he correlates of protection against HIV infection remain an area of intense study and debate. Some preventive and therapeutic HIV vaccines in development have focused on stimulating CD8+ T cell immunity. Recent small animal studies, however, suggest that CD4+ T cells may play a critical role in nurturing CD8+ T cells that are more effective in controlling viral replication. Thus immunization strategies that induce both CD4+ and CD8+ T cell immunity should be pursued.

Introduction

Early in the HIV epidemic, cell mediated immunity that involved CD4+ and CD8+ T cells was recognized to play a potential role in the control and prevention of disease (1, 2). The temporal relationship between the expansion of cytotoxic CD8+ T cells during primary HIV-1 infection, just prior to a decline in virus levels to a virologic set-point, supported their effector function in slowing disease progression. Furthermore, exposed but uninfected cohorts displayed strong CD8+ T cell responses as well, supporting their potential involvement in preventing disease (3, 4). However, numerous studies have demonstrated that HIV can escape the cytolytic and non-cytolytic activity of so called "killer T cells" and this may be associated with progression of disease (5, 6, 7). A question arises as to whether the inability of the immune system to prevent or control HIV infection is related in part to qualitative or quantitative deficiencies of other immune cells which may have a direct or indirect impact on the generation of effective CD8+ T cell killers.

CD4+ T cell helper function and CD8+ T cells

CD4+ T cells have been well recognized for their function in providing "help" to other immune cells including CD8+ T cells (8, 9). CD4+ T cells are thought to help regulate other cell types through production of various cytokines and by delivering co-stimulatory molecules (10, 11). The immunopathogenesis of HIV infection is characterized by a quantitative and qualitative depletion of CD4+ T cells early in infection (12). Recent studies in animals (13, 14, 15) suggest that defects in CD4+ T cells may have an impact on the ability of CD8+ T cells to control virus. These findings may have direct relevance to the further understanding of the immunopathogenesis of HIV-1 infection as well as effective vaccine strategies.

Shedlock and Shen have recently demonstrated that in small animals CD4+ T cells are critical during a priming phase for the generation of memory CD8+ T cell recall responses (13). In a separate study, Sun and Bevan suggest that protective CD8+ T cell memory wanes in small animals devoid of CD4+ T cells and that the CD8+ T cells are defective in their ability to respond to secondary antigen encounters (14). Janssen et al. have also documented the requirement for CD4+ T cell help during the priming of CD8+ T cells to support the development of functional CD8+ memory T cells that exhibit a secondary expansion during a re-encounter with antigen (15). Thus, a recurring theme of these recent studies is that long-term control of viral infection by CD8+ T cells may require the presence of stimulated CD4+ T cells during the initial priming with antigen. Most interestingly, these studies suggest that the requirement for CD4+ T cells may not be apparent initially, during acute exposure, but rather later, upon chronic re-exposure to antigen.

CD4+ T cell helper function may thus play a critical role in controlling HIV-1 infection by nurturing CD8+ T cells during their initial exposure to antigen, rendering them more effective in controlling disease over time. The results of the recent studies noted above may have implications for HIV vaccine development. Although many current experimental HIV vaccines are designed to stimulate predominantly CD8+ T cell responses, a vaccine strategy suggested as a consequence of these recent findings would also focus on stimulating CD4+ T cell immunity. This goal might be accomplished by combining vaccine constructs (e.g., DNA and protein) or through the use of appropriate adjuvants such as CpG (16). Such an approach would aim to provide adequate CD4+ T helper cell function during the priming of CD8+ T cells.

In a prophylactic setting, the benefits of priming CD8+ T cells in the context of adequate CD4+ T cell help, via vaccination, might be realized upon re-exposure to antigen, at which time the appropriately nurtured CD8+ T cells would be capable of mounting a heightened secondary response that would otherwise not occur in the absence of adequate CD4+ T cell help.

In a therapeutic setting, immunization strategies which induce both CD4+ and CD8+ T cell responses may lead to more durable CD8+ T cell activity in the face of established chronic infection, resulting in reduced viral burden. Subjects undergoing highly active antiretroviral therapy (HAART) may require immunization to stimulate both CD8+ T cells as well as CD4+ T cells, as these cells become quiescent due to lack of antigenic stimulation while on suppressive therapy (17, 18). Spikes of autologous virus during structured treatment interruptions, following a course of immunization, might then activate the appropriately nurtured CD8+ T cells to undergo secondary expansion that may result in enhanced control of the virus, potentially prolonging the time that subjects could remain off HAART (19).

Conclusion

The hypothesis that immunization strategies that induce both CD4+ and CD8+ T cell responses may improve long-term CD8+ functional memory responses, resulting in greater virologic control, should be examined in both preventive and therapeutic vaccine settings.

References and notes