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Finding A Cure for HIV/AIDS
Transcript of Finding A Cure for HIV/AIDS
Biotech and Bioengineering
FINDING A CURE FOR
What is HIV/AIDS?
A History of AIDS
A CURE FOR AIDS
HIV is a retrovirus
HIV - Human Immunodeficiency Virus
retrovirus - retro = backwards
Single-stranded RNA, template for DNA synthesis
Contains 2 identical molecules of RNA and 2 molecules of reverse transcriptase.
Envelope made up of 2 layers of lipids derived from host
Glycoproteins enable HIV to bind to receptors on certain leukocytes
Protein capsid encloses the virus genome
2 identical copies of RNA
2 molecules of reverse transcriptase
The Replicative Cycle of HIV
HIV releases viral proteins
into host cell
Reverse transcriptase catalyzes
the synthesis of viral RNA into DNA
Viral DNA is incorporated into
Viral DNA is transcribed into
RNA, either for next viral generation
or for translation into viral proteins
Viral proteins assemble into
new HIV virus, which buds off
How does HIV/AIDS affect the immune system?
Once inside the body HIV infects T-helper cells
Latency: the virus "hides" in the cytoplasm or chromosomes of host cell, shielded from the immune system
Over time loss of T cells leads to impairment of both humoral and cell-mediated immune responses
3 stages of HIV progression
-Catagory A: headache, muscle ache, sore throat, fever, and swollen lymph nodes within three weeks of exposure, but some are asymptomatic. Hard to detect without a blood test.
-Category B: indications of immune system failure begin. Persistent infections such as yeast infections, shingles, and certain cancerous conditions of the cervix
-Category C: AIDS. Infections occur that normally do not occur to healthy people like yeast infections of the esophagus, bronchi, and lungs; Pneumocystis pneumonia (a fungal infection); toxoplasmosis (caused by a protozoan that is spread by cats); Kaposi’s sarcoma (a rare cancer of the skin) and tuberculosis.
Overview of the immune system
Helper T cells trigger both humoral or cell-mediated responses. They bind to antigen-presenting cells – cells that display both classes of major histocompatibility complex molecules (MCH) MCH I and MCH II. The antigen-presenting cell can be a dendritic cell, macrophage, or B cell. Once a helper T cell binds to an antigen-presenting cell, it proliferates into activated helper T cells, which in turn may trigger either humoral or cell-mediated response.
Antibodies help neutralize or eliminate toxins and pathogens in the blood and lymph
Helper T cells secrete cytokines, triggering B cells.
B cells proliferate into memory B cells and plasma cells.
Plasma cells secrete antibodies that mark pathogens for destruction
HIV (the virus that causes AIDS) probably transfers from chimpanzees to humans in Africa
HIV probably enters the US
AIDS is detected in California and New York
AIDS is detected in several European
countries. Name AIDS created
Scientists identified HIV as the
cause for AIDS
AZT -first medication - for
AIDS is created
Combination antiretroviral treatment is shown to be highly effective against HIV.
22 million people are living
with HIV worldwide
The first HIV vaccine candidate to undergo
a major trial is found to be ineffective.
4 million people in developing and transitional countries are receiving treatment for HIV; 9.5 million are still in immediate need of treatment.
About 34 million people are living with AIDS worldwide
In the 1980s life expectancy for AIDS patients did not exceed a few years
Now there are 31 antiretroviral drugs approved by the FDA.
These drugs lower virus level to undetectable but do not completely eliminate the virus
AIDS is difficult to treat because HIV has high mutation rates, leading to rapid evolution of resistance to new drugs
Five Classes of Antiretroviral Drugs
Challenges to Vaccine Development
Rapid mutation rates
Chimpanzees needed as test subjects. Ethical concern
Vaccines usually trigger antibodies. But in the case of AIDS antibodies alone may not be enough. Need to trigger both humoral and cell-mediated response.
Some viral subtypes may be more common in a specific region of the world than others. Should HIV vaccines be developed for specific geographic regions?
Cons of HAART
Serious side effects such as kidney, liver, and pancreatic problems; changes in fat metabolism; increased risk for strokes and heart attacks
Chronic inflammation and immune dysfunction still persist after treatment, potentially leading to non-AIDS mortality
May not be fully suppressive.
Virus replication still persists and debilitates T cells
Hard to adhere to rigorous drug regimen
Many individuals lack access to life-long therapy
Hematopoietic-Stem-Cell-Based Gene Therapy for HIV
1.HSCs must be identified and expanded
2.HSCs must then be modified with insertion of novel gene functions
3.The selected gene functions must be able to confer HIV resistance in progeny T cells and myeloid cells (cells that are not lymphocytes)
4.The cells must be introduced into the patients safely and effectively
5.Clinical trials must demonstrate efficacy
Identification and Expansion
"True" self-renewing HSCs are found within a CD34+ population
Most successful reagent to expand HSC ex vivo is Stem-Regenin 1
Introduction of novel gene functions into HSCs
Lentivirus and foamy virus vectors integrate new genes into the DNA and have limited risk for malignant transformation.
Selection of Genes to confer resistance to HIV
CCR5 is a G-protein coupled receptor that plays a part during entry of "R5" strains of HIV
People with 2 copies of a mutation in the CCR5 gene are resistant to HIV
HIV progresses more slowly in heterozygous individuals
Goal: knock out/suppress CCR5 genes in HSCs with DNA-editing enzymes
1) Reverse Transcriptase (RT) Inhibitors interfere with reverse transcription, a critical step during the HIV life cycle when the enzyme RT converts HIV RNA to HIV DNA. There are two main types of RT inhibitors.
2) Protease Inhibitors interfere with the protease enzyme that HIV uses to produce infectious viral particles.
3) Fusion/Entry Inhibitors interfere with the virus' ability to fuse with the cellular membrane, thereby blocking entry into the host cell.
4) Integrase Inhibitors block integrase, the enzyme HIV uses to integrate genetic material of the virus into its target host cell.
5) Multidrug Combination Products combine drugs from more than one class into a single product, called highly active antiretroviral therapy (HAART). This works because even though mutations in the virus can evolve at high rate, making it resistant to treatment, it’s unlikely for the virus to develop resistance to all different drugs in the therapy at the same time.
Reece Campbell Biology 9th Edition
Cell-mediated Immune Response
T cells destroy affected host cells
Helper T cells bind to antigen
Cytotoxic T cells recognize and bind to fragments of foreign proteins produced by infected cells. Trigger apoptosis
Most prevalent in impoverished countries in Africa
Lack of access to education
Inadequate funding for prevention materials
Two-thirds of all people infected with HIV live in sub-Saharan Africa, although this region contains little more than 12 percent of the world’s population.
•Of the roughly 28 million people infected with HIV in sub-Saharan Africa, only 36,000 received drugs in 2002
Hematopoietic-Stem-Cell-Based Gene Therapy for HIV Disease
Leo Lefrançois, Ph.D.
Professor and Chairman, Department of Immunology, UCONN Health Care Center
Gerald H. Friedland, M.D.Professor of Medicine (AIDS), Yale School of Medicine
Richard Moore, MD, MHSc
Professor of Medicine and Epidemiology,
Johns Hopkins Bloomberg School of Public Health
What are your thoughts on stem cell gene therapy as treatment/cure for AIDS? Do you think it is a viable option? What is the future of HIV/AIDS research?
Answer (From Dr. Moore)
"This approach is intriguing, and may be a viable option, but is currently a relatively long way from human testing. It is likely that antiretroviral drug therapy will continue to be the most effective mode of treatment for the next 5-10 years. These drugs are not curative, but todays drugs are less toxic and easier to use than earlier antiretroviral drugs. They are also becoming much less costly as more generic formulations become available. I agree that we need a cure, and this is one of the potential ways to a cure. In the meantime, we need to increase access to antiretroviral drug therapy because of its proven benefit in viral suppression, reducing clinical disease progression and slowing transmission."