Immunotherapy for Infectious Diseases

Immune Reconstitution with Antiretroviral Chemotherapy 169
cyte proliferative responses after 1 year of HAART therapy (77). The selective failure of
tetanus responses to increase is probably owing to the infrequency of exposure to tetanus
compared with Candida, CMV, MAC, and MTB, to which individuals are probably reexposed
endogenously. Indeed, a tetanus booster vaccination given to subjects after 1 year
of HAART therapy resulted in reconstitution of tetanus-specific lymphocyte proliferative
responses (117), suggesting that antigen-specific precursors had not been completely eliminated
in these subjects, but only depleted. These findings suggest that HAART improves
the immune system’s ability to respond to antigen on exposure but that HAART does not
reconstitute preexisting responses in the absence of reexposure. Thus, the rejuvenated
immune system on HAART is not identical to the one prior to HIV-1 infection.
Delayed-type hypersensitivity (DTH) skin test responses are lost in chronic HIV-1
infection and are prognostic of disease progression independently of CD4� T-cell
count and lymphocyte proliferative responses (112,118). DTH responses to Candida
and mumps were found to be recovered in adults with moderately advanced HIV-1 disease
after 1 year of treatment with HAART (77). However, the recovery of responses
was asynchronous; Candida responses were restored within 12 weeks of therapy,
whereas mumps responses only increased after 12 weeks of therapy. One interpretation
of these findings is that HAART reconstituted the booster phenomenon (119) such that
the mumps skin test at week 12 boosted preexisting mumps-specific memory cells,
resulting in subsequent positive DTH responses. These findings support the hypothesis
that reexposure to antigen is necessary to reconstitute functional immune responses.
Although improvements in functional immunity in individuals treated with HAART
have been demonstrated by numerous studies, few studies have actually compared
these reconstituted responses with those in HIV-1-seronegative individuals. Lymphoproliferative
responses to Candida normalized relative to HIV-1-seronegative individuals
in one study (77). However, although lymphoproliferative responses to tetanus
toxoid as well as keyhole limpet hemocyanin increased in HAART-treated HIV-1infected
individuals after vaccination, they were still significantly lower than those in
HIV-1-seronegative controls who received the same vaccines (117).
A study of pneumococcal vaccination in HIV-1 infected individuals receiving
HAART found that antibody responses were poor, regardless of the degree of virus
suppression on HAART (120). In contrast, antibody responses to pneumococcal vaccination
in recent HIV-1 seroconverters have been reported to be equivalent to those in
HIV-1-seronegative individuals (121), suggesting that chronic untreated HIV-1 infection
may induce a long-term deficit in immune responsiveness that cannot be completely
reversed by HAART. HAART regimens themselves may impair immune
responsiveness. Protease inhibitors have been shown to exhibit an antiproliferative
effect on human cells in vitro (122) and also to impair antigen presentation and CTL
activity in mice (123). Thus, functional immune reconstitution is substantial, but not
necessarily complete, in individuals treated with HAART, although the reasons why
this immune reconstitution is incomplete remain to be determined.
IMPACT OF HAART ON HIV-1-SPECIFIC IMMUNE RESPONSES
It is not fully understood why most HIV-1-infected individuals are unable to mount
an immune response that is capable of controlling and eradicating HIV-1 replication.
Loss of HIV-1-specific CD4� T-lymphocyte proliferative responses, which usually