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in Response to p24 Antigen in HIV-Infected Individuals: Potential Contribution of Anergy to HIV-Specific Unresponsiveness
*
Laboratory of Immunoregulation and
Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, and
Warren Magneson Clinical Research Center, National Institutes of Health, Bethesda, MD 20892
It has been suggested that CD4+ T cell proliferative
responses to HIV p24 Ag may be important in the control of HIV
infection. However, these responses are minimal or absent in many
HIV-infected individuals. Furthermore, while in vitro and in vivo
responses to non-HIV recall Ags improve upon administration of highly
active antiretroviral therapy, there does not appear to be a
commensurate enhancement of HIV-specific immune responses. It is
possible that CD4+ p24-specific T cells are deleted early
in the course of infection. However, it is also possible that a
discrete unresponsiveness, or anergy, contributes to the lack of
proliferation to p24. To evaluate the possible contribution of
unresponsiveness to the lack of CD4+ T cell proliferation
to p24 in HIV-infected individuals, we attempted to overcome
unresponsiveness. CD40 ligand trimer (CD40LT) and IL-12 significantly
increased PBMC and CD4+ T cell proliferative responses to
p24 Ag in HIV-infected, but not uninfected, individuals. No increase in
proliferative response to CMV Ag was observed. CD40LT exerted its
effect through B7-CD28-dependent and IL-12- and IL-15-independent
mechanisms. Finally, the increase in proliferation with CD40LT and
IL-12 was associated with an augmented production of IFN-
in most,
but not all, individuals. These data suggest the possible contribution
of HIV-specific unresponsiveness to the lack of CD4+ T cell
proliferation to p24 Ag in HIV-infected individuals and that clonal
deletion alone does not explain this phenomenon. They also indicate the
potential for CD40LT and IL-12 as immune-based therapies for HIV
infection.
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