MCB 720
Virology Practicum
HIV Life Cycle
Colored slide: H-72
WBCs
CDC Classification System for HIV-Infected Adults
and Adolescents
Clinical Categories
CD4 Cell Categories
Asymptomatic,
Acute HIV, or PGL
A.
B. Symptomatic
C. AIDS-Indicator
Conditions*
Conditions, #* not A
or C
(1) ≥500 cells/µL
A1
B1
C1
(2) 200-499 cells/µL
A2
B2
C2
(3) <200 cells/µL
A3
B3
C3
Key to abbreviations:
CDC = U.S. Centers for Disease Control and Prevention;
PGL = persistent generalized lymphadenopathy.
# For symptomatic conditions, see Table 2 .
* For AIDS-indicator conditions, see Table 3 .
HIV Classification:
CDC and WHO Staging Systems
July 2006
HIV Life Cycle
Atripla (Sustiva/Viread/Emtriva) – Approved July 11th, 2006
Replication
The replication process is catalyzed by an
enzyme; DNA dependent DNA polymerase
2-deoxy Thymidine and AZT
2-deoxythymidine
Zidovudine or azidothymidine (AZT)
Virus release and maturation
Viral Protease
Polypeptide
cleavage
160
Cellular
protease
Polypeptide cleavage
Viral
Protease
Polypeptide cleavage
Viral
Protease
Polypeptide cleavage
Viral ‘Env’ proteins
(gp120, gp41)
Viral ‘Gag’ Proteins
(p17, p24, p9, p6)
Viral ‘Pol’ proteins
(Reverse Transcriptase, RNAse,
Integrase, Protease)
HIV Protease Inhibitors
•
•
Aspartyl protease
Interrupts the viral replication
cycle and suppresses new rounds of
infection
 Examples:
 Invirase (squinavar) – Roche
Fortovase (squinavar) –Roche
Crixivan (indinavar) – Merck
Norvir (ritonavir) – Abbott
Viracept (nelfinavir) – Roche
Agenerase (amprenavir) – Glaxo Welcome
Novir
Viracept
Crixivan
DESCRIPTION
REYATAZ® (atazanavir sulfate) is an azapeptide
inhibitor of HIV-1 protease.
The chemical name for atazanavir sulfate is
(3S,8S,9S,12S )-3,12-Bis(1,1-dimethylethyl)-8hydroxy-4,11-dioxo-9-(phenylmethyl)6-[[4-(2-pyridinyl)phenyl] methyl]2,5,6,10,13-pentaazatetradecanedioic acid
dimethyl ester, sulfate (1:1). Its
molecular formula is C38H52N6O7•H2SO4,
which corresponds to a molecular weight of
802.9 (sulfuric acid salt). The free base
molecular weight is 704.9. Atazanavir sulfate
has the following structural formula:
Mechanism of Action
Atazanavir (ATV) is an azapeptide HIV-1 protease
inhibitor (PI). The compound selectively inhibits
the virus-specific processing
of viral Gag and Gag-Pol polyproteins in HIV-1
infected cells, thus preventing formation of
mature virions.
Reyataz is manufactured by Bristol-Myers
Squibb and was approved for the treatment
of HIV by the U.S. FDA in 2006.
DESCRIPTION
FUZEON (enfuvirtide) is an
inhibitor of the fusion of HIV-1
with CD4+ cells. Enfuvirtide is
a linear
36-amino acid synthetic
peptide with the N-terminus
acetylated and the C-terminus
is a carboxamide.
It is composed of naturally
occurring L-amino acid
residues.
Mechanism of Action
Enfuvirtide interferes with
the entry of HIV-1 into cells
by inhibiting fusion of viral
and cellular
membranes. Enfuvirtide binds
to the first heptad-repeat
(HR1) in the gp41 subunit of
the viral
envelope glycoprotein and
prevents the conformational
changes required for the
fusion of viral
and cellular membranes.
2006
gp120
gp41
CD4
CCR5
Emini, E. & Koff, W.C. Developing an AIDS vaccine; Need, Uncertainly, Hope.
Science, 304: 1913, 2004
Maraviroc – CCR5 blocker
•
Pfizer Gets the Nod from FDA for First-in-Class HIV Drug
Aug 7 2007, 12:53 PM EST
•
FDA has given Pfizer the go-ahead for its first-in-class HIV medication, maraviroc. The
company expects that the drug, which will be sold under the trade name Selzentry, will be
available in the U.S. by the middle of September.
•
•
•
•
•
After receiving a unanimous vote of support from an FDA advisory committee in April, the
agency stalled by sending Pfizer an approvable letter in June. The final sanction of the
drug drove Pfizer’s shares up 60 cents, or 2.6%, to $24.11 at 4:01 p.m. in New York Stock
Exchange composite trading.
Pfizer is awaiting approval from the EMEA and is submitting marketing applications to
other regulatory bodies. On June 20, an EMEA advisory committee vouched in favor of
maraviroc, which will be sold in the EU as Celsentri.
Rather than fighting HIV inside white blood cells, maraviroc prevents the virus from
entering uninfected cells by blocking the predominant route of entry, the CCR5 coreceptor. Among patients who have previously received HIV medications, approximately
50% to 60% have circulating CCR5-tropic HIV-1, according to the FDA.
•
The agency granted accelerated approval to Selzentry in combination with other
antiretroviral drugs in adults with CCR5-tropic HIV-1 who have been treated with other
HIV medications and who have evidence of elevated levels of HIV in their blood. A
diagnostic test is required to confirm whether a patient is infected with CCR5-tropic
HIV-1, which is also known as R5 virus.
•
Longer-term data will be required before the FDA can consider traditional approval for
Selzentry, Pfizer notes.
CD4+ T cell
Integrase Inhibitor
•
Merck & Co. Gets the Green Light for HIV Treatment in EU
Dec 21 2007, 12:38 PM EST
•
The European Union Commission approved Merck & Co. first-in-class HIV therapy
Isentress® (Raltegravir). The drug will be marketed for use in combination with
other antiretroviral products against HIV-1 infection in treatment-experienced
adults with evidence of HIV-1 replication despite ongoing antiretroviral therapy
(ART).
•
The commission’s decision is applicable to the 27 member states of the EU.
Separate national licenses will also be issued in European Economic Area member
states Iceland and Norway, according to Merck, also known as Merck Sharp &
Dohme (MSD) in some countries.
•
Isentress is already sanctioned in North America. MSD says that it is also
moving forward with filings in other countries around the world.
•
Isentress is the first approved integrase inhibitor. It inhibits the insertion of
the HIV DNA into human DNA by the integrase enzyme. Inhibiting integrase
from performing this essential function blocks the ability of the virus to
replicate and infect new cells. Other drugs target the other two enzymes
critical to HIV replication, protease and reverse transcriptase. Pfizer’s
Maraviroc, on the other hand, which received FDA approval in August, blocks the
CCR5 co-receptor.
“Raltegravir is an important new advancement in the treatment of HIV because
it is the first therapy in a new class of drugs that attacks the virus in a
completely different way from other available medicines,” notes Ken Frazier, evp
and president, global human health, Merck.
•
Combination Treatment
NYSE | BMY 24.79 | +0.23 | 1:30 PM EDT | 17 Jul
2006
Top Story
FDA Approves
ATRIPLA™ (efavirenz 600 mg/ emtricitabine 200 mg/ tenofovir disoproxil
fumarate 300 mg), The First Once-Daily Single Tablet Regimen For Adults With
HIV-1 Infection
Princeton, NJ and Foster City, CA (July 12, 2006) -- Bristol-Myers
Squibb Company (NYSE: BMY) and Gilead Sciences, Inc.
(Nasdaq: GILD) today announced the U.S. Food and Drug
Administration (FDA) has granted approval of ATRIPLA™
(efavirenz 600 mg/ emtricitabine 200 mg/ tenofovir disoproxil
fumarate 300 mg) for the treatment of HIV-1 infection in adults.
ATRIPLA is the first-ever once-daily single tablet regimen (STR)
for HIV intended as a stand-alone therapy or in combination
with other antiretrovirals. The product combines SUSTIVA®
(efavirenz), manufactured by Bristol-Myers Squibb, and
Truvada® (emtricitabine and tenofovir disoproxil fumarate),
manufactured by Gilead Sciences. Truvada itself is a fixed-dose
product that contains two of Gilead's anti-HIV medications,
Viread® (tenofovir disoproxil fumarate) and Emtriva®
(emtricitabine), in a single once-daily tablet for use as part of
combination therapy. ATRIPLA will be available in the United
States within seven business days.
Atripla (Sustiva/Viread/Emtriva) – Approved July 11th, 2006
www.stanford.edu/.../2005gongishmail/HIV.html
HIV Life Cycle
with Drug Targets
Dideoxynucleoside HIV Drugs
AZT – Retrovir
ddI – videx
ddC – Hivid
d4T – Zerit
3TC - Epivar
Dideoxynucleotides
Non-nucleoside Reverse
Transcriptase Inhibitors (NNRTI)
• Non-competitive inhibitors of RT
• Can synergize or be additive to NA
• Examples:
–
–
–
–
TIBO
Neviapine
Pyridones
Atevirdine (BHAP)
Rapid Development of Drug Resistance
Drugs for HIV
• Protease Inhibitors
Activity of the HIV Protease
How Protease
Inhibitors Work; Their
Mechanism of Action
This article was provided
by San Francisco
General Hospital.
It is a part of the publication
HIV Newsline, June, 1996
HIV Life Cycle
Colored slide: H-91
HIV Drugs in the Pipeline
Approved
Oct, 2007
HIV Life Cycle
Group 1
Group 3
Group 2
Table 2.
CDC Classification System:
Category B Symptomatic Conditions
•
Category B symptomatic conditions are defined as symptomatic conditions occurring in
an HIV-infected adolescent or adult that meet at least 1 of the following criteria:
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–
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•
•
•
•
•
•
•
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a) They are attributed to HIV infection or indicate a defect in cell-mediated immunity.
b) They are considered to have a clinical course or management that is complicated by HIV
infection.
Examples include, but are not limited to, the following:
Bacillary angiomatosis
Oropharyngeal candidiasis (thrush)
Vulvovaginal candidiasis, persistent or resistant
Pelvic inflammatory disease (PID)
Cervical dysplasia (moderate or severe)/cervical carcinoma in situ
Hairy leukoplakia, oral
Idiopathic thrombocytopenic purpura
Constitutional symptoms, such as fever (>38.5°C) or diarrhea lasting >1 month
Peripheral neuropathy
Herpes zoster (shingles), involving ≥2 episodes or ≥1 dermatome
Table 3. CDC Classification System:
Category C
AIDS-Indicator Conditions
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•
•
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Bacterial pneumonia, recurrent (≥2 episodes in 12 months)
Candidiasis of the bronchi, trachea, or lungs
Candidiasis, esophageal
Cervical carcinoma, invasive, confirmed by biopsy
Coccidioidomycosis, disseminated or extrapulmonary
Cryptococcosis, extrapulmonary
Cryptosporidiosis, chronic intestinal (>1-month duration)
Cytomegalovirus disease (other than liver, spleen, or nodes)
Encephalopathy, HIV-related
Herpes simplex: chronic ulcers (>1-month duration), or bronchitis, pneumonitis, or esophagitis
Histoplasmosis, disseminated or extrapulmonary
Isosporiasis, chronic intestinal (>1-month duration)
Kaposi sarcoma
Lymphoma, Burkitt, immunoblastic, or primary central nervous system
Mycobacterium avium complex (MAC) or M kansasii , disseminated or extrapulmonary
Mycobacterium tuberculosis , pulmonary or extrapulmonary
Mycobacterium , other species or unidentified species, disseminated or extrapulmonary
Pneumocystis jiroveci (formerly carinii ) pneumonia (PCP)
Progressive multifocal leukoencephalopathy (PML)
Salmonella septicemia, recurrent (nontyphoid)
Toxoplasmosis of brain
Wasting syndrome due to HIV (involuntary weight loss >10% of baseline body weight) associated with either
chronic diarrhea (≥2 loose stools per day ≥1 month) or chronic weakness and documented fever ≥1 month