Mysteries of HIV pathogenesis explained

Infection and loss of CD4 helper T cells is considered an underlying mechanism for the progressive demise of the immune system in HIV-infected patients. But it fails to provide an adequate explanation for certain clinical observations. For example, why do some patients remain relatively healthy with CD4 counts of fewer than 200 while others with similar or even higher CD4 counts succumb to Kaposi sarcoma? New data from Liu and colleagues (page 1182) suggest that a recently identified subpopulation of blood dendritic cell (DC) able to produce copious amounts of type I interferon may provide some of the answers to this conundrum. These cells are variously termed DC2s, interferon-producing cells (IPCs), or plasmacytoid DCs. The investigation analyzed the number of IPCs in peripheral blood of HIV-infected patients at different stages of disease and showed a progressive depletion with increasing plasma virus load, an observation confirmed by our own recent studies (Donaghy et al, Blood, in press). Furthermore, patients who were able to suppress virus growth and remained healthy for more than 10 years were found to have elevated numbers of IPCs compared with uninfected controls. Perhaps the most striking finding was the correlation between low numbers of IPCs (fewer than 2/μL was considered critical) and opportunistic infections. The finding of Kaposi sarcoma patients with low IPC numbers but high CD4 T-cell counts was also revealing. These findings contrasted with patients showing IPC counts higher than 2 IPCs/μL who remained healthy despite very low CD4 T-cell numbers. The critical role of IPCs in HIV pathogenesis indicated by these studies suggests that monitoring IPC numbers may be of value and that strategies that increase the numbers of these cells, such as treatment with flt-3 ligand, may have therapeutic value.