Day17: Yet another hypothesis for chronic immune activation

One major field of study in HIV is the difference in pathogenicity between SIV and HIV, since many species of monkeys which acquire SIV do not develop immunodeficiency. One of the observed differences is that monkeys which do not develop immunodeficiency do not show chronic immune activation upon SIV infection, while chronic immune activation is one of the hallmarks of HIV infection. Recently, Rawson and colleagues report in Nature Medicine that the chronic immune activation observed in HIV infection may be related to antigen processing during cell death.

 

Apotosis (pronounced apo-toe-sis) is the process of programmed cell death. When a cell suffers certain types of insults or is signaled in certain specific manners, the cell starts a chain reaction that leads to an orderly death of the cell. The cellular DNA is cleaved, the membrane “blebs” (breaks into smaller particles, similar to budding) and changes composition, and the cell is taken in by antigen presenting cells (APCs) for orderly disposal. This process is important during development and is also a pivotal process in the proper maintenance of the immune system. One key class of proteins in this process is the caspases. These proteins are the initial effectors of the chain reaction leading to apoptosis. They are proteases, similar to HIV protease in function, but they have different specificities.

 

According to the recent Nature Medicine paper, active apoptosis leads to an alteration of normal antigen processing. The authors took non-apoptotic and apoptotoc cells and used proteomics to determine differences in protein abundance for the two conditions. Using mass spectrometry, the authors observed that several of the proteins that had reduced abundance during apoptosis are proteins known to be targets in autoimmunity. The authors then tested the immunogenicity of the identified peptides for HIV-positive and HIV-negative subjects. Effector CD8 cells for the HIV-positive subjects showed greater responses to the peptide pool than HIV-negative subjects. After several rounds of in vitro stimulation, CD8 cells from HIV-negative subjects also reacted to the peptide pool, suggesting that CD8 cells specific for these epitopes are present in uninfected subjects, but are ignorant of their target.

 

The authors further confirmed the existence of self-reactive CD8 cells in HIV-positive subjects by tagging these cells with pentamers and analyzing the frequency using flow cytometry. In HIV-negative subjects, these reactive cells numbered less then 0.02% of CD8 cells. The number of positive CD8 cells for HIV-positive subjects was much higher. The number of self-reactive CD8 cells in HIV-positive subjects directly correlated with the percentage of apoptotic CD4 cells. The strength of self-reactive response inversely correlated with the number of live non-apoptotic CD4 cells in each HIV-positive subject.

 

The data also show that APCs presented with lysed apoptotic cells are better at stimulating CD8 responses against the self-reactive peptides than APCs presented with lysed non-apoptotic cells. When the apoptotic cells were cultured with caspase inhibitors, APC activation of CD8 effectors was decreased.  I am not entirely sure how they managed to generate apoptotic cells in the presence of a caspase inhibitor (particularly caspase 8 when they used a fas-method of apoptosis induction) and the methods do not clearly define this. Or maybe I am too dense to understand what they actually did here, but it seems problematic to me.

 

The study suggests that the autoreactive CD8 cells may contribute to CD4 loss during HIV infection. In the context of chronic immune activation, these CD8 cells, which would normally not be activated, undergo clonal expansion and are primed by cross-presenting APCs. This cross-presentation was blocked by caspase inhibitors, suggesting that the peptide fragments necessary for this self-reactivity are dependent upon caspases and may be directly cleaved by the caspases. It is easy to imagine a feedback cycle where HIV-associated apoptosis results in the priming of self-reactive CD8 cells, which in turn cause more apoptosis and a resulting chronic immune activation. As usual, more research will need to be done to determine if this hypothesis is correct, but if it is it may be possible to break the cycle of chronic immune activation in HIV-infected individuals and, hopefully, decrease HIV pathogenesis.