Antigen Burden Is a Major Determinant of Human Immunodeficiency Virus–Specific CD8+ T Cell Maturation State
The majority of untreated human immunodeficiency virus (HIV) type 1–infected individuals ultimately develop uncontrolled viremia and progressive disease. Cytotoxic T lymphocytes (CTLs) are known to play an important role in controlling HIV-1 replication, which has led to an increasing interest in augmenting conventional antiretroviral therapy with therapeutic vaccination. The successful development of a therapeutic vaccine will rely on the ability to correlate an aspect of the immune response with clinical outcome. In this study, the CD8+ T cell maturation status of antigen-specific cells in models of well and poorly controlled virus infections were compared, to show that a memory phenotype predominates when antigen loads are absent or low. In HIV-1 infection, the emergence of memory CD8+ T cells was found to occur only in individuals with highly suppressed viral replication for an extended duration. Such assessments of the immune response may provide a refined measure of virus control
Several lines of evidence indicate that human immunodeficiency virus (HIV) type 1–specific cytotoxic T lymphocytes (CTLs) play an important role in containing initial HIV-1 infection and maintaining long-term control of viral replication. Their appearance in blood coincides with the initial decrease in plasma virus load (PVL) during acute HIV-1 infection and potent CTL responses have been associated with delayed progression to AIDS. The appearance of CTL escape mutants and their positive association with disease progression suggest that there is selective pressure placed on the virus by this arm of the immune system. Finally, HIV-1–specific CTL responses also have been demonstrated in several cohorts of individuals who were heavily exposed to HIV-1 yet remained clinically uninfected, which suggests that CTL responses also may play a role in protection against chronic HIV-1 infection.
Despite the marked antiviral effect of HIV-1–specific CTLs, most untreated individuals eventually develop uncontrolled viremia and progressive disease. Although longer term control of viremia can be achieved with antiretroviral therapy (ART), ART, as currently given, may be associated with side effects and does not eradicate the virus, which thereby necessitates lifelong therapy. The difficulties associated with ART, as well as the data suggesting that cell-mediated immune (CMI) responses are important in the control of initial HIV-1 infection, have lead to an increasing interest in augmenting conventional ART with therapeutic vaccination. An important component in the development of such a vaccine will be the ability to correlate a facet of the antigen specific T cell response with clinical outcome after vaccination.