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Snapshot
  • A 27-year-old male presents to the urgent care clinic with a two-week history of fever, a macular rash, and generalized lymphadenopathy. He denies sore throat, genital ulcers, and urethral discharge. Sexual history reveals the patient habitually has unprotected sex with both male and female partners, the last encounter a month prior to onset of illness. He was treated for gonorrhea about four months ago. An ELISA screening test came back positive and this was confirmed by Western blot.
Introduction
  • Classification
    • (+) ssRNA retrovirus
      • HIV
  • Pathogenesis 
    • transmission
      • sex
        • most common mechanism of transmission
        • HIV present in seminal fluid and vaginal/cervical secretions
        • virus enters body through small ulcerations in mucosa of vagina, penis, rectum, and urethra
      • IV drug use with needle sharing
      • crosses placenta
        • 30% transmission rate
      • blood transfusion
      • needle sticks 
        • 0.3% risk if stuck with needle contaminated with HIV infected blood
    • reservoir
      • human
    • 4 stages of infection 
      • flu-like illness (acute stage)
      • feeling fine (latent stage)
        • virus replicates in lymph nodes
      • falling CD4 count
      • final crisis
Molecular Biology
  • Structure 
    • diploid genome
      • homodimer of ssRNA with associated nucleocapsid proteins
    • capsid and envelope surround the RNA dimer
      • p24 capsid protein
      • gp41 and gp120 envelope proteins
  • Genetics
    • regulatory genes
      • tat and rev
        • required for viral replication
      • nef
        • decreases expression of MHC I on surface of infected cells
    • 3 structural genes code for specific proteins
      • env codes for glycoproteins
        • gp120
          • enables attachment to host T cell 
          • binds CD4 and CCR5 on host cell
            • allows viral entry into cell by fusion with cell membrane
        • gp41
          • enables fusion and entry
          • "Forty-one enables Fusion"
        • both gp120 and gp41 are formed from cleavage of gp160 in host ER and Golgi
      • gag codes for
        • p24 and p7 
          • nucleocapsid proteins in virion core
      • pol codes for
        • reverse transcriptase
        • integrase
          • integrates viral DNA into host DNA
        • protease
          • pol mutations confer resistance to reverse transcriptase and protease inhibitors 
  • Life cycle 
    • HIV binds to a receptor and a co-receptor
      • CCR5 (a chemokine receptor) and CD4 on macrophages
      • CXCR4, CCR5, and CD4 on T cells
      • CCR5 mutations confer immunity (homozygote) or slower course of disease (heterozygote)
    • HIV empties the contents of its virion into the infected cell
    • using its own reverse transcriptase, HIV synthesizes double-stranded DNA from single-stranded RNA
    • using its own integrase enzyme, HIV inserts the viral DNA into the host DNA
    • host RNA polymerase synthesizes HIV mRNA and host machinery assembles HIV proteins
    • using its own protease enzymes, the new HIV proteins are cleaved to form smaller proteins
    • a new virus is packaged and buds off from the host cell
Evaluation
  • Diagnosis of HIV
    • ELISA is the first step in diagnosis
      • high false-positive rate (high sensitivity and low specificity)
      • rules OUT the possibility of infection
    • Western blot is then used to confirm positive results
      • high false-negative rate (low sensitivity and high specificity)
      • rules IN the diagnosis of infection
    • both tests detect antibodies to HIV proteins
      • antibodies take 3-6 weeks to develop
      • tests can be falsely negative in first 1-2 months of infection
      • tests can be falsely positive in babies born to infected mothers
        • anti-gp120 crosses placenta
      • IgM against envelope antigens can remain normal or elevated
        • IgM production does not require CD40L found on CD4+ T-cells
    • the presence of viral RNA or antigens (e.g. p24) can also be tested directly
  • Diagnosis of AIDS 
    • ≤ 200 cells/μL CD4+ (normal: 500-1500)
    • CD4+ percentage <14%
    • HIV positive with AIDS-associated infection
      • e.g., P. jiroveci pneumonia
  • Viral load tests
    • PCR used to monitor effects of therapy on viral load
  • Characteristics
    • RNA
      • single-stranded
      • positive-sense
      • linear
    • icosahedral
    • enveloped
Presentation
  • CD4 < 400 cells/μL blood
    • constitutional symptoms ("wasting syndrome")
      • weight loss
      • fever
      • night sweats
      • adenopathy
    • bacterial infections
      • M. tuberculosis
      • H. influenzae
      • S. pneumoniae
      • Salmonella
    • oral thrush (Candida albicans)
    • tinea pedis
    • reactivation VZV
  • CD4 < 200 cells/μL blood
    • PCP (Pnuemocystis jiroveci pneumonia)
    • Cryptococcus neoformans
    • Cryptosporidium
    • Coccidioidomycosis
    • reactivation HSV
    • Iospora
  • CD4 < 100 cells/μL blood
    • Toxoplasma gondii
    • Histoplasmosis
    • Candida albicans esophagitis 
  • CD4 < 50 cells/μL blood
    • M. avium-intracellulare
      • prophylaxis with azithromycin  
    • CMV
      • retinitis and esophagitis
    • Cryptococcus neoformans
      • meningoencephalitis
  • HIV in the neonate (a ToRCHeS infection)
    • recurrent infections
      • oral thrush
      • interstitial pneumonia
    • chronic diarrhea
    • lymphopenia
  • HIV encephalitis
    • HIV crosses the BBB via infected macrophages
    • results in inflammation in the brain
      • appearance of microglial nodules with multinucleated giant cells
    • occurs late in the course of HIV infection
    • JC virus can cause progressive multifocal leukoencephalopathy 
  • AIDS dementia complex
    • mental status changes
    • depression
    • ataxia
    • seizures
    • urinary and bowel incontinence
  • DDx for ring-enhancing brain lesion in AIDS patient
    • toxoplasmosis
    • primary CNS B-cell lymphoma
      • associated with EBV
Differential
  • Other causes of immune suppresion
    • cancer chemotherapy
    • organ transplant patients
    • congenital immunodeficiencies
Treatment
  • Over 25 HIV drugs exist in multiple categories including 
    • CCR5 inhibitors
    • fusion inhibitors
    • reverse transcriptase inhibitors
    • integrase inhibitors
    • protease inhibitors
  • Highly active antiretroviral therapy (HAART)
    • combines multiple drugs with multiple mechanisms of action to prevent resistance
      • e.g. tenofovir + emtricitabine + efavirenz or many other possible combinations
  • Pregnancy
    • use zidovudine (ZDV, AZT) to prevent mother-to-fetus transmission 
Prognosis, Prevention,  and Complications
  • Prognosis
    • has improved but depends on multiple factors
      • most important access to proper drug treatment
    • poor prognostic factors include
      • high viral RNA loads
      • CD4 count < 200 cells/μL blood
  • Prevention
    • no effective vaccine
    • secondary prevention
      • chemoprophylaxis based on CD4 count
      • to prevent opportunistic infections
  • Complications
    • with HAART therapy, side effects of individual drugs
      • see sections on individual drug families
 

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