - Prophylactic treatments for opportunistic infections (depends on the CD4 count) e. g. Gangciclovir for CMV, Pentamidine for Pneumocystis carinii and toxoplasmosis

Question 43

ARV Therapy (Treatment)

Answer 43

Standard of Care uses combination of AT LEAST THREE ARV DRUGS. Usually from two different classes: 1 NNRTI + 2 NRTIs 1 PI + 2 NRTIs 1 II + 2 NRTIs ***Testing for resistance to ARV is commonplace***

Question 44

HIV (Prevention)

Answer 44

1) Public education 2) Accidental health risk exposure risk reduce --> Prophylactic antivirals 3) Mother-to-infant spread reduced --> Antiviral treatment of mother and child, refrain from breastfeeding, caesarian section delivery 4) NO VACCINE AVAILABLE