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.
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, Retrovirâ ), ddI
(didanosine, Videxâ ), ddC (zalcitibine, Hividâ ), d4T (stavudine, Zeritâ ), 3TC
(lamivudine, Epivirâ ), efavirenz (Sustivaâ ), delavirdine (Rescriptorâ ) and
nevirapine (Viramuneâ ). 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 (Crixivanâ ), nelfinavir (Viraceptâ ), ritonavir
(Norvirâ ) and saquinavir (fortovaseâ and inviraseâ ). 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.
|
back
want more?
