12th World AIDS Conference
  
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BASIC SCIENCE - TRACK A
BASIC SCIENCE - TRACK A
Summary of Thursday, 2 July, 1998

 

Thursday’s basic science sessions focused on how HIV reproduces and causes disease and on immune and therapeutic approaches to inhibit HIV replication and transmission.

  • Direct infection and destruction of CD4+ T cells by HIV may not be the only reason for CD4+ T cell decline in HIV disease. Rather, HIV may be disturbing the immune system and causing immune responses that result in damaging effects. Some have proposed that HIV causes immune responses that program cells to die rather than persist and function (i.e. undergo programmed cell death, apoptosis). In Tuesday’s basic science summary we highlighted work suggesting that direct infection of CD4+ cells alone does not adequately explain observations of immune defects in HIV disease. Rather, cells from HIV infected people did not appear to mature properly, in the thymus, in laboratory experiments. In other words, not only does HIV infect and destroy CD4+ T cells it also may interfere with the ability of new T cells to develop. While the experimental system that was set up in the laboratory may not reflect what is actually happening in a person infected with HIV, it does provide information that should be further examined in studies in people. It is important to remember that these types of alternative proposals about how HIV causes AIDS and how the immune system is damaged do not remotely suggest that HIV does not cause AIDS. Rather, they provide additional insight into the ways that HIV may be creating defects in the immune system and point the way to future directions in AIDS research.

  • Another proposal on how HIV may cause immune defects was put forward during the opening address to conference participants on Thursday morning. It was suggested that HIV cause a phenomenon called clonal exhaustion. Immune cells which seek out and destroy HIV infected cells (i.e. HIV-specific CD8+ T Cells) replicate dramatically in response to HIV infection. These cell’s ability to persist and function is highly dependent on support from chemicals (cytokines) produced by CD4+ T cells. Of course, the CD4+ T cells providing this support are activated and as such are targets for HIV infection and destruction. In other words, the cells that attack and destroy HIV infected cells appear to lack the support, from CD4+ T cells, necessary for them to fight their immunologic battle. These HIV-specific CD8+ cells initially increase in numbers and then rise to the challenge of HIV infection, but then, may attack both uninfected and infected CD4+ T cells. Thus these extremely active CD8+ cells could be a major cause of CD4+ cell destruction in HIV disease.

  • It’s important to remember, when learning about these different ideas, that they are findings made in the laboratory and may not be actually what is happening in people.

  • Understanding how HIV infects a cell and takes over the cell’s machinery in order to reproduce has lead to many strategies to inhibit HIV replication. By learning that HIV needs to undergo a process called reverse transcription in order to take over the machinery of a cell, compounds to target this process were developed. These include AZT (zidovudine, Retrovir‚ ), ddI (didanosine, Videx‚ ), ddC (zalcitibine, Hivid‚ ), d4T (stavudine, Zerit‚ ), 3TC (lamivudine, Epivir‚ ), efavirenz (Sustiva‚ ), delavirdine (Rescriptor‚ ) and nevirapine (Viramune‚ ). Similarly, by using the HIV protease enzyme HIV can assemble into viable infectious virions. This observation lead to the development of protease inhibitors. These include indinavir (Crixivan‚ ), nelfinavir (Viracept‚ ), ritonavir (Norvir‚ ) and saquinavir (fortovase‚ and invirase‚ ). In order to reproduce, obviously, viral enzymes, reverse transcriptase and protease, are critical. The virus, however, also relies on cellular factors in order to reproduce. In a featured address at today’s sessions, a drug called hydroxyurea was highlighted as a drug that inhibits cellular factors. This drug is currently widely available in the United States of America and elsewhere and is commonly used to treat a disease called leukemia. Studies of the use of hydroxyurea have moved forward and are summarized in clinical science, Track B, session highlights. This represents another example of basic science exploration leading to new approaches in therapy being tested in the clinic. A number of other new compounds are also moving forward. Particular emphasis was given to new therapies that inhibit reverse transciptase, like AZT and the other drugs mentioned previously. These include abacavir, adefovir and D-D4FC. Encouraging was news that some of these new therapies appear to penetrate tissues where HIV might hide (e.g. the brain).

  • On Thursday, several sessions today were dedicated to the future development of an AIDS vaccine. While no surprising information came to light, slow steady progress in this area of exploration continues. Of important note, much discussion took place regarding whether or not the science yet supported moving forward with human studies of vaccines which include a live, yet weakened, form of HIV itself. In unity the scientific community feels that this type of vaccine approach should not be used in humans right now. Interest was very high, however, in pursuing laboratory experiments (in animals and test tubes) of live HIV vaccines, in search of better vaccine candidates.

  • One vaccine study in humans, which involved the use of canarypox virus with an HIV protein (gp120), showed that after four vaccine shots (delivered over time) an immune response to the vaccine was evident in 40 to 70 percent of the volunteers who received it. Research was confounded by study results, however, which showed that even those who did not receive the vaccine appeared to demonstrate some of these same immune responses. Further research is necessary in order to understand and interpret these observations.

Closing comments from the rapporteurs team :
To all of you who have been reading the basic science summaries, we have striven to bring you highlights from the 12th world AIDS conference in Geneva in a way that is meaningful to the non-scientist.

It is our hope that we have been able to impart a greater understanding of major themes in basic science research and inspire an appreciation of the importance of this type of research endeavour. In many regards, basic science discovery and exploration paved the way for current advances in anti-HIV therapy and is the cornerstone for future advances.

The current progress in anti-HIV research are far from perfect and are not accessible to the majority of people living with HIV, globally. Improved understandings of HIV disease and the immune response will lead to better, hopefully more accessible, less expensive and less toxic therapies

We hope that our efforts in communicating basic research themes will inspire the community of people living with HIV/AIDS, clinician/physicians and others to engage with basic science researchers and help shape a research agenda which will accelerate the advances necessary to find a long-standing effective treatment and an effective vaccine.

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