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6 & 7

Terms in this set (75)

vaccine to block HIV infection is ideal prevention method
• vaccines for human viruses (smallpox, polio, measles, influenza)
may be difficult to develop an effective HIV vaccine
• HIV evades the immune system in an infected individual
• high mutation rate of the virus, particularly env gene
• ability of the virus to establish a latent state in some cells
• ability of the virus to spread by cell-to-cell contact

vaccine must raise protective immune response
• HIV evades the immune system so efficiently
• difficult for vaccine to prevent HIV infection
• differences in HIVs found in various parts of the world
• targeted geographical vaccines will probably be necessary

HIV vaccines under development
• large-scale production of viral proteins
• env proteins (e.g., gp120) & gag protein

• clinical trials: most raise anti-HIV antibody responses but fail to protect from infection
vaccine research focused on SIVs
• closely related to HIV
• some strains cause AIDS in monkey species
• chimpanzees are only monkeys HIV can infect
• virus does not readily cause AIDS in animals
• test analogous SIV vaccines in rhesus monkeys
• inhibition of SIV infection or disease
• killed SIV virus vaccine→protection against
low levels virus

• humoral immune system produces antibody molecules
cellular immune system produces antigen-specific T-cells
• most original anti-HIV vaccines induce antibody responses
• cellular immunity to HIV is important for resistance to HIV
vaccines need to induce cellular immunity to HIV
• live viruses more likely to induce cellular immunity
attenuated virus: infect without disease (Sabin poliovirus vaccine)
• some attenuated SIVs act as vaccines in laboratory settings
• attenuated HIV vaccine not pursued: safety concerns
• mutation in the vaccinated person→could cause AIDS
• genetic engineering: introduce HIV genes into other attenuated virus strains

first steps for vaccine trials
• do test vaccines induce antibodies (or other immune response)
• are there any harmful side effects (phase I clinical trials)
• proper dose to produce an immune response
• other large-scale trials test if vaccine prevents HIV infection
Testing an HIV vaccine in humans
• bioethical issues involved in using humans
• trials must consider scientific, human & societal aspects
2009: clinical trial conducted by U.S. Army in Thailand
• attenuated smallpox virus that expresses HIV protein
• followed by "booster" with HIV envelope protein
• modest prevention of infection may have occurred
• if confirmed, it establishes proof of concept = a vaccine against HIV can be developed
steps between compound identification and drug approval:
1. How can effective doses of the compound be delivered?
2. Are there side effects (toxicity), and can effective doses be delivered without side effects?
3. Does the compound inhibit HIV replication in humans?
4. Is compound as or more effective than available drugs?
• must satisfy these questions for approval:
•-enormous amount of effort
•-enormous amount of time (5-10 years)
•-enormous amount of money (billions of dollars)
•-many compounds with laboratory activity aren't usable as drugs
•high cost associated with developing a new drug is reflected in the final cost of the drug to the user

• laboratory experiments identify a potential antiviral compound with promise as an anti-HIV drug
• Phase I clinical trials: (often using uninfected individuals)
• small number of individuals
•-determine safety of the compound (toxicity or side effects)
•-methods to deliver useful concentrations of drug into body
•-do not test for effectiveness of the compound
Phase II clinical trials: (HIV-infected individuals)
• limited size, test the compound's effectiveness (efficacy)
• may be measured by a reduction in
•-laboratory measures of viral infection (decrease in virus)
•-increase in measures of immune function (increase in CD4 cells)

Phase III clinical trials:
• large-scale efficacy trials of a compound
• typically conducted in multiple locations
• efficacy of compound is compared with efficacy of currently
available therapies
• must show efficacy before compounds receive FDA approval

• improvements in existing formulations of drugs
current combination therapies for HIV are complicated
• adhere to strict routines
• time-release capsules decrease number of times drug taken
HIV infection likely requires lifelong treatment
• interfere with the ability of the virus to enter cells
• potential class of antivirals
• inhibit entry process→inhibit spread
new classes of drugs:
• "fusion inhibitor" Fuzeon (or T-20)
•-blocks infection by inhibiting entry of virus core into cell
• maraviroc blocks CCR5 interaction with HIV
•-prevents initial infection & spread
AIDS facts and statistics are frightening & depressing because a cure has not been developed yet
• infected individuals develop AIDS 10-12 years after infection
• therapies developed in 5-10 years may help current infections
rate of scientific progress in epidemics
• plague (black death)
•-epidemics as early as the fifth or sixth century
•-well-documented deaths in 14th and following centuries
•-agent (Yersinia pestis) isolated in 1894
•-therapy = development of classical antibiotics in the 1940s
• recognized as an epidemic disease in the 1880s
• infectious agent (poliovirus) isolated in the late 1940s
• disease brought under control by development of polio vaccines (1955)

• disease first recognized in 1981
• causative agent (HIV) was isolated in 1983-1984
• AZT developed by end of 1986, in wide use in 1987
• protease inhibitors & triple therapies introduced in 1996
• introduction of ART has led to a decrease in the rate of death from AIDS
• US: 45% decrease in deaths from AIDS in the first half of 1997
•-does not mean that number of HIV-infected people has decreased
•-does not mean that rate of new HIV infections has decreased
• ART inhibits progression of HIV-infected people to AIDS
rate of progress in AIDS research has actually been very rapid in historic terms

• new approaches to further reduce rate of AIDS deaths
• decrease in AIDS deaths requires access to antiviral drugs
• progress in AIDS research
•-molecular biology, virology & immunology advances last 40 years
•-retrovirus life cycle worked out (1970s-1980s) after discovery of reverse transcriptase
•-understanding different kinds of lymphocytes
•-techniques to identify CD4 on T-helper cells is >30 years old
•-advances helped rapid progress in AIDS research
this is why funding basic scientific research is critical to human health
new effective solutions to HIV/AIDS will be developed in the not-too-distant future