Immunotherapy for Infectious Diseases

Host Cell-Directed Approaches 223
CD8 T-cells in the control of viral load is also supported by a recent investigation
involving SIV-infected rhesus macaques. Deletion of CD8� cells via the administration
of monoclonal antibodies prompted a rapid increase in viremia (28,29), strongly
implying that an active immune response is maintaining the viral load set point.
All currently approved therapies for HIV infection target a viral enzyme (either
reverse transcriptase or protease). If viral replication could be safely inhibited by targeting
a host element, this would provide several theoretical advantages. In many
instances, host factors in general may be more conserved throughout the population
compared with the highly variable and changeable nature of viral proteins. Unlike the
rapidly growing and genetically unstable virus quasispecies, host factors would not
be predicted to respond quickly to drug pressure in the selection process for drugresistant
variants. Treatment strategies directed at host cells have the potential to be
synergistic with antiviral regimens, while minimizing risks of cross-resistance or shared
toxicities with drugs from the currently available therapeutic classes. A key unanswered
question is which host factors, if any, can be successfully targeted by therapeutic
interventions. We describe several potential approaches to host cell-based
therapies: blocking host cell entry, modulating the immune activation state, increasing
absolute lymphocyte cell counts, increasing the clearance of the latently infected cell
pool, and enhancing immune control over viral replication. Based on the diverse lines
of evidence outlined above and the suggestion that viral suppression alone is insufficient
in the quest for a cure, researchers have recently focused particular attention on
the latter strategy: stimulation of HIV-specific cellular immune responses in addition
to striving for complete viral suppression with HAART (30–32).
TARGETING CELL ENTRY
A logical therapeutic strategy is to intervene at the level of the initial interactions
between HIV and target cells. Theoretically, successfully targeting the process of viral
entry into host cells would provide certain advantages over drugs that inhibit viral
enzymes brought into play in the later steps of the viral life cycle. For more than a
decade, it has been known that a critical initial step in the viral entry process is the
binding of portions of the HIV surface glycoprotein (gp120) to the CD4 receptor,
expressed primarily on T-helper lymphocytes. In 1988, in vitro data suggested that
recombinant, soluble CD4 could competitively inhibit HIV infection and syncytium
formation, presumably by acting as a decoy and binding to gp120 in place of susceptible
CD4-expressing T-cells (33–36). However, clinical trials did not demonstrate any
antiviral effects in vivo (37). Another series of in vitro studies in 1988 suggested the
potential for sulfated polyanionic substances to interfere nonspecifically with the binding
of HIV to T-cells, resulting in potent inhibition of viral replication (38–40). Unfortunately,
clinical trials were unsuccessful owing to poor absorption of oral dextran
(41,42) and severe adverse events related to intravenous dextran (43).
Between 1995 and 1997, a number of investigative groups reported that
�-chemokines and their derivatives had a significant inhibitory effect on viral replication
in vitro (44–47). The initial observations occurred at a time when the CD4 receptor
was the only well-characterized cell entry mechanism for HIV. More than a decade
after the identification of the key interactions between HIV and the CD4 receptor, it is
now clear that HIV must bind to two distinct molecules on the cell surface before it