HIV Antiretroviral Treatment

1
HIV Antiretroviral Treatment

• By Richard Britt
• Dr. Buynak
• Spring 2006

2
Human Immunodeficiency Virus

• HIV is a Retrovirus which means
• It contains a single-stranded RNA genome
• The HIV will incorporate its own genome into
  its host cell and hijack the normal functions of
  the cell to replicate itself
• This process will eventually lead to cell
  destruction
• The target for HIV is the CD-4 Helper T-Cells,
  which are the backbone of the immune system.

3
Symptoms

• The Majority of Symptoms of an HIV infection do
  not show up until the disease has already begun
  to damage the immune system
• The incubation time for an HIV infection can be
  several weeks to several years
• General symptoms include
• Lack of energy, weight loss, frequent fevers and
  sweats, persistent or frequent yeast infections,
  persistent skin rashes or flakey skin, short-term
  memory loss, and mouth, genital, or anal sores
  from Herpes infections

4
Opportunistic Infections

• HIV infection is usually discovered when a
  patient is diagnosed with an unusually severe or
  persistent infection
• Opportunistic infections include
• Bacterial, Fungal, Parasitic, and Viral
  Infections
• These infections will be more severe because the
  persons immune system will be surpressed by the
  HIV disease.

5
HIV Details

• RNA Genome is 9 kilobases long and contains 9
  genes that encode 15 different protiens
• Fusion targets of the viral surface envelope
  glycoprotiens is the CD4 receptor and its
  co-receptor CCR5 on the surface of the
  T-lymphocyte
• Envelope contains the following viral enzymes
• Reverse Transcriptase, Integrase, RNAse-H

6
Basic Steps

• HIV fuses with host cell and releases its genome
  and enzymes into the cell
• RNA genome is transcribed by Reverse
  Transcriptase into a single stranded viral DNA
• Reverse Transcriptase acts as DNA Polymerase and
  transcribes the single stranded DNA into a Double
  Stranded Viral DNA
• DNA is then transported into the cell nucleus and
  is integrated into the host cell DNA by the viral
  enzyme integrase.

7
HIV Lifecycle
8
More Basic Steps

• Normal functions of the cell resume except now
  instead of transcribing RNA for the regular
  proteins of the cell it is transcribing viral
  mRNA
• Viral Proteins are produced in one large
  multi-protein chain from the viral mRNA
• Viral Components move toward the cell membrane
  and bud off into new immature virions

9
HIV Lifecycle
10
More Basic Steps

• Viral enzyme protease cleaves itself from the
  viral protein mass
• The Viral Protease then matures the virion by
  cutting up the protein mass into the individual
  viral enzymes
• The virion is a mature and infectious virus

11
HIV Lifecycle
12
Mature HIV Virus
Life Cycle Animation
13
Nucleoside Reverse Transcriptase Inhibitors
(NRTIs)

• Zidovudine first drug in this class approved by
  the FDA on March 20, 1987
• This class of drugs works by inhibiting the
  action of the viral enzyme reverse transcriptase.
• This is accomplished by taking the place of a DNA
  peptide and prematurely terminating the
  transcription process
• NRTIs are phosphorylated three times after they
  enter the cell to become successful inhibitors

Zidovudine (AZT or azidothymidine)
14
Nucleotide Reverse Transcriptase Inhibitors
(NtRTIs)

• In the same class of drugs as NRTIs however these
  are not required to be phosphorylated after they
  enter the cell.
• Same mechanism of action as NTRIs

Tenofovir Disproxil Fumarate (Viread)
Life Cycle Animation
15
Non-Nucleoside Reverse Transcriptase Inhibitors
(NNRTIs)

• Also act as inhibitors of the viral enzyme
  reverse transcriptase however mechanism of action
  is different
• This class of drugs works by non-competitive
  inhibition
• The drug binds to the viral enzyme at a place
  other than the active site and changes the
  conformation of the active site decreasing the
  enzymes affinity for nucleoside binding.

Nevirapine (Viramune)
Life Cycle Animation
16
Protease Inhibitors

• These work by competitive inhibition of the viral
  enzyme protease
• These drugs irreversibly bind to the active site
  of protease preventing it from completing the
  maturation of the virion
• Protease inhibitors prevent immature virions from
  becoming mature, infectious Viruses

Sequinavir (Invirase) Low Bioavailability
Ritonvir (Norvir) More successful because it
inhibits Cytochrome P450 3A4 which breaks down
Protease Inhibitors
Life Cycle Animation
17
Mature HIV Virus
Life Cycle Animation
18
Fusion Inhibitors

• Newest Class of Drugs
• This drug binds to the glycoprotein gp41 in the
  viral envelope inhibiting its fusion with the
  CD4 receptor on the host cell and thus
  preventing the cells infection.
• Usually used as a last line option for most
  patient because it is only available as an
  injection and its high cost
• More than 25000 per year

Enfuvirtide (Fuzeon)
Life Cycle Animation
19
Fusion Inhibitors vs. Other Classes of Drugs
20
History of Drug Development

• 1985 research on anti-viral medication begins
• 1987 First drug Zidovudine produced
• First NRTI
• Early life extending properties except only
  temporarily worked as patients became immune
• Mid-1990s Protease Inhibitors and NNRTIs
  Developed
• 1995 first protease inhibitor Sequinavir
  approved by the FDA
• Low Bioavailability led to the development of a
  second protease inhibitor Ritonvir
• 1996 first NNRTI, Nevirapine approved by FDA
• March 2003 First Fusion Inhibitor Enfuvirtide
  approve by FDA

21
Current ResearchHIV Vaccine

• Two methods of vaccine research showing promise
• Recombinant Subunit Vaccines
• Live Recombinant Vaccines

22
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23
Disadvantages

• Recombinant Subunit Vaccine
• If the recombinant viral envelope proteins that
  are included in the vaccine arent close enough
  in structure and composition to the actual HIV
  envelope proteins the antigens that are produced
  will be ineffective in fighting an actual HIV
  infection
• Live Recombinant Vaccine
• Can actually cause disease when it is trying to
  prevent it
• Usually occurs when the person is
  immunocompromised

24
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