HIV

• Key targets for antiviral chemotherapy

  • Fusion
  • CCR5
  • Reverse transcriptase
  • Integrase
  • HIV aspartyl Protease
• HIV replication cycle (simplified)

  1. Envelope proteins→T-helper cells + CCR5

  2. RNA →RT→ssDNA→RT→dsDNA

  3. V-dsDNA→integrase enzyme→h-DNA

  4. V/H-DNA→ RNA polymerase→ mRNA

  5. mRNA→ emvlope proteins / polyprotein chain
• HIV specifically targets


  T helper cells by binding to CD4 molecules and second receptor CCR5 (chemokine coreceptor), leading to membrane fusion and viral entry
• Reverse transcriptase (RT)


  A key enzyme of HIV that converts viral RNA into ssDNA (using host's nucleotide) with multiple errors as RT poor proofreading ability, this high error rate contributes to the high mutation rate of HIV, making it challenging to develop effective treatments
• Integration of viral DNA

  Into the host chromosome allows HIV to evade the immune system and establish lifelong infection. This integration process is mediated by the integrase enzyme, which creates a nick in the host DNA and inserts the viral DNA.
• RNA polymerase


  Creates mRNA from the integrated DNA produced by HIV that encodes various viral proteins, including envelope proteins. These proteins are crucial for viral assembly and infection of other cells. Also produces multi protein organ.
• HIV aspartyl Protease enzyme


  Cleaves the polyprotein chains of HIV, allowing for the assembly of mature infectious virions. Inhibition of protease activity is a target for antiretroviral therapy.
• HIV replication leads to the production of numerous viral particles, enabling the virus to spread and maintain the infection. This continuous viral replication is a major challenge in the treatment of HIV.
• Types of illness/pathology that causes AIDS but not HIV

  • Kaposi sarcoma
  • Pneumonia
  • Salmonella septicemia
• When to start treatment (British HIV Association Guidelines)


  • Before immune system is irreversibly damaged
  • CD4 count <350 cells/mm3 (PHI)
  • Patient with diagnosis of AIDS / clinical symptoms of immunosuppression (Rapid weight loss, Unexplained fatigue, Fever/profuse night sweats, Red/brown/pink/purplish blotches under skin/ inside mouth, nose or eyelids)
• What drugs to start with (British HIV Association Guidelines)

  • 2NRTI + PI (2015 regimen)
  • Follow European Aids Clinical Society EACS Guidance (2022 regimen)
• 1st line regimen


  1. 2NRTI + INSTI
  2. 2NRTI + INSTI or NNRTI or Boosted PI
• Salvage therapy


  For patients who have failed at least two antiretroviral regimens
• Resistance testing is important
• Treatment aim


  Decrease viral load in quantity and length of time, prevent mortality and morbidity associated with chronic HIV infection whilst minimizing drug toxicity
• Rationale for combination therapy

  1. Preservation of specific anti-HIV immune responses
  2. Reduction in morbidity associated with high viraemia and CD4 depletion during acute infection
  3. Reduction in the risk of onward transmission of HIV

  To enhance efficacy of a single agent, minimize toxicity by reducing individual doses, and prevent or delay drug resistance
• First Line (Therapy Naïve) regimen design

  • 2 NRTIs (backbone of therapy) + NNRTI

  2NRTIs + ritonavir boosted-PI

  2NRTIs + INI
• Contraindicated regimens in therapy naïve

  • Stavudine + Zidovudine (both thymidine analogues, antagonistic)

  Stavudine + Didanosine (increased risk of toxicities, lactic acidosis and pancreatitis)

  Emtricitabine + Lamivudine (similar resistance profiles)

  Saquinavir, Darunavir, Tipranavir used alone (should be combined with ritonavir)

  Atazanavir + indinavir (additive hyperbilirubinemia)
• Side effects of antiretroviral drugs

  • NRTIs: Renal dosage adjustment, liver toxicity, lactic acidosis, mitochondrial toxicity

  NNRTIs: One mutation = resistance to all NNRTIs, P450 interactions, increased transaminase levels, rash, hypersensitivity, Stevens-Johnson syndrome, CNS symptoms

  PIs: Hyperglycemia, lipodystrophy syndrome, hyperlipidemia, increased hepatic transaminases
• Consequence for patient


  Complex disease=complex treatment, Side effects affect quality of life, adherence, and management of the condition & length of life
• Entry Inhibitors


  • Blocks binding of viral envelope, gp120, to CCR5 to prevent membrane fusion events necessary for viral entry. Fulfill Lipinski RO5.
• Fusion Inhibitors


  • Binds viral gp41 surface protein, Prevents HIV from binding to the surface of CD4 lymphocytes. Does not fulfill Lipinski RO5, used as salvage therapy.
• Nucleoside Reverse Transcription Inhibitors (NRTIs)

  Made of modified nucleoside that terminates replication by incorporating into proviral DNA and preventing integration into host cell genome.
• Non-Nucleoside Reverse Transcription Inhibitors (NNRTIs)

  Synthetic drugs that bind to a hydrophobic pocket in reverse transcriptase during enzyme-substrate binding, acting at the same step of replication as NRTIs. Issue is rapid resistance.
• Tenofovir DF/Viread


  Made of nucleotide unlike the rest nucleosides based.
• HIV integrase strand transfer inhibitor


  Inhibits the integrase enzyme, preventing integration of viral DNA into the host cell genome.
• Substrates for reverse transcriptase

  Incorporates itself into proviral DNA, cannot be integrated into host cell genome as it is malformed
• Zidovudine/Retrovir (AZT, ZDV)


  Gold standard treatment
• Zidovudine (AZT, ZDV)


  • Thymidine analogue
  • For CD4 cell count < 500/mm3 or symptomatic HIV-infected women in 2nd & 3rd trimester
  • Zidovudine analogue (ZDV) with N=N+=N = functional group, allows binding but can't be phosphorylated = terminates transcriptase
  • IV ZDV during labour and delivery + new born (6wks)
• Zidovudine (AZT, ZDV) toxicity

  • Neutropenia, anemia, leucopoenia
• Stavudine/Zerit


  Toxic side effects
• Non-Nucleoside Reverse Transcription Inhibitors (NNRTIs)

  Synthetic drugs that have no structural similarities to nucleosides, act at the same step of replication as NRTI, bind to hydrophobic pocket in RT during enzyme-substrate binding
• NNRTIs


  • Efavirenz
  • Nevirapine
• Issue with NNRTIs is rapid resistance
• Tenofovir DF/Viread


  Made of nucleotide unlike the rest nucleosides based
• HIV integrase strand transfer inhibitors

  As of 2012/2015 it is part of BHVIA haart regimen, once upon a time an adjuvant solely, antiviral activity against resistant cells to PIs, NRTIs & NNRTIs
• Mechanism of Action: Protease Inhibitors

  Gag= group antigens, pol=RT, Proteases cleaves the polypeptide (Gag) and (GagPol) at 9 discrete points (after phenylalanine/tyrosine/proline) to yield functional proteins, it is a unique target as no mammalian exhibits this specificity (geometry of Active site)
• Protease Inhibitors


  • Work in acute and chronically infected cells, recognizes the AA sequence that is cleaved by HIV, used in combo w/ other antiretroviral
• Protease Inhibitor interactions


  CYP450 metabolized, Ketoconazole, Other Protein inhibitors (low doses of ritonavir boosts other PI)
• Protease Inhibitor side effects

  • Lipodystrophy syndrome (fat redistribution, insulin resistance, dyslipidemia)