HIV = Human Immunodeficiency Virus • HIV is an RNA virus which contains two identical strands of (+)ssRNA in its capsid. • HIV is a retrovirus (i.e. viral RNS serves as template for the synthesis of a complementary DNA) • HIV infection usually progresses to AIDS
AIDS = Acquired Immunodeficiency Syndrome. • This stage of HIV infection is usually characterized by opportunistic diseases, including Pneumocystis carinii pneumonia, Kaposi sarcoma, cytomegalovirus disease, etc.
HIV-1 is responsible for AIDS in America, Europe, and Asia • HIV-2 occurs mainly in western Africa • At present, anti-HIV drugs are aimed at two targets: reverse transcriptase and HIV protease.
Good animation of HIV-1 Lifecycle: • http://www.sumanasinc.com/webcontent/animations/content/lifecyclehiv.html • Link
Introduction to HIV treatment:Resistance • http://biocreations.com/animations/english_HIV/main.swf
HIV Lifecycle and Opportunities for New Therapeutic Agents • http://www.roche-hiv.com/portal/eipf/pb/hiv/Roche-HIV/demonstrationoffusioninhibition
Treatment of HIV • When HIV replicates (makes new copies of itself) it often makes mistakes. • Taking two or more antiretrovirals at the same time vastly reduces the rate at which resistance develops • The term Highly Active Antiretroviral Therapy (HAART) is used to describe a combination of three or more anti-HIV drugs.
Treatment of HIV • Current classes of antiretroviral drugs include: • Nucleoside/Nucleotide Reverse Transcriptase Inhibitors • Non-Nucleoside Reverse Transcriptase Inhibitors • Protease Inhibitors • Fusion or Entry Inhibitors • Integrase Inhibitors
Nucleoside/Nucleotide Reverse Transcriptase Inhibitors • These were the first type of drug available to treat HIV infection in 1987. • NRTIs (also known as nucleoside analogues or nukes) interfere with the action of an HIV protein called reverse transcriptase, which the virus needs to make new copies of itself. • NRTIs are sometimes called the "backbone" of combination therapy because most regimens contain at least two of these drugs.
Antiretroviral Agents Currently Available (generic name/Trade name) Nucleoside Analogs (NRTI’s) • zidovudine/Retrovir(AZT, ZDV) • didanosine/Videx, Videx EC (ddI) • zalcitabine/HIVID (ddC) • stavudine/Zerit (d4T) • lamivudine/Epivir (3TC) • abacavir/Ziagen (ABC)
Nucleoside Reverse Transcriptase Inhibitors (NRTI’s) didanosine/Videx, Videx EC (ddI) zalcitabine/HIVID (ddC) Zidovudine/Retrovir (AZT, ZDV)
Nucleoside Reverse Transcriptase Inhibitors (NRTI’s) Stavudine/Zerit (d4T) Lamivudine/Epivir (3TC) Abacavir/Ziagen (ABC)
Nucleotide Reverse Transcriptase Inhibitor Tenofovir disoproxil fumarate
Mechanism of action of AZT • Link • Link
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI’s) • Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs), started to be approved in 1997. • Like the Nucleoside Inhibitors, NNRTIs (also known as non-nucleosides) stop HIV from replicating within cells by inhibiting the reverse transcriptase protein.
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI’s) • nevirapine/Viramune (NVP) • delavirdine/Rescriptor (DLV) • efavirenz/Sustiva (EFV) • NNRTI’s are generally hydrophobic molecules that bind to an allosteric binding site • Binding to this allosteric site locks the neighboring substrate-binding site into an inactive conformation. • However, resistance to NNRTI’s can develop rapidly, and thus they are used in combination with NRTI’s • Link
Protease Inhibitors • indinavir/Crixivan • ritonavir/Norvirs • aquinavir/Invirase, Fortovase • nelfinavir/Viracept • amprenavir/Ageneras • elopinavir/ritonavir, Kaletra
Modeling an inhibitor after the transition state may result in a tighter-binding inhibitor But the actual transition state (in box above) is chemically unstable, so a number of more stable “transition state isosteres” have been devised.
HIV Protease Inhibitors Indinavir/Crixivan
HIV Protease Inhibitors Ritonavir/Norvir
HIV Protease Inhibitors Nelfinavir/Viracept
Tipranavir Tipranavir, or tipranavir disodium, is a nonpeptidic protease inhibitor (PI) manufactured by Boehringer-Ingelheim under the trade names Aptivus®. It is administered with ritonavir in combination therapy to treat HIV infection and is given as two 250mg capsules together with 200mg of ritonavir twice daily.
Tipranvir • Tipranavir has the ability to inhibit the replication of viruses that are resistant to other protease inhibitors and it recommended for patients who are resistant to other treatments. Resistance to tipranavir itself seems to require multiple mutations.
Animation of tipranavir, a new HIV protease inhibitor • http://biosingularity.wordpress.com/2007/07/04/super-3d-animation-that-shows-the-mode-of-action-of-an-hiv-drug
Fusion or Entry Inhibitors • Entry inhibitors prevent HIV from entering human immune cells. • There are several key 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 coreceptor • CXCR4, another chemokine coreceptor found on CD4+ cells • gp41, a HIV protein, closely associated with gp120, that penetrates the cell membrane
Approved Entry Inhibitors • Maraviroc (brand-named Selzentry, or Celsentri outside the U.S.) • Enfuvirtide (INN) is an HIV fusion inhibitor, It is marketed under the trade name Fuzeon (Roche).
Maraviroc • Approved in April, 2007 and marketed by Pfizer