This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.It is widely accepted that destruction of CD4+ T cells is the primary cause of immunodeficiency and death from HIV-1 infection in humans as well as in SIV-infected macaques. However, most opportunistic infections, (a hallmark of AIDS), are caused by agents such as Pneumocystis carinii, that under normal circumstances may not require acquired immunity to prevent. This suggests that innate immune responses may also be critically affected during progression to AIDS. We therefore examined whether the kinetics and dynamic changes in cells of monocyte/macrophage lineage could be linked to the pathogenesis of AIDS in the rhesus macaque model. In this study we show that a massive turnover of peripheral monocytes caused by death of tissue macrophages is associated with SIV infection of macaques and that high monocyte turnover predicted the progression to AIDS. All infected monkeys that died with AIDS demonstrated significantly higher turnover of monocytes compared to uninfected and persistently infected animals. Detailed kinetics of monocyte maturation showed that this high turnover occurred mainly in CD14 single positive monocytes, a subset known to be rapidly recruited to inflamed tissues. This was directly confirmed in lymph node tissue of an infected monkey. In a longitudinal study of a cohort of SIV-infected monkeys, the animal that demonstrated early high monocyte turnover was a rapid progressor and died with AIDS despite similar high viral load and low CD4 counts compared to the other animals in the cohort. Our results underscore the importance of the monocyte/macrophages in the pathogenesis of AIDS and suggest new immunotherapeutic approaches to prevent AIDS progression.
Showing the most recent 10 out of 352 publications
