WHY ARE ONLY CD4+ AND NOT CD8+ T CELLS LOST IN HIV INFECTION?

Although many of the data discussed in this chapter underline the importance of chronic immune activation in HIV pathogenesis, one question remains to be answered: If chronic immune activation causes CD4⁺ T cells to decline, and if both CD4⁺ and CD8⁺ T cell turnover are increased during HIV infection, why then is the CD8⁺ T cell pool not progressively depleted? As already mentioned, increases in T cell proliferation and apoptosis, telomere shortening, and TREC dilution in HIV- infected individuals are even more pronounced in CD8⁺ T cells than in CD4⁺ T cells.

To answer this question, it is important to note that although CD4⁺ T cell depletion is the main characteristic of HIV infection, other changes in T cell subsets typically occur during HIV infection. After an initial increase due to peripheral expansion, the CD4⁺ memory T cell population is progressively depleted. Because of a massive expansion of the memory CD8⁺ T cell pool in response to HIV infection, total numbers of CD8⁺ T cells are typically increased throughout the asymptomatic phase of infection. However, depletion of the naive T cell compartment is not restricted to CD4⁺ T cells, as naive CD8⁺ T cells begin to decline shortly after infection as well.³⁵,³⁶,⁶⁴ Eventually, shortly preceding AIDS diagnosis, even total CD8⁺ T cell numbers start to decline.

We argue that naive CD8⁺ T cell loss might be as important as naive CD4⁺ T cell loss and is driven by similar mechanisms. Thus, based on data outlined in this chapter, we hypothesized that HIV induces continuous activation of naive CD4⁺ and naive CD8⁺ T cells that are recruited to become memory and effector T cells and are thereby lost from the naive T cell pools.

depletion.⁷ In addition, intrinsic differences in cell survival kinetics between activated CD4⁺ and CD8⁺ T cells are likely to be the cause of differences between total CD4⁺ and CD8⁺ T cell numbers in the blood of HIV-infected individuals.

Differences in CD4⁺ and CD8⁺ T cell dynamics upon antigen-induced T cell activation are not specific for HIV infection. Given the different physiological tasks of CD4⁺ T cells (giving help to induce other immune responses) and CD8⁺ T cells (creating effector cells to actively kill infected cells), it may not be surprising that the CD8⁺ T cell population is more prone to induce and maintain large clones of effector cells than the CD4⁺ T-helper population. In mice infected with LCMV, LCMV-specific CD8⁺ T cells expanded about 20-fold more than LCMV-specific CD4⁺ T cells. Moreover, after the contraction phase of the immune response, when the antigen was cleared, the size of the antigen-specific CD8⁺ T cell pool remained stable, whereas LCMV-specific CD4⁺ T cells continued to decrease over time.⁹¹ A similar decline in antigen-specific CD4⁺ T cell memory cells was found in mice upon infection with Listeria monocytogenes.⁹² Furthermore, Ahmed et al. recently showed that murine memory CD8⁺ T cells are less sensitive to apoptosis than naive CD8⁺ T cells.⁹³ In contrast, when primed T cell receptor transgenic CD4⁺ T cells were rechallenged after transfer to normal mice, the transgenic cells initially expanded but progressively declined due to apoptosis after 2 days.⁹⁴

These results indicate that the size of the memory CD4⁺ T cell pool diminishes with time, whereas expanded CD8⁺ T cell clones show a much longer survival, also during other infections.

In HIV-infected individuals, labeling studies with deuterated glucose confirmed differences in T cell dynamics between CD4⁺ and CD8⁺ T cells. After a 7-day labeling period, Mohri et al. observed that CD4⁺ and CD8⁺ T cell proliferation were increased in HIV-1 infected humans as compared with uninfected individuals. Remarkably, however, T cell death rates were increased only in the CD4⁺ T cell population, which led them to conclude that CD4⁺ T cell depletion in HIV infection is caused by selectively increased CD4⁺ T cell destruction. More recently, the same data were analyzed using a two-compartment model, describing a resting T cell pool and an activated pool. When the labeling dynamics of CD4⁺ and CD8⁺ T cells in HIV-infected individuals were compared to those of healthy controls, it was found that CD4⁺ T cells, but not CD8⁺ T cells, entered the activated compartment more quickly during HIV infection. CD4⁺ T cells in the activated pool had increased proliferation and death rates, but HIV infection did not affect the size of the activated pool. In contrast, the activated CD8⁺ T cell compartment became larger during HIV infection, due to diminished reversion of activated cells into the resting pool, whereas proliferation and death rates remained unaffected by HIV infection.⁷⁶ The fact that CD8⁺ T cells in HIV infection have shorter telomeres and more severely diluted TRECs than CD4⁺ T cells also suggests that activated CD4⁺ T cells are more prone to die than activated CD8⁺ T cells.