[Letter to ACT UP Treatment and Data Committee from National Institutes of Health]

Treatment and Data Committee ACT UP

2

the actual spread of HIV and hence the ultimate production of virions. The
virions themselves are then trapped in the FDC processes. Therefore, AZT or
any other antiretroviral would have its effect on cutting down the production
of virus which would then secondarily decrease the number of virions on the
FDCs since their numbers would not be constantly replenished by an ongoing
infectious process. It is important to point out at this time that we should
not focus so much on the trapping of virions as being necessarily the primary
negative component of the process in the lymph node. If viral replication is
decreased and hopefully shut off completely, then the virions would not be
trapped on the FDCs and so other cells would not come into contact with this
virus. I must point out at this time that we have not formerly proven that
the trapped virus on the FDCs are in fact infectious to other cells or whether
they serve merely as a stimulus for the ultimate degradation of the FDCs
themselves. In other words, trapping in and of itself may not be a totally
negative phenomenon. If the virus is trapped and elicits an appropriate
immune response, then this is a positive aspect of the trapping. However,
because the virus is constantly produced, it is difficult for the FDCs to rid
themselves of virus, which may be one of the major reasons why chain of events
are triggered which ultimately lead to the decline of the FDCs.
3. Studying the pathogenic mechanisms of HIV infection in the lymph
node will be important to establish the scientific basis for therapeutic
strategies. Without getting into the argument of the Concorde results versus
the U.S.A. results, I think that it is reasonable to say that we do not feel
that AZT is such a highly effective drug that we could recommend giving it at
the very earliest possible time when you find out that someone is HIV infected
regardless of their CD4 count. We would need a clinical trial to answer that
question. However, it is important to understand when it would be appropriate
to start therapy when we do in fact have a highly effective therapy.
Therefore, the fact that we do not have a highly effective drug at this point
does not have any impact on our work since it is still necessary to fully
delineate the mechanisms which will help us make a decision when better drugs
do come along.
4. Certainly we are considering other alternatives. I firmly believe
that we should take a multifaceted approach towards the therapy of HIV.
Included in this should be the best anti-retroviral agents we have as well as
other drugs which may have impact on the pathogenesis. For example, we know
that cytokines are highly potent in upregulating HIV expression. Therefore,
agents which can selectively block certain cytokines should certainly be used
in clinical trials. Pentoxyphilin does block TNF production and the effect of
TNF on HIV infected cells. In this regard, there is a clinical trial ongoing
with the use of pentoxyphilin. N-acetyl cysteine (NAC) can block the
induction of HIV expression but can only do so at extremely high doses. NAC
may have another effect (as I am sure you are aware) of replenishing low
levels of glutathione in the immune competent cells. NAC has already been
used in a phase I clinical trial. Either NAC will go to a phase II trial or
another drug such as procystine which is similar in it's effect will be used
to test some of these alternative approaches.
5. It is unclear why the virus is not degraded. It very well may be
that virus is slowly degraded by being phagocytized off the FDC processes by