Here we find that in rapid progressors SIV-specific CTL develops initially, but quickly disappears from the body, except for the CNS. In the general CD8 T cell compartment, striking changes develop - a decrease in CCR5+ and CD11a high cells, in temporal association with a loss of virus-specific CTL, and a failure to proliferate. In addition to the characteristic decrease in memory CD4 cells, we also find a loss of CD11a+ in the CD4 population. These changes on CD4 cells are closely correlated to changes on CD8 cells in rapid progressors, and inability to control viral load. We then asked whether these CD4 changes could be driven by the CTL loss and resulting high viral load. In infected animals in which CD8 cells were experimentally depleted at infection, rapid progression was accompanied by similar CD4 changes, leading us to consider whether changes in CD4 cells can result from a failure of CD8 responsiveness.
The alterations in the CD8 T cell compartment were beyond the inability to recognize immunodominant epitopes Gag and Tat, reaching the totality of the CD8 population regarding the expression of surface molecules (CCR5 and CD11a). In addition, CD8 proliferation was lower in RAPs than in REGs. In the CD4 compartment we observe a loss of memory CD4 cells, confirming previous reports [5
]. In addition, there is a loss of cells expressing high levels of CD11a in the CD4 population.
These experiments reveal a correlation between rapid progression in SIV-infected animals and a failure to enrich and maintain major anti-viral CD8 specificities. Others have reported dysfunctions in the CD4 cell population in rapid progressors as related to defects on memory replenishment [5
], as well as defects in CD8 T cells/CTL [11
]. Although these facts are interconnected, the instructive events were never well clarified. Our findings reveal that the wheel of rapid progression may reside primarily in the CD8 compartment.
The expression of CD95 and CD11a on CD4 cells was lower in the RAP than in the REG group, confirming the correlation of a restricted availability of memory cells with the development of disease [5
]. We determined that such findings could develop following CD8 failure, experimentally induced by CD8 cell depletion. Overall, our data indicates the connection between the collapse of the epitope recognition and immunodominance patterns in CD8 cells and CD4 memory availability. The nature of the CD8 requirements during the early acute phase is not clear, and may not be restricted to priming, recognition and effector activity against viral epitopes. The outcome, in terms of CD4 changes and rapid disease was identical in natural and experimentally induced rapid progression. Thus the dysfunction identified by the decline on memory and activated CD8+ T cells is as profound as if such cells were eliminated.
A similar outcome was previously obtained by an approach that utilizes blockage of co-stimulatory signals, which, as a result, attenuates SIV-specific CTL response and decreases CD8 proliferation, leading to an increase in viremia and rapid progression [26
]. In fact, rapid progressors failed to maintain proliferation activity in the whole CD8 population following the acute infection. This could be due to functional exhaustion or impaired induction of CD8 cells, classically attributed to defective CD4 help [27
The use of CD8 depletion to accelerate disease strongly suggests CD8 cells are pivotal in early viral load control. Moreover, CD8-depleted animals developed CD4 cells that phenotypically resemble those found in spontaneous rapid progression. However, CD8 depletion potentially disturbs homeostatic and antigen-driven proliferation of CD4+ cells, and eliminates NK cells (expressing CD8 in rhesus monkeys). Nevertheless, mathematical models that take into account the balance between virus and target cells, examining both non-manipulated infection and animals in which co-stimulatory blockage was performed to modulate CD8 response, indicate that at early periods of infection (first month after inoculation) viral control is due to CTL, in a positive correlation either with CD8+ T cells as a whole or with the Tat and Gag CTLs individually in MamuA*01 animals [29
]. From our work, we suggest that the CD8 functional aspects that define progression at initial time-points result from the viral-host interactions, but are in fact not restricted to the virus-specific population.
Since rapid progression is correlated with encephalitis, the brain findings are particularly interesting. In REG animals, the MamuA*01-restricted immunodominant anti-Tat and anti-Gag CD8 CTL represent close to 50% of the brain accumulating CD8 cells [21
]. Interestingly, in RAP animals the brain environment still supports CD8 accumulation, however the proportion of SIV Tat and Gag-specific CD8 cells among the brain-infiltrating CD8 cells is strikingly lower. Thus possibly the proportion of immunodominant CTLs rather than the brain CD8 accumulation per se
, affects the viral control and protection from encephalitis.
The development of CD4 deficits and rapid progression to AIDS as a result of loss of control over viral load due to CD8 defects represent an alternative perspective to other concepts, in which loss of CD4 memory and helper activity actually lead to AIDS. Our results indicate that in SIV-infected macaques a collapse of CD8 cells can potentially sign for the damage to the CD4 memory pool related to rapid progression. The basis of the global defect in CD8 cells should be investigated in depth, and may give important clues for the development of therapeutic strategies, aimed at maintaining functional CTL. The importance of these findings resides on the out-of-the-ordinary perspective and understanding of the necessity of therapeutic approaches that focus on better virus-specific CD8 expansion, as well as on the search for mechanisms of global CD8 response regulation, and biomarkers that identify the CD8 collapse related to progression.