HIV Pathophysiology

Aka: HIV Pathophysiology, HIV Genome

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II. Pathophysiology: General

  1. HIV is a single-stranded RNA Retrovirus, a Sexually Transmitted Infection as well as bloodbourne pathogen
    1. HIV 1 is the most common worldwide HIV form and is the major cause of AIDS
    2. HIV 2 causes a similar presentation to HIV 1 and is found in South Africa and India
  2. HIV is a Retrovirus (Retroviridae)
    1. Retroviruses transcribe DNA from single stranded RNA (+ssRNA) via their own reverse transcriptase enzyme
    2. Virus then inserts its DNA into the host DNA via integrase enzyme
  3. HIV Structure
    1. HIV Is a spherical enveloped virion with a central cylindrical nucleocapsid
    2. Outer wall of HIV is a lipid bilayer membrane
      1. Membrane contains embedded Glycoproteins (gp120 is external, gp41 is transmembrane)
      2. P10 protease is present between this outer wall and the nucleus-like structure's capsid membrane
    3. Nucleus-like structure is surrounded by capsid wall (p17) and contains RNA and enzymes
      1. RNA Dimer: 2 identical strands of single stranded RNA
      2. Three Enzymes: p32 Integrase, p64 reverse transcriptase, protease
      3. Nucleocapsid composed of capsid Proteins (CA, esp. p24) surrounds the RNA dimer and enzymes

III. Pathophysiology: HIV Infection

  1. HIV infects T Helper Cells (CD4+ Cells)
    1. CD4+ Cell to CD8+ Cell ratio is normally 2:1
    2. CD4+ Cell to CD8+ Cell ratio drops as low as 0.5 : 1 in HIV and AIDS
  2. Host Cell Binding
    1. HIV gp160 (gp120 + gp41) binds to CD4 receptors on T Helper Cells
    2. Gp160 also binds tp Macrophages, Monocytes and CNS Dendritic Cells
  3. Host Cell fusion and penetration
    1. Virus envelope fuses with the host cell membrane, and RNA infiltrates the host cytoplasm
    2. CD4 Coreceptors (CCR5 or CXCR4) must be present on the host cell surface for HIV penetration
      1. Decreased HIV risk in patients with lower levels of CCR5 on CD4+ cells
      2. Lymphocyte derived Proteins (e.g. RANTES, MIP1) bind CCR5 and also reduce HIV risk
  4. Proviral DNA generation
    1. Complementary DNA (cDNA) is formed from HIV RNA via reverse transcriptase enzyme
    2. cDNA penetrates the host cell's nucleus and integrates with host DNA via HIV integrase enzyme
    3. Integrated DNA may remain dormant until activated for viral replication
      1. Activation may be triggered by T Cell activation by coinfection (e.g. Tb, CMV, PJP, HSV)
      2. T Cell activation releases Proteins that bind HIV LTR and lead to HIV DNA Transcription
  5. HIV DNA Transcription and translation
    1. Proviral DNA is transcribed into Messenger RNA (mRNA)
    2. mRNA is translated into HIV viral Proteins
  6. HIV Budding
    1. Single stranded RNA and viral Protein enzymes are repackaged into virions
    2. Virions bud through the host cell surface, taking with them part of the host cell membrane
    3. T cells die as thousands of virions are released
  7. T Cell Death Mechanisms
    1. HIV Virion budding (see above)
    2. Multinucleated Giant cells
      1. Infected T Cells may fuse with other T Cells via surface binding to gp160
      2. Fused cells form multinucleated giant cells (syncytial giant cells)
      3. HIV may be passed from cell to cell via fusion, bypassing antibodies external to the cells
    3. CD8+ Cytotoxic T Cell response
      1. Cytotoxic T cells may destroy infected CD4+ Cells marked by surface gp160
    4. Bystander CD4+ Helper T Cell Death
      1. Fas-mediated apoptosis (programmed cell death) may occur in activated, but uninfected CD4+ Cells
      2. Apoptosis may also be triggered in bystander CD4+ T cells by HIV Proteins (e.g. Tat, Nef, Vpu)
  8. Other immune cell HIV effects
    1. B Cell Dysfunction
      1. Polyclonal B Cell activation by HIV results in hypergammaglobulinemia
      2. Diminished response to new Antigens (e.g. infections, Immunizations)
      3. Autoantibody formation resulting in Autoimmune Conditions
    2. Monocyte and Macrophages as trojan horse, HIV reservoirs
      1. HIV actively replicates with these cells without host cell destruction
      2. Monocyte and Macrophages may cross the blood brain barrier and expose the CNS to HIV
  9. Reactivation and Propagation
    1. HIV proviral DNA is activated after a latent period of months to years
    2. Reactivation and propagation via HIV Budding results in progressive CD4+ T Cell destruction

IV. Pathophysiology: HIV Genome

  1. Retrovirus Genome Sequences (common to all Retroviruses)
    1. Long Term Repeat Sequences (LTR)
      1. LTRs are found at each end of the transcribed DNA strands, flanking the intervening genes
      2. LTRs serve 2 purposes
        1. Sticky Ends
          1. Serves as a target for the integrase enzyme
          2. Allow for easier insertion into host DNA
        2. Promotor
          1. Enhances viral DNA Transcription after it has been inserted into host DNA
    2. Group Antigen (gag) codes for major Retroviral structural Proteins
      1. Nucleocapsid Proteins (NC)
      2. Capsid Proteins (CA, esp. p24)
      3. Matrix Proteins (MA)
    3. DNA Polymerase (pol) codes for major Retroviral enzymes
      1. P64 reverse transcriptase
      2. P32 Integrase
      3. Protease
        1. Protease cleaves gag and pol Proteins from the precursor molecules (enzyme activation)
    4. Envelope Protein (env) codes for surface Glycoproteins
      1. GP160 binds CD4 receptors
      2. GP 160 is composed of 2 subcomponents
        1. GP120 (head)
        2. GP41 (stem)
  2. Early HIV Specific Genome Sequences
    1. Transactivator Protein (tat)
      1. Binds viral genome and activates transcription
    2. Regulator of Expression of Virion Proteins (rev)
      1. Binds the rev response element (RRE) within the Env gene
      2. Increases reading of gag, pol and env, increasing generation of HIV virions
    3. Negative Factor (nef)
      1. Decreases CD4 and MHC1 expression on surface of infected CD4+ Cells
      2. Suppresses cytotoxic T cell response (CD8) that would otherwise kill HIV infected cells
  3. Late HIV Specific Genome Sequences
    1. Virion Infectivity Factor (vif)
      1. Integral to dsDNA generation from HIV RNA
      2. Blocks APOBEC3
        1. APBEC3 is an innate viral defense, restricting viral replication
        2. APBEC3 modifies DNA, changing cytosine to uracil (resulting in G-A mutation)
    2. Viral Protein R (vpr)
      1. Regulates nuclear import of HIV1
      2. Allows for HIV replication within non-dividing cells (e.g. Macrophages)
    3. Viral Protein U (vpu)
      1. Decreases CD4 and MHC1 expression on surface of infected CD4+ Cells
      2. Enhances HIV virion release from infected cells

V. Pathophysiology: HIV Genome Heterogeneity

  1. HIV replication is subject to frequent mutations and significant genetic variation (heterogeneity)
    1. Expressed Proteins maintain their function despite gene mutations
    2. Resulting Proteins are different enough to escape consistent Antigen detection (e.g. Vaccines, Immunity)
  2. Several HIV genes have hypervariable regions with high mutation rates
    1. Env gene mutations (esp. gp120 encoded region)
    2. Reverse Transcriptase mutations
  3. Major HIV subgroups based on gag and env Protein variation have been developed (Groups A-K)
    1. Subtype B is most common in North America and Europe

VI. Course

  1. See HIV Course

VII. References

  1. Gladwin, Trattler and Mahan (2014) Clinical Microbiology, Medmaster, Fl, p. 268-75
  2. Mahmoudi (2014) Immunology Made Ridiculously Simple, MedMaster, Miami, FL
  3. (2016) Transfus Med Hemother 43(3):203-22 +PMID: 27403093 [PubMed]
  4. McLaren (2021) Nat Rev Genet 22(10):645-57 +PMID: 34168330 [PubMed]

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