HIV

Question 1

Origins of AIDS epidemic

Answer 1

• entered humans from chimps before 1930 in east central Africa
  1996- HAART began with good outcomes
  2003- global rollout of antiretrovirals

2014: 36.9 million adults/kids living with HIV–most in sub-saharan Africa (25.8 million) with South Africa having the highest prevalence
- more prevalent in certain subgroups in US

Question 2

Markes of HIV dz

Answer 2

• CD4 lymphocyte count: as they are main host cell; correlates with disease progression
• Plasma HIV RNA level– measure of extent of ongoing replication in lymphoid tissue; copies per ml blood

want to see undetectable viral load–suggests minimal replication rate and low potential for developing resistance to drugs

Question 3

How does HIV get into CD4 cell

Answer 3

• uses CD4 receptor and co-receptor, either CCR5 or CXCR4
• no current drug inhibiting CD4 binding but one in research
• have medication blocking CCR5 receptor. Virus mutates to use CXCR4 and are resistant to CCR5 blockers

Steps:

1) CD4 binding
2) gp120 conformational change and co-receptor binding
3) gp41 conformational change/fusion

Question 4

CCR5 delta-32 mutation

Answer 4

natural polymorphism with 32 bp deletion in CCR5 gene– frame shift and protein truncation so that CCR5 not expressed on cell surface; relatively resistant to HIV or have more benign clinical course

Allele Distribution: seems to be most common in Caucasians both worldwide and in N America/Europe

~1% homozygosity in Caucasians

Question 5

Primary HIV infection

Answer 5

• often associated with acute febrile illness, mono-like with or without aseptic meningitis
• usually 2-3 weeks after HIV exposure
• occurs in >50% pts but often unrecognized–maybe think just another viral illness
• if untreated, CD4 count is depleted; think about 1/3 or more new infections in acute period when ppl don’t know they are infected but have HUGE viral load

Signs/Sxs:
- fever, fatigue, maculopapular rash, myalgia, headache, pharyngitis, cervical nodes, arthralgia, oral ulcers, odynophagia, weight loss, diarrhea, oral candidiasis, photophobia

Question 6

Risk of transmission

Answer 6

varies during infection course; Acute “early” pts perhaps responsible for lots of transmission

Question 7

Natural Hx of HIV infection

Answer 7

acute illness, then if untreated CD4 count will drop, making you more likely to get certain opportunistic infections which occur at certain CD4 counts

Question 8

Opportunistic infection

Answer 8

• infection that takes advantage of weakened immune system to cause an illness; see with HIV, chemo, glucocorticoid therapy
• many of these happen when CD4 low

Question 9

Pneumocystic Pneumonia

Answer 9

(PCP) opportunistic infection;

diffuse infiltrate in lungs

Question 10

Opportunistic infections in HIV

Answer 10

• Kaposi sarcoma– interaction between HIV and HHV-8; reddish-purple vascular tumors
• PCP
• Oral thrush
• CMV retinitis –infiltrate and hemorrhage around fovea– CD4 count

Question 11

Targets for antiretroviral therapy

Answer 11

Entry inhibitors (target fusion or CCR5)
Reverse transcriptase inhibitors (NRTI-nucleosides/nucleotides– and NNRTIs)
- Integrase inhibitors
- Protease Inhibitors

Question 12

Effects of Antiretroviral Therapy

Answer 12

Virologic/immunologic effect:

• potent inhibition of viral replication
• Early HIV: prevent immunologic deterioration
• Advanced HIV: allows immunologic recovery

Clinical effect:

• prevent opportunistic infections/improve existing ones
• reduce hospitalization, long term care facility use, meds for OIs, and cost

Question 13

Factors contributing to HIV evolution

Answer 13

• genetic diversity (introduction of mutations–especially since RT is error prone)
• fast replication rate
• selective pressures (genetic bottle necks)
• A population of viruses exists in single infected person– “quasispecies”–genetically distinct viral variants evolve from initial virus inoculum
• variants due to error prone nature of viral replication
• quasispecies more closely related to each other than to virus in other infected persons

IMPORTANT TO ADHERE TO THERAPY TO AVOID RESISTANCE!

Question 14

expected response to antiretroviral therapy

Answer 14

• reduce HIV-1 RNA, ideally to undetectable levels-if doesn’t happen in 1st month expect drug resistance or non-adherence
• increase CD4 lymphocyte count (may or may not happen in 1st month)
• improved existing opportunistic complications
• decreased morbidity/mortality
• reduced HIV transmission (sexually and to infants)

Question 15

Pre-Exposure Prophylaxis

Answer 15

(PrEP)

• HIV negative person takes combination of HIV medications to prevent acquisition of HIV infection
• increased risk of HIV acquisition–maybe in relationship with HIV+, IV drug user, MSM, risky behavior
• take 2 drugs: tenofovir-emtricitabline

Question 16

Key points

Answer 16

• HIV introduced into humans in 20th century
• mainly causes disease via CD4 T-lymphocyte produced immunodeficiency
• virus can cause acute mono-like illness at onset; most subsequent illnesses related to malignancies/opportunistic infections
• antiretroviral agents block viral entry, RT, integration, or maturation of virions. Need 3 drug combo to fully inhibit/prevent resistance. ART also prevents transmission
• Pts on ART have potential yo live normal lifespan