Immunotherapy for Infectious Diseases

Host Cell-Directed Approaches 225
sponding to segments of gp41 have been shown to disrupt the folding and unfolding
of the gp41 tertiary structure necessary for membrane fusion to occur. A 36-amino acid
peptide, T-20, was found to be a particularly potent inhibitor of HIV-1 in vitro. This
agent demonstrated a 50% inhibitory concentration (IC 50) of 1.7 ng/mL in T-cell lines
(60). In the first clinical trial of a peptide fusion inhibitor, intravenous T-20 resulted in
significant, dose-related declines in plasma HIV RNA levels (25). There was an approx.
99% reduction in viral load during short-term T-20 administration in the four subjects
in the highest dose group tested (100 mg twice daily). An analysis of viral dynamics
showed that the initial slope of virus decline, a measure of antiretroviral potency, was
comparable to that achieved with other approved HIV therapies including three- and
four-drug combinations of reverse transcriptase and protease inhibitors. The second
clinical trial of T-20, recently completed, involved 78 subjects enrolled at multiple sites
around the United States (61). This trial allowed heavily pretreated patients to add
T-20 therapy to their preexisting oral antiretroviral regimens. Over a 28-day administration
period, dose-related reductions in plasma HIV RNA levels were demonstrated that
confirmed the findings in the phase I trial. Thus, these findings provide proof of concept
that therapeutics targeting a viral entry event can result in safe and clinically
meaningful inhibition of viral replication. However, this approach to blocking viral
entry is not directly aimed at a conserved host target, as exemplified by the suggestion
that selection for resistant viral variants is possible (62,63).
TARGETING CELL ACTIVATION STATE
Closely related to direct inhibition of HIV cell entry is the concept of modulating
host cell activation status, to influence the progression of disease favorably. It has been
recognized for many years that activated lymphocytes are more susceptible to HIV
infection than resting or quiescent cells (64). Nonspecific T-cell stimulation factors,
such as phytohemagglutinin and interleukin-2 (IL-2), are routinely utilized in the laboratory
to increase HIV infectivity in cell culture experiments. Clinical trials evaluating
IL-2 infusions as a strategy to increase absolute CD4 numbers (see below)
demonstrated that some patients receiving inadequate antiretroviral therapy had bursts
of viremia corresponding to the immunoactivation state induced by potent T-cell stimulation
(65). Possible clinical correlates include observations that nonspecific antigenic
stimulation, such as routine influenza (66), pneumococcal (67), or tetanus toxoid (68)
vaccinations, may transiently stimulate HIV replication in the absence of adequate antiretroviral
suppression. Such effects have not been demonstrated among patients effectively
suppressed on HAART. Similarly, there appear to be temporary increases in
plasma viral load when patients develop opportunistic infections, despite adherence to
antiretroviral medications (69,70). These bursts of viral activity subside as concomitant
infections are treated.
Although immunosuppressive therapy is obviously not an attractive option for widespread
use among patients with acquired T-cell deficiency, preliminary studies have
been carried out to explore the potential for limiting T-cell activation as a therapeutic
strategy. Particularly in the pre-HAART era, such approaches were frequently a last
resort for palliative reasons when conventional therapeutic options had been exhausted.
Pilot studies explored the safety and feasibility of using agents such as pentoxyfylline
(71,72) and thalidomide (56,73) as inhibitors of tumor necrosis factor (TNF) to limit