Immunotherapy for Infectious Diseases

Active Immunization for HIV Infection 185
One hypothesis that would explain the lack of T-helper function after HIV infection
would be the deletion of activated CD4� T-cells during the earliest stages of acute
infection. Alternatively, these cells may undergo activation-induced cell death owing to
overstimulation at the time of maximum virus load (57). The result would be a lack of
CD4 T-cell help, and therefore inadequate help to maintain CTLs with optimal function.
In a manner similar to that seen in the LCMV model, CTLs may then be unable
to protect against new viral variants that arise, or be unable to expand to sufficient levels
to suppress viremia even in the absence of escape mutations (56,58).
Immune Escape
Escape from established immune responses is likely to be a major factor for HIV disease
progression, since the infidelity of the viral reverse transcriptase results in rapid generation
of viral mutations, and viral diversity may be a substantial hurdle for HIV-specific
immunotherapies. Even a single mutation within a defined CTL epitope can be sufficient
to abrogate CTL recognition, either by altering residues that are critical for contact with
the TCR or that are necessary for peptide binding to the HLA class I molecule. Some
longitudinal studies have demonstrated escape from CTL recognition over the course of
HIV infection (59), or after adoptive transfer of HIV-specific CTLs (60). Other studies
have demonstrated that for some epitopes, lack of HLA binding may be a major reason
for the lack of CTL recognition (61). However, this is not a universal finding, and some
mutations within CTL epitopes can be cross-recognized by HIV-specific CTLs (62,63).
Although mutations within viral regions flanking CTL epitopes may be another potential
mechanism for immune escape, this has not been demonstrated in studies thus far (64).
Successful approaches to immune-based therapy may need to target HIV-1 epitopes
that are relatively conserved (65); unfortunately, there are few available data describing
CTL epitopes that do not tolerate variation. Immune-based therapy may be much
more successful in subjects identified shortly after acute infection, when the viral quasispecies
diversity is much more limited (66), but this would limit the number of subjects
that could be treated. Current approaches will rely on augmenting helper and CTL
responses in subjects already suppressed on HAART in the hope that CTL responses
able to recognize HIV variants will be able to suppress viral replication in the presence
of adequate helper responses, or that in the presence of adequate help new CTL
responses able to recognize potential escape variants will be generated.
IMMUNE RECONSTITUTION IN THE ERA OF HAART
Infection with HIV is associated with destruction of the thymic and lymph node
architecture (67), and before the advent of HAART there was speculation that irreversible
damage might occur early after infection. Since the introduction of HAART,
there is now hope that the immune system has the ability to recover after suppression
of viral replication, which is reflected in the dramatic decrease in the incidence of
opportunistic infections after successful HIV-specific therapy. The immune recovery
inflammatory syndromes that have been described reflect the restoration of immunity
against opportunistic infections. One report described five subjects with CD4 cell
counts below 50 cells/mm 3 who developed fever and severe lymphadenitis 1–3 weeks
after beginning indinavir therapy. Lymph node biopsies showed focal lymphadenitis
caused by unsuspected Mycobacterium avium complex infection, which was probably