The document discusses HIV and its life cycle. It notes that HIV has a single-stranded RNA genome and hijacks host cells like CD4+ T-cells. It describes the stages of the HIV life cycle within a host cell, including attachment, fusion, reverse transcription of its genome, integration into host DNA, production of new virions, and cell destruction. The document also summarizes different classes of antiretroviral drugs that target different stages of the viral life cycle, including reverse transcriptase inhibitors, protease inhibitors, fusion inhibitors, and integrase inhibitors. It provides examples of drug regimens used to treat HIV.

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DR RAHUL KUNKULOL
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2. • It contains a single-stranded RNA genome
• Incorporate genome into host cell and hijack
the normal functions of the cell to replicate
Eventually lead to cell destruction
• Target for HIV :
• CD4+ Helper T-Cells, Backbone of the
immune system
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ANTIGEN DESTRUCTION
Innate immunity

4. • Attachment And Membrane Fusion
• Uncoating
• Reverse Transcription
• Integration
• Transcription Of Viral Genome
• Translation Of Proteins
• Post Translational Modification
• Assembly
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• Fusion targets of the viral surface envelope
glycoproteins gp120 and other non
specified proteins on the surface of the T-
lymphocyte :
• CD4+ receptor
• Chemokine co-receptors
• CCR5
• CXCR4

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8. • Membrane protein gp120 binds CD4
receptor on lymphocytes and macrophages
• Other non-specified viral membrane
proteins bind chemokine co-receptors
(major co-receptors are CCR5 and CXCR4)
• HIV fuses with host cell and releases its
genome and enzymes into the cell
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9. • 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
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• DNA is then transported into the cell
nucleus and is integrated into the host
cell DNA by the viral enzyme integrase.

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• 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

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• 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

14. Nucleoside reverse transcriptase inhibitors NRTI
Nucleotide reverse transcriptase inhibitors NtRTI
Non-nucleoside reverse transcriptase inhibitors NNRTI
Protease inhibitor PI
Fusion inhibitor
HIV Integrase inhibitor
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• 1985 – Research on anti-viral medication begins
• 1987 – First drug Zidovudine produced (NRTI)
• Early life extending properties except only
temporarily worked as patients became immune
• Mid-1990s – Protease Inhibitors and NNRTIs
• 1995 – first protease inhibitor Sequinavir FDA
approved
• 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
approved by FDA

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• Thymidine analogue
• Cellular enzyme phosphorylate to the
triphosphate
• Inhibits the action of the viral enzyme reverse
transcriptase.
• Accomplished by incorporation in DNA peptide
• Prematurely terminating the transcription process

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Adverse effect:
• Granulocytopenia and anemia: 45% in AIDS
but 5% if asymptomatic HIV
• Severe headache, nausea, insomnia, myalgia
• Rare ADR: hepatomegaly, lactic
acidosis, encephalopathy

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• Now used only in combination with
ARVs
• NOTE: ↓mortality & opportunistic
infections, gain weight, better quality
of life, delays signs and symptoms of
AIDS

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• Deoxycytidine analogue
• Inhibits reverse transcriptase and DNA
polymerase in HBV.
• Systemic toxicity is low, and is well tolerated.
• Resistance rapid
• Used in combination with other ARVs
• Chronic hepatitis B

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ZALCITABINE
(azt)
DIDANOSINE
( ddI )
STAV
( d4T )
LAMI
( 3TC )
ZALCI
( ddC )
Analog Thymidine Adenosine Thymidine Cytidine Cytidine
Notes Avoid BM
suppressive
drugs
Avoid
neuropathy
drugs
Avoid
neuropathy
drugs
Active
against
HBV also.
Avoid
neuropathy
drugs
and
antacids.
Adverse
effects
Anemia
Neutropenia
Pancreatitis
Neuropathy
Sensory
Neuropathy
Headache Pancreatitis
Neuropathy

22. • No Phosphorylation
required after they
enter the cell.
• Same mechanism of
action as NTRIs
• Nausea and
vomiting are the
disadvantages
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Tenofovir Disproxil Fumarate

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:Rarely used due to a high pill burden
• Mechanism: different with NRTIs
• Used in combination with NRTIs and PI
• Toxicity: rash

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• Inhibitors of the viral enzyme reverse transcriptase
however mechanism of action is different
• This class of drugs works by noncompetitive
inhibition
• Binds to the viral enzyme at a place other than the
active site
• Changes the conformation of the active site
• Decreasing the enzyme’s affinity for nucleoside
binding.

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• More potent against HIV-I but donot
inhibit HIV II.
Adverse effects :
• Hepatotoxicity
• Stevens – Johnson syndrome
• It is an inducer of Cyto P 450

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• Drugs :
• Saquinavir
• Ritonavir
• Indinavir
• Nelfinavir
• Mechanism: Inhibit precursor molecules
convert to mature virions during HIV
replication

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• 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
Ritonvir
More successful because it inhibits Cytochrome
P450 3A4 which breaks down Protease Inhibitors
Sequinavir
Low Bioavailability

28. Oral
Absorption
Excretion Comments
Saquinavir Poor Feces With ritonavir
Indinavir Good Feces Hepatitis : jaundice
Renal stones
Ritonavir Good Feces Liver toxicity
Increase plasma conc.
of other PI
Nelfinavir Good Feces Diarrhea

29. • Newest Class of Drugs
• Drug binds to the glycoprotein gp41 in the
viral envelope inhibiting its fusion with the
CD4+ receptor on the host cell
• Usually used as a last line option
• Only available as an injection and its high
cost : More than $25000 per year

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• HIV INTEGRASE, an enzyme required for
integration of viral DNA into cellular
DNA.
• By blocking integration, an integrase
inhibitor would prevent HIV from infecting
"new" cells, but would not have any effect
on cells with established infection.

32. • Multi - drug regimen used for the
treatment of HIV infection is referred as
HAART --
“Highly active anti-retroviral drugs”.

33. Currently the recommendation for HIV / AIDS
patient is either
• TWO NUCLEOSIDE REVERSE TRANSCRIPTASE
INHIBITORS + ONE PROTEASE INHIBITORS
• TWO NUCLEOSIDE REVERSE TRANSCRIPTASE
INHIBITORS + NON-NUCLEOSIDE RT INHIBITORS
• 3 NUCLEOSIDE REVERSE TRANSCRIPTASE
INHIBITORS

34. • Stavudine + Lamivudine + Nevirapine
• Zidovudine + Lamivudine + Nevirapine
• Stavudine + Lamivudine + Efavirenz
• Zidovudine + Lamivudine + Efavirenz
• PI –based regimens :- (Disadvantages)
High pill burden
Significant interactions with other drugs
RESERVED FOR SECOND LINE THERAPY