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Strong recommendation: See SH/SGs/HIV testing, legal issues and discrimination for more details/examples for this lecture.

New notes


  • The replicative cycle of viruses, using 
HIV-1 as the main example
  • Targets for antiviral therapy, as they 
relate to the replicative cycle
  •  Major antiviral drug classes:
    • mechanism of action
    • examples
    • limitations
  • Combination therapy


  • By the end of this lecture you should be able to explain the mechanisms by which the major classes of antiviral agents work, in particular in terms of the stages of the replicative process which they attack.
  • point out some of the limitations of antiviral agents, such as latent virus, limited spectrum of activity, achievement of inhibitory concentrations and drug resistance, and explain how they arise.

Examples of pathogenic viruses

  • Viral infections are common in humans
  • DNA viruses:
    • Poxviruses (smallpox)
    • Herpesviruses (chickenpox, shingles, cold sores, glandular fever)
    • Adenoviruses (sore throat, conjunctivitis)
    • Papillomaviruses (warts)
  • RNA viruses:
    • Orthomyxoviruses (influenza)
    • Paramyxoviruses (measles, mumps, respiratory tract infection)
    • Rubella viruses (German measles)
    • Rhabdoviruses (rabies)
    • Picornaviruses (colds, meningitis, poliomyelitis)
    • Retroviruses (AIDS, T-cell leukaemia)
    • Arenaviruses (meningitis, Lassa fever)
    • Hepadnaviruses (serum hepatitis)
    • Arboviruses (arthropod-borne encephalitis, various febrile illnesses)
  • Viral infections are very common in humans

How do viruses get around host defences?

  • Viruses can interfere with cytokine signalling, for example by trapping cytokines with “pseudoreceptors”
  • Viruses can turn off the surface protein markers on infected cells, enabling the virus to remain undetected
  • Viruses can interfere with apoptotic pathways
  • Viruses can “fool” the natural killer cells by mimicking surface protein markers of host cells
  • In most cases, except in immunocompromised hosts, host defenses prevail, most viral infections eventually generally resolve spontaneously
  • Exceptions: Lassa fever, Ebola virus and HIV infections have a high mortality, if untreated

Immunomodulators: Antibodies

  • Has some limited success sometimes
  • Immunoglobulin:
    • pooled immunoglobulin contains antibodies against some viruses present in the population
    • antibodies “neutralise” virus, prevent attachment to host cells
    • needs to be used before onset of signs and symptoms - massive limitation
    • can prevent or attenuate measles, infectious hepatitis, German measles, rabies
    • hyperimmune globulin specific against particular viruses (more refined)
    • therefore helpful when there is an epidemic going around
  • Palivisumab:

Immunomodulators: Interferons (IFNs)

  • Inducible proteins, synthesised by mammalian cells
  • Produced commercially using recombinant DNA technology
  • Involved in cell growth, regulation, modulation of immune reactions
  • IFN-γ produced by T lymphocytes in response to antigens in general, not just viruses
  • IFN-α and IFN-β produced in various cells of immune system also in response to viruses and cytokines
  • IFNs bind to receptors on host cells, induce production of enzymes inhibiting translation of viral mRNA
  • Broad spectrum of action
  • Have to be injected, do not cross blood-brain barrier, relatively short half-life
  • Unwanted effects common
  • Not ideal, but a possibility for treating viral infections


  • Not a treatment, but a prevention
  • Success for some diseases:
    • polio, smallpox, influenza A and B, hepatitis B
  • Prospects remote for vaccines against many viruses, including human immunodeficiency virus (HIV)
  • Reasons include antigenic drift (among many other reasons):
    • mutations lead to presentation of different antigenic structures
    • they mutate very quickly -- vaccine becomes useless very quickly

Virus replication

Replication of a DNA virus
Replication of an RNA virus
  • DNA viruses (viral nuclear material is DNA), example herpesvirus:
    • viral DNA enters host cell nucleus
    • transcription catalysed by host cell enzymes in nucleus
    • translation by host ribosomes
    • virus proteins generated: some are enzymes, which synthesise more viral DNA, some are structural proteins
    • assembly and release of complete virions from host cell (budding)
    • in blue: antiviral agents and their site of action
  • RNA viruses, example influenza A virus:
    • viral RNA serves as its own mRNA
    • host cell nucleus not necessarily involved in replication (doesn't need to get to nucleus because it serves as its own mRNA)
    • translation, assembly, release as for DNA viruses
    • in blue: antiviral agents and their site of action
    • most important for treating influenza A is targeting the RELEASE of the virus (budding - below)
  • Retroviruses: see later, different mechanism!!!

Zanamivir, Oseltamivir

  • IMPORTANT: RNA viruses have a particular way of attaching themselves to the host cell:
  • Infection with influenza viruses begins with attachment of viral hemaglutinin to neuraminic (sialic) acid residues on the host cell by covalent bonds
  • Viral particle enters via endocytosis
  • Viral M2 protein (an ion channel) acidifies endosome
  • Disassembly of virion
  • Two older drugs block M2, not much used any more
  • In order for the mature, new virion to be released, viral neuraminidase catalyses breaking of bonds between particle coat and host sialic acid
  • Zanamivir, oseltamivir inhibit viral neuraminidase (for influenza A and B)
    • This prevents spread of the infection


  • HIV is an RNA retrovirus, specifically a lentivirus (perfected its virulence):
    • only ONE, or at most a handful of infectious virions enough for sexual acquisition of HIV infection (so effective in setting itself up that you only need 1 particle)
    • evolved to establish chronic, persistent infection
    • host CD4+ (helper) T-lymphocyte count declines steadily, risk of opportunistic diseases (due to immunocompromised state - "AIDS") and ultimately death increases
    • LATE onset of clinical symptoms (8 to 10 years after sexual acquisition of HIV-1 infection)
    • some infected cells may harbour nonreplicating, but infectious virus for years, until the cell is activated and transcription occurs
    • “silent” replication, mainly in the lymph nodes, constant following infection, no true viral latency after infection, until immune response fails, plasma virus titre increases, opportunistic diseases occur = AIDS
  • Two forms:
    • HIV-1 responsible for human AIDS, distributed around the world
    • HIV-2 also causes immune suppression, less virulent, confined to parts of Africa
  • WHO: In 2004, an estimated 42 million people were living with HIV infection
    • majority in resource-poor countries
    • fewer than 5% of people who would benefit from combination antiretroviral therapy receive it (poor countries)
  • NB: virion = one virus particle
  • People don't die from HIV infection, they die from opportunistic infection (due to AIDS - immunocompromised) that their bodies can no longer fight

HIV-1 Replicative Cycle - Overview


  • There are a number of different attack points (indicated)
    • Also, can attack integrase
  • Available antiretroviral agents in blue

Virus Structure

  • The mature virion consists of:
    • nucleocapsid core surrounded by a lipid bilayer (envelope), derived from host cell plasma membrane
    • some small regulatory proteins to enhance virion production or combat host defenses
    • envelope contains two proteins responsible for attachment and fusion, gp120 and gp41
  • The nucleocapsid (analogous to cell nucleus, but not in a cell!) contains:
    • two copies of a small RNA genome (9,300 base pairs)
    • viral enzymes: reverse transcriptase, protease, integrase

Attachment and Fusion

  • Virion binding through gp120, major targets: CD4 receptors on lymphocytes and macrophages
  • Coreceptor required, generally chemokine receptor CCR5 (present on macrophages, initial target) or CXCR4 (on T-lymphocytes; associated with advancing disease)
  • Maraviroc blocks the CCR5 receptor
  • Fusion of virus lipid bilayer with host cell lipid bilayer controlled by gp41
  • Uncoating of capsid releases full length viral genomic RNA and viral enzymes into cytoplasm

HIV Entry Inhibitors

  • Enfuvirtide only approved for use in 2007
  • Only HIV entry inhibitor, works through selective inhibition of HIV-mediated membrane fusion
  • 36 amino acid synthetic peptide, sequence derived from part of gp41, binds to and blocks gp41
    • Only works for HIV-1, but this is the more virulent virus
  • Not active against HIV-2, active against a broad range of HIV-1 isolates, including against viruses which have become resistant to other antiretroviral agents
  • IC50 in vitro between 0.1 nM and 1.7 μM
    • NB: The half maximal inhibitory concentration (IC50) is a measure of the effectiveness of a compound in inhibiting biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance (inhibitor) is needed to inhibit a given biological process (or component of a process, i.e. an enzyme, cell, cell receptor or microorganism) by half. In other words, it is the half maximal (50%) inhibitory concentration (IC) of a substance (50% IC, or IC50). It is commonly used as a measure of antagonist drug potency in pharmacological research.
  • Problems: Expensive to manufacture, must be administered by subcutaneous injection twice daily
    • Used as a last-resort drug
  • Resistance can develop through specific mutations in gp41 (renders agent less and less active)
  • Single amino acid substitutions can confer up to 450 fold resistance in vitro
    • Nervous about giving too much too early --> becomes useless quickly
  • Main adverse effects are injection-site reactions
  • Orally available small molecule entry inhibitors are under development

Reverse Transcription

  • Three steps, catalysed by the viral enzyme reverse transcriptase (RT)
  • First step: synthesis of a complementary DNA strand from the viral RNA strand
    • this occurs at the polymerase active site
    • the DNA-RNA duplex is short-lived
  • Second step: RT has a 2nd active site, an RNAse H, which degrades the original RNA
  • Third step: synthesis of a complementary DNA strand from the DNA strand synthesised in the first step
    • this occurs at the polymerase active site
    • this creates a full-length double-stranded DNA copy of the virus
  • RT is error-prone, lacks a proofreading function, mutations are quite frequent
    • Virus doesn't bring proofreading machinery
    • Mutations --> make virus more likely to become resistant
  • RT inhibitors are one of the mainstays of antiviral therapy (see later)
  • All clinically used RT inhibitors inhibit the synthesis of DNA, the polymerase action of RT


  • Viral integrase enzyme (IN) catalyses integration of the viral DNA duplex into host chromosome
  • Integration is a complex, multistep process
  • For those interested:
    • IN catalyses two reactions:
      • 3’ processing of the viral DNA in the cytoplasm, producing a “reactive” 3’ end, with a 2 nucleotide overhang at the 5’ end of the complementary strand
      • whole complex then transported into the nucleus
      • IN then catalyses the first step of integration into the host chromosomal DNA in a complicated strand transfer reaction, leading to an intermediate which is repaired by host cell enzymes
  • The first integrase inhibitor has been approved for clinical use in 2007 (C.S. Adamson, E.O.Freed, Drug Discovery Today, 13 (9- 10), March 2008, pp 424-432):
    • Raltegravir
    • inhibits strand transfer specifically, which reduces toxicity of earlier IN inhibitors

Transcription, Translation

  • After integration, the virus may remain in a quiescent state, not producing RNA or protein, but replicating as the cell divides
  • Activation of a cell harbouring virus, leads to production of viral RNA and proteins
  • Viral proteins are synthesised as three major polyproteins, which need to be further processed (chopped up) by a viral protease enzyme:
    • gag encodes structural proteins
    • pol encodes the 3 enzymes (RT, IN, protease)
    • env encodes envelope proteins
  • Protease inhibitors are one of the mainstays of antiviral therapy (see later)

Assembly, Budding, Release

  • Structural proteins assemble around 2 complete single stranded viral RNA copies to form a nucleocapsid
  • Envelope proteins assemble at the cell surface, in cholesterol-rich lipid rafts, nucleocapsid cores are directed there
  • The whole assembly buds through the cell membrane, creating a new HIV particle
  • RT is incorporated into the new virion, so that replication can begin immediately after the virus enters a new cell
  • So far, none of these processes have been targeted by approved anti-HIV agents
  • For influenza viruses, the release of new virions has been targeted successfully (Zanamivir, Oseltamivir, vide supra)

Most commonly prescribed antiretroviral agents

  • Reverse transcriptase inhibitors
  • Protease inhibitors

Reverse Transcription Review

  • Three steps, catalysed by the viral enzyme reverse transcriptase (RT)
  • First step: synthesis of a complementary DNA strand from the viral RNA strand
    • this occurs at the polymerase active site
  • Second step: RT has a 2nd active site, an Rnase H, which degrades the original RNA; no antiviral agents yet approved which attack this function
  • Third step: synthesis of a complementary DNA strand from the DNA strand synthesised in the first step
    • this occurs at the polymerase active site
    • this creates a full-length double-stranded DNA copy of the virus
  • DNA viruses also have a viral polymerase to make their own DNA for incorporation into new virions
    • Note that what we inhibit in RT is a polymerase active site that makes DNA -- the same drugs can be used (to some extent)
  • RT is error-prone, lacks a proofreading function, mutations are quite frequent

Reverse Transcriptase Inhibitors

Thymidine and AZT have similar chemical structures, except that AZT is missing the 3' OH, so acts as a chain terminator in DNA synthesis. Downstream, this prevents synthesis of functional viral proteins.
  • Nucleoside analogues (analogue of the substrate of the RT enzyme's polymerase active site); called NRTIs:
    • phosphorylated by host cell enzymes to give 5’-triphosphate
    • compete with equivalent substrate, can be problematic in rapidly dividing cells
    • incorporated into growing viral DNA strand by RT or by viral polymerases (DNA viruses)
    • lack 3’ OH group, so chain termination occurs (cannot be further phosphorylated to continue the chain of the polymer)
    • some of the common side effects due to inhibition of host cell DNA polymerases (which we need!), particularly in fast growing, dividing cells such as stomach lining, leading to gastrointestinal disturbances (nearly 100% of patients)
    • viral DNA polymerase inhibitors for DNA viruses fall under this category
    • Aciclovir is very specific for herpes simplex and has very few unwanted effects, can be given orally, intravenously or topically
    • Resistance
  • More on NRTIs:
    • AZT (zidovudine), first approved treatment for HIV
  • Nucleotide analogues:
    • same mechanism of action as nucleosides
    • tenofovir: already phosphorylated once, but still needs further phosphorylation (works a bit faster -- only needs to be phosphorylated once by the host cell)
Examples of NNRTIs. These are allosteric inhibitors of the RT enzyme.
  • Non-nucleoside RT inhibitors (NNRTIs)
    • Chemically diverse allosteric inhibitors
    • Do not compete with endogenous nucleosides
    • Do not need to be phosphorylated
    • Bind somewhere completely different at a different site of the enzyme (like putting a bit of sand in the mechanism of the RT)
    • Nevirapine, Efavirenz both given orally
    • Side effects common
    • Resistance

Protease Inhibitors (PIs)

Examples of protease inhibitors. These drugs are competitive inhibitors for the protease enzyme that slices up the polyprotein produced from translation of viral mRNA (which is produced by transcription of the integrated DNA product of reverse transcription of the initial viral RNA). Normally, the protein "slices" produced from protease action would make up the viral components that are budded from the cell. The protease inhibitor interrupts the viral life cycle at the stage of slicing, leaving a useless viral polyprotein.

(Inhibits the enzyme that chops up the polyprotein transcribed from viral genomic material)

  • Generally given orally
  • Competitive inhibitors, “peptide-like”, mimic cleavage site of the viral polyproteins
  • side effects common

Combination Therapy for HIV

  • RT inhibitors and protease inhibitors can be used in combinations as they have different mechanisms of action
    • Enhance each others' action by attacking different sites of the process -- virtually never give a single antiviral therapy to patients
  • Combination treatment is also known as HAART: highly active antiretroviral therapy
  • HAART typically involves three drugs, from at least two classes
  • Most common: two different nucleoside RT inhibitors + one non-nucleoside RT inhibitor or one protease inhibitor

HAART: highly active antiretroviral therapy

  • HIV replication inhibited
  • Presence of HIV RNA in plasma reduced to undetectable levels
  • Patient survival greatly prolonged
  • Complex, expensive regimen, lifelong treatment, many unwanted effects lead to compliance difficulties
    • Problem: people stop taking it when they start to feel better due to side effects
  • Virus not eradicated, lies latent in host genome of memory T cells, ready to reactivate if therapy is stopped
  • Negative drug interactions can occur between HAART components
  • Presently, no cross-resistance, but this is expected because of the high mutation rate of the virus
    • This is a problem that we're expecting to come up


  • Difficult choices: check latest information
  • Pregnant or breastfeeding women:
    • avoid damage to fetus or baby
    • prevent transmission
    • Zidovudine (AZT) alone or as a component of combination therapy is often used
  • After accidental exposure:
    • only if there is a high risk of infection
    • Zidovudine alone or Zidovudine containing combination therapy is often used
  • Treatment of HIV infection is complex and so is not undertaken by a normal GP, but instead by specialist doctors


  • Experiences from the development of antiviral agents have provided useful general insights with practical implications:
  • Although many compounds show antiviral activity in vitro, most affect some host cell function and are associated with unacceptable toxicity in human beings.
  • Effective agents typically have a restricted spectrum of antiviral activity and target a specific viral protein, most often an enzyme involved in viral nucleic acid synthesis (polymerase or reverse transcriptase) or viral processing protein (protease).
  • Single-nucleotide changes leading to critical amino acid substitutions in a target protein often are sufficient to cause antiviral drug resistance. Indeed, the selection of a drug- resistant variant indicates that a drug has a specific mechanism of antiviral action.
  • Current agents inhibit active replication, so viral replication may resume following drug removal. Effective host immune responses remain essential for recovery from infection. Clinical failures of antiviral therapy may occur with drug-sensitive virus in highly immunocompromised patients or following emergence of drug-resistant variants.
  • Most drug-resistant viruses are recovered from immunocompromised patients or those with chronic infections (e.g., HBV) with high viral replicative loads and repeated or prolonged courses of antiviral treatment. (Influenza A virus is an exception.)
  • Current antiviral agents do not eliminate nonreplicating or latent virus, although some drugs have been used effectively for chronic suppression of disease reactivation.
  • Clinical efficacy depends on achieving inhibitory concentrations at the site of infection, usually within infected cells. For example, nucleoside analogs must be taken up and phosphorylated intracellularly for activity; consequently, concentrations of critical enzymes or competing substrates influence antiviral effects in cells of different types and in different metabolic states.
  • In vitro sensitivity tests for antiviral agents are not standardized, except for selected viruses (e.g., herpes simplex virus), and results depend on the assay system, cell type, viral inoculum, and laboratory. Therefore, clear relationships among drug concentrations active in vitro, those achieved in blood or other body fluids, and clinical response have not been established for most antiviral agents.

Additional resources

Old notes


  • Viral infections are common in humans
  • Several types of viruses
    • DNA viruses
    • RNA viruses – esp. retroviruses (AIDS)
  • Viruses have several ways of getting around host defences
    • Interference with cytokine signalling – trapping cytokines with pseudoreceptors
    • Inactivation of surface protein markers on infected cells to prevent detection of virus
    • Interference with apoptotic pathways
    • Tricking of NK cells by mimicking of surface protein markers of host cells
      • In most cases, host defences prevail and viral infections are resolved spontaneously
        • Exceptions: Lassa fever, Ebola, HIV


  • Antibodies
    • Immunoglobulin contains antibodies that can protect against viruses
      • Antibodies neutralise viruses and prevent their attachment to host cells
      • A dose of immunoglobulin can prevent or attenuate measles, infectious hepatitis, rabies
        • However, needs to be given before the onset of symptoms
      • Can be highly specific to a particular disease
    • Eg: Palivisumab – a monocloncal antibody used against respiratory syncytial virus
      • Involves a intramuscular injection for infants
  • Interferons (IFNs)
    • Proteins that are synthesised by mammals
      • Can be produced commercially using recombinant DNA technology
    • Involved in cell growth, regulation and modulation of immune reactions
    • IFN-γ is produced by T cells to coordinate the immune response (especially, activate macrophages)
      • IFN-α and IFN-β are also used in response to viruses
    • Bind to receptors on host cells and induce production of enzymes that inhibit translation of viral mRNA
    • Injected, don’t cross BBB, short half-life
      • Side-effects because IFNs have many uses
  • Vaccination
    • Successful for some diseases like polio, smallpox, influenza A and B, hepatitis B (based on memory T and B cells)
    • HIV vaccine unlikely because of antigenic drift – mutations lead to antigenic resistance

Virus replication

Replication of A) DNA and B) RNA viruses
  • DNA viruses
    • Process:
      • DNA enters host cell nucleus
      • Transcription is catalysed by host cell enzymes
      • Translation by ribosomes
      • Virus proteins are generated – enzymes for synthesising viral DNA, structural proteins
      • Assembly and release of virions
  • RNA viruses
    • Process:
      • Viral RNA serves as its own mRNA
      • Host cell nucleus is not necessarily required for replication
      • Translation, assembly and release is the same as for DNA viruses
  • Retroviruses have a different mechanism Eg: Zanamivir, Oseltamivir
  • Influenza viruses begin infection by attachment of viral hemagglutinin to neuraminic (sialic) acid resides on the host cells (covalent bonds)
    • Virus then enters by endocytosis
    • Viral M2 protein (ion channel) acidifies endosome and the virion disassembles
      • For virion release, viral neuraminidase catalysese break the bonds between the particle coat and the host sialic acid
      • Thus, antiviral drug Azanmivir, oseltamivir inhibits viral neuraminidase and thus stops infection HIV
  • An RNA retrovirus – a lentivirus
    • Only one virion is required for sexual acquisition of infection
    • A chronic, persistent infection
      • Host CD4 + T cell count declines steadily increasing the risk of opportunistic diseases and death
      • Late onset of clinical symptoms (8-10 years)
      • In ‘latent’ period, silent replication occurs in the lymph nodes
  • Two forms
    • HIV-1, most common
    • HIV-2, less virulent, confined to parts of Africa
  • Fewer than 5% of people who would benefit from combination antiretroviral therapy receive it

Antiviral (HIV) mechanisms

Mechanism of action of various viral inhibitory drugs
  • Blocking entrance to the cell
    • Virus structure
      • Virion: nucleocapsid core with a lipid bilayer (envelope) derived from the host cell plasma membrane
        • Small regulatory proteins that enhance virion production and deal with host defences
        • Envelope has gp120 and gp41, proteins important for attachment and fusion
        • Nucleocapsid contains two copies of RNA genome (10 000 base pairs) and viral enzymes: reverse transcriptase, protease, integrase
    • Attachment and fusion
      • Virion binds through gp120 targeting CD4 receptors on lymphocytes and macrophages
      • Requires a coreceptor – chemokine receptor (CCR5, macrophages, initial attack) or CXCR4, T-cells, advancing disease
        • Fusion of virus lipid bilayer with host lipid bilayer, controlled by gp41
        • Capsid is uncoated releasing viral RNA and viral enzymes into cytoplasm
    • Entry inhibitors
      • Enfuvirtide – approved 2007
        • HIV entry inhibitor that selectively inhibits HIV-mediated membrane fusion
          • Binds and blocks gp41
        • Active against HIV-1 but not HIV-2
        • Expensive to manufacture and administered subcutaneously 2x/day
        • Resistance
          • Via mutations to gp41, a single AA substitution can result in 450x resistance
        • AE – injection site reactions
      • Oral alternatives are underdevelopment
  • Reverse transcriptase inhibitors
    • Reverse transcription process:
      • Synthesis of a complementary DNA strand from viral RNA strand
        • Occurs at the polymerase active site
      • Reverse transcriptase has a 2nd active site – RNAse H
        • Allows degradation of original RNA
      • Synthesis of a complementary DNA strand
        • Occurs at the polymerase active site
        • Thus, a full-length double-stranded DNA copy of the virus is produced
    • RT is error-prone and lacks a proof-reading function, thus much mutation
      • Clinically, RTIs inhibit steps 1 and 3, the polymerase action
    • Integration
      • Viral enzyme integrase catalyses the reaction to integrate the viral DNA into the host chromosome
        • Complex, multistep process:
    • Processing of viral DNA in cytoplasm creating a reactive end
    • Transport into nucleus
    • Strand transfer reaction occurs and then host cell enzymes repair the new DNA
      • Raltegravir – integrase inhibitor approved for clinical use 2007
        • Inhibits strand transfer thus reducing toxicity since integrase has other uses in the body
  • Protease inhibitors
    • After integration into DNA, virus may remain quiescent and reproduces as the cell divides (cell mitosis)
      • Once cells are activated, virus begins producing viral RNA and proteins
    • Viral proteins are synthesised as 3 major polyproteins that need a viral protease enzyme to be split further
      • Gag – structural proteins
      • Pol – 3 enzymes (RT, IN, protease)
      • Env – envelope proteins
    • Protease inhibitors prevent proteases cutting up the proteins and thus prevent virus function
    • Assembly of virions
      • Viral RNA copies are surrounded with structural proteins to form the nucleocapsid
      • Envelope proteins assemble on the cell surface and nucleocapsid cores are directed there
      • The virion buds through the cell membrane creating a new HIV particle
  • None of these processes associated with assembly has been successfully targeted for HIV therapy

Reverse transcriptase inhibitors

  • Nucleoside analogues
    • Process:
      • Phosphorylated by host cell enzymes giving a 5’-triphosphate
      • Compete with equivalent substrate in reverse transcriptase action of creating DNA
      • Incorporated into DNA strand by RT or viral polymerases (DNA viruses)
        • Lack of the 3’ OH groups causes chain termination
      • Side effects – inhibition of host cell DNA polymerases can lead to GIT disturbance (fast growing/dividing cells)
    • Aciclovir – specific for herpes simplex, can be given intravenously/topically
Molecular structure of AZT
    • Nucleoside reverse transcriptase inhibitors (NRTIs)
      • AZT (zidovudine) – first approved HIV treatment
      • 3TC (lamivudine), ABC (abacavir) – given orally
  • Nucleotide analogues
    • Same mechanism as nucleoside analogues but requires fewer phosphorylation steps
    • Eg: tenofovir
  • Non-nucleoside RT inhibitors (NNRTIs)
    • Allosteric inhibitors – causes enzyme to maintain the inactive conformation
    • Don’t compete with endogenous nucleosides and don’t need to be phosphorylated
    • Eg: nevirapine, Efavirenz – orally given
    • Side effects
  • All RTIs have problems with resistance

Protease inhibitors

  • Generally given orally
  • Competitive inhibitors – compete for substrate
    • Mimic cleavage site of viral polyproteins
  • Common side effects

Combination HIV therapy

  • Known as HAART: highly active antiretroviral therapy
    • Normally involves 3 drugs from at least 2 classes
    • Commonly: two different NRTIs + (a NNRTI or a PI or an INI)
  • Effects
    • HIV replication is inhibited
    • Presence of HIV in plasma is reduced
      • Thus patient survival prolonged
  • However, requires a complex, expensive regimen of drugs lifelong – often many side effects
    • Virus is not eradicated, lies latent in host genome of memory T cells, just reproduction stopped
    • HAART may have negative drug-interractions
    • Cross-resistance (resistance to one drug through exposure to another) not yet seen, but expected due to high mutation rate


  • Difficult choices
  • Pregnant women/breast-feeding women
    • Avoids damage/transmission to fetus/baby
    • Use: AZT (Zidovudine) or combination therapy
  • Accidental exposure
    • Only if high risk of infection
    • Use: Zidovudine or combination therapy