Download HIV - SMU

HIV
Characteristics of the virus
Characteristics of the virus


Icosahedra (20 sided), enveloped virus of the
lentivirus subfamily of retroviruses.
Two viral strands of RNA found in core
surrounded by protein outer coat.
 Outer
envelope contains a lipid matrix within which
specific viral glycoproteins are imbedded.
 These knob-like structures responsible for binding to
target cell.

HIV
• HIV is a RETROVIRUS. A Retrovirus is a
ribonucleic acid (RNA) virus that must reverse to
the Deoxyribonucleic acid (DNA) before
reproducing/replicating.
• It is the DNA gene that enables the Virus to
replicate. HIV invades mainly the helper T cells to
replicate itself.
• No Cure
prevalence
prevalence

Estimated HIV/AIDS prevalence among young adults (15-49) by country as of 2008.
Stage 1 - Primary

Short, flu-like illness - occurs one to six
weeks after infection

no symptoms at all

Infected person can infect other people
Stage 2 - Asymptomatic

Lasts for an average of ten years

This stage is free from symptoms

There may be swollen glands

The level of HIV in the blood drops to very
low levels

HIV antibodies are detectable in the blood
Stage 3 - Symptomatic

The symptoms are mild

The immune system deteriorates

emergence of opportunistic infections
and cancers
Stage 4 - HIV  AIDS

The immune
system weakens

The illnesses
become more
severe leading to
an AIDS
diagnosis
Opportunistic Infections
associated with AIDS
 Bacterial
Tuberculosis
(TB)
Strep pneumonia
 Viral
Kaposi
Sarcoma
Herpes
Influenza
(flu)
Opportunistic Infections
associated with AIDS
 Parasitic
Pneumocystis
 Fungal
Candida
Cryptococcus
carinii
HIV/AIDS Transmission
Sexual
Mother-to-child
Blood products
Multiple infection
Transmission
Life Cycle of HIV

There are 7 steps in the life cycle of HIV, they
are Binding, Reverse transcription,
Integration, Transcription, Translation,
Assembly, Budding.
Treatment
When several such drugs, typically three
or four, are taken in combination, the
approach is known as Highly Active
Antiretroviral Therapy, or HAART.
 The decision on when to start treatment
should take into account , HIV viral load,
treatment history, resistance profiles and
patient preference.

Ann. Intern. Med. 137 (5 Pt 2): 381–433. PMID 12617573
APPROACHES FOR
TREATMENT OF AIDS






NATURAL ANTI HIV AGENTS
CHEMOKINE (CCR5 and CXCR4) RECEPTOR
ANTAGONIST
ANTI-SENSE OLIGONUCLEOTIDES
ANTI-CD4 MONOCLONAL ANTIBODY TNX 355
NANOTECHNOLOGY FOR HIV/AIDS
TREATMENT
MEDICINAL CHEMISTRY FOR THE
TREATMENT OF AIDS
Classes of drugs
Antiretroviral (ARV) drugs are broadly classified
by the phase of the retrovirus life-cycle that the
drug inhibits.
 Reverse-transcriptase inhibitor(RTI)
 Protease inhibitors (PIs)
 Integrase inhibitors
 Entry inhibitors (or fusion inhibitors)
 Maturation inhibitors
Reverse-transcriptase inhibitor
RTIs come in three forms:
 Nucleoside analog reverse-transcriptase
inhibitors (NARTIs or NRTIs)
 Nucleotide analog reverse-transcriptase
inhibitors (NtARTIs or NtRTIs)
 Non-nucleoside reverse-transcriptase
inhibitors (NNRTIs)
Mechanism

When HIV infects a cell, reverse transcriptase
copies the viral single stranded RNA genome
into a double-stranded viral DNA. The viral DNA
is then integrated into the host chromosomal
DNA, which then allows host cellular processes,
such as transcription and translation to
reproduce the virus. RTIs block reverse
transcriptase's enzymatic function and
prevent completion of synthesis of the
double-stranded viral DNA, thus preventing
HIV from multiplying
Zidovudine(Azidothymidine,AZT)



AZT was the first approved treatment for HIV,
sold under the names Retrovir and Retrovis.
AZT use was a major breakthrough in AIDS
therapy in the 1990s.
AZT slows HIV spread significantly, but does not
stop it entirely.
World Health Organization. March 2005. Retrieved 2006-03-12
Tenofovir

Tenofovir disoproxil fumarate (TDF or PMPA),
marketed by Gilead Sciences under the trade
name Viread, belongs to a class of antiretroviral
drugs known as nucleotide analogue reverse
transcriptase inhibitors (NRTIs), which block
reverse transcriptase, an enzyme crucial to viral
production in HIV-infected people.
Emau P, Jiang Y, Agy MB, et al. (2006).
Efavirenz



brand names Sustiva and Stocrin
NNRTI
Unlike NRTIs, which bind at the enzyme's active
site, NNRTIs act allosterically by binding to a
distinct site away from the active site known as
the NNRTI pocket.
Ren J, Bird LE, Chamberlain PP, et al. (2002). "Structure of HIV-2 reverse
transcriptase at 2.35-A resolution and the mechanism of resistance to nonnucleoside inhibitors". Proc Natl Acad Sci USA 99 (22): 14410–15.
doi:10.1073/pnas.222366699. PMID 12386343
Protease inhibitors (PIs)
PIs prevent viral replication by inhibiting
the activity of proteases
 Protease inhibitors were the second class
of antiretroviral drugs developed.

Rang, H. P., Dale, M. M., Ritter, J. M., & Flower, R. J. (2007). Rang and Dale's
Pharmacology (6th Edition ed.). Philadelphia: Churchill Livingstone Elsevier.
Saquinavir


Saquinavir was the first protease inhibitor (and
sixth antiretroviral) approved by the Food and
Drug Administration (FDA).
HIV protease is vital for both viral replication
within the cell and release of mature viral
particles from an infected cell. Saquinavir inhibits
both HIV-1 and HIV-2 proteases.
FortovaseTM (saquinavir) soft gelatin capsules. Product information
Integrase inhibitor

Integrase inhibitors are a class of
antiretroviral drug designed to block the
action of integrase, a viral enzyme that
inserts the viral genome into the DNA of
the host cell.
Steigbigel RT, Cooper DA, Kumar PN, et al. (July 2008).
Raltegravir


Raltegravir (MK-0518, brand name Isentress)
Raltegravir targets integrase, an HIV enzyme
that integrates the viral genetic material into
human chromosomes, a critical step in the
pathogenesis of HIV. The drug is metabolized
away via glucuronidation
Savarino A (December 2006). "A historical sketch of the discovery and development of
HIV-1 integrase inhibitors". Expert Opin Investig Drugs 15 (12): 1507–22.
Entry inhibitor


Entry inhibitors, also known as fusion inhibitors
This class of drugs interferes with the binding, fusion and
entry of an HIV virion to a human cell. By blocking this
step in HIV's replication cycle, such agents slow the
progression from HIV infection to AIDS
An HIV virion binds to a CD4+ human cell.
The two bottom pictures depict two
proposed models of HIV fusion with the cell.
Biswas P, Tambussi G, Lazzarin A (2007). "Access denied? The status of coreceptor inhibition to counter HIV entry" (abstract page). Expert Opin Pharmacother
8 (7): 923–33. doi:10.1517/14656566.8.7.923. PMID 17472538
Proteins involved in the HIV entry
process.





CD4, a protein receptor found on the surface of helper T
cells in the human immune system, also called CD4+ T
cells
gp120, a protein on HIV surface that binds to the CD4
receptor
CCR5, a second receptor found on the surface of CD4+
cells, called a chemokine co-receptor
CXCR4, another chemokine co-receptor found on CD4+
cells "parang gago"
gp41, a HIV protein, closely associated with gp120, that
penetrates the cell membrane
Maraviroc


brand-named Selzentry, or Celsentri outside the U.S.
Maraviroc is an entry inhibitor. Specifically, maraviroc is
a CCR5 receptor antagonist, and binds to the chemokine
receptor CCR5 and blocks the HIV gp120 (V3 loop) from
associating with the receptor. HIV is then unable to bind
and enter human macrophages.
Levy JA (January 2009). "HIV pathogenesis: 25 years of progress and persistent
challenges". AIDS 23 (2): 147–60. doi:10.1097/QAD.0b013e3283217f9f.
PMID 19098484
CCR5-receptor antagonists

Figure 1 HIV entry into CD4+ cell via CCR5 co-receptor.
Maturation inhibitor

Maturation inhibitors inhibit the last step in gag
processing in which the viral capsid polyprotein
is cleaved, thereby blocking the conversion of
the polyprotein into the mature capsid protein.
Because these viral particles have a defective
core, the virions released consist mainly of noninfectious particles. Alpha interferon is a
currently available agent in this class. Two
additional ones under investigation are bevirimat
and Vivecon.
Alpha Interferon

Interferons (IFNs) are proteins made and
released by lymphocytes in response to
the presence of pathogens—such as
viruses, bacteria, or parasites—or tumor
cells.
Liu YJ (2005). "IPC: professional type 1 interferon-producing cells and
plasmacytoid dendritic cell precursors". Annu Rev Immunol 23: 275–306.
The Move Toward Lower Pill Burdens
Regimen
Dosing
1996
Zerit/Epivir/Crixivan
10 pills, Q8H
1998
Retrovir/Epivir/Sustiva
5 pills, BID
2002
Combivir (AZT/3TC)/EFV
3 pills, BID
2003
Viread/ Emtriva/Sustiva
3 pills, QD
2004
Truvada/Sustiva
2 pills, QD
Daily pill burden
Reading:
Thakur, D. S. et al. “Anti-HIV Agents: A Step Toward Future” International
Journal of Pharmaceutical Sciences Review and Research (2010) Vol. 3,
pp. 10-18.
Questions:






Q: What is the ETIOLOGY of AIDS?
Q: How many steps are there in the life cycle of HIV and
what are they?
Q: What is CCR5 and how it relates with HIV?
Q: In natural anti HIV agents, what structure does
prostratin have and where does it comes from and how it
possibly works?
Q: How does maraviroc works to treat HIV?
Q: Give two example of structure of classical
antiretroviral agents, and what function group do you
think is they have in common?