Critical Role for Monocytes/Macrophages in Rapid Progression to AIDS in Pediatric Simian Immunodeficiency Virus-Infected Rhesus Macaques

Abstract

Infant humans and rhesus macaques infected with the human or simian immunodeficiency virus (HIV or SIV), respectively, express higher viral loads and progress more rapidly to AIDS than infected adults. Activated memory CD4 T cells in intestinal tissues are major primary target cells for SIV/HIV infection, and massive depletion of these cells is considered a major cause of immunodeficiency. Monocytes and macrophages are important cells of innate immunity and also are targets of HIV/SIV infection. We reported previously that a high peripheral blood monocyte turnover rate was predictive for the onset of disease progression to AIDS in SIV-infected adult macaques. The purpose of this study was to determine if earlier or higher infection of monocytes/macrophages contributes to the more rapid progression to AIDS in infants. We observed that uninfected infant rhesus macaques exhibited higher physiologic baseline monocyte turnover than adults. Early after SIV infection, the monocyte turnover further increased, and it remained high during progression to AIDS. A high percentage of terminal deoxynucleotidyltransferase dUTP nick end label (TUNEL)-positive macrophages in the lymph nodes (LNs) and intestine corresponded with an increasing number of macrophages derived from circulating monocytes (bromodeoxyuridine positive [BrdU] CD163), suggesting that the increased blood monocyte turnover was required to rapidly replenish destroyed tissue macrophages. Immunofluorescence analysis further demonstrated that macrophages were a significant portion of the virus-producing cells found in LNs, intestinal tissues, and lungs. The higher baseline monocyte turnover in infant macaques and subsequent macrophage damage by SIV infection may help explain the basis of more rapid disease progression to AIDS in infants. HIV infection progresses much more rapidly in pediatric cases than in adults; however, the mechanism for this difference is unclear. Using the rhesus macaque model, this work was performed to address why infants infected with SIV progress more quickly to AIDS than do adults. Earlier we reported that in adult rhesus macaques, increasing monocyte turnover reflected tissue macrophage damage by SIV and was predictive of terminal disease progression to AIDS. Here we report that uninfected infant rhesus macaques exhibited a higher physiological baseline monocyte turnover rate than adults. Furthermore, once infected with SIV, infants displayed further increased monocyte turnover that may have facilitated the accelerated progression to AIDS. These results support a role for monocytes and macrophages in the pathogenesis of SIV/HIV and begin to explain why infants are more prone to rapid disease progression.

Lack of susceptibility in neonatally infected rhesus macaques to simian immunodeficiency virus-induced encephalitis

“…Our previous studies have observed distinct differences in plasma viral load and monocyte turnover in macaques infected with SIV as neonates compared with adults (Hasegawa et al 2009;Merino et al 2017;Sugimoto et al 2017). It should be noted that those studies examined dynamic changes across the stages of SIV infection: acute, chronic, or AIDS.…”

“…Forty-eight hours prior to necropsy, either 5bromo-2′-deoxyuridine (BrdU; Sigma-Aldrich, St. Louis, MO) or 5-ethynyl-20-deoxyuridine (EdU; Molecular Biology, Carlsbad, CA) thymidine analogs were intravenously administered to some of the animals. BrdU was intravenously injected at a concentration of 30 mg/kg for neonatal animals and 60 mg/kg for adult animals, while EdU was administered at a dose of 50 mg/kg for adult animals (Cai et al 2015;Sugimoto et al 2017). Twenty-four hours after BrdU or EdU injection, blood samples were obtained to determine monocyte turnover.…”

“…Peripheral blood mononuclear cells (PBMCs) were collected and frozen using freezing media or stained for flow cytometry. For calculation of monocyte turnover within 48 h of necropsy, the PBMCs were stained using previously described methods and analyzed on an LSR II flow cytometer (BD Biosciences) to detect the surface markers of monoclonal antibodies and intracellular BrdU or EdU (Hasegawa et al 2009;Cai et al 2015;Sugimoto et al 2017). Data was analyzed using FlowJo software (TreeStar).…”

“…This was also observed in the brain in association with higher SIV tissue viral loads and increased rate of SIVE (Hasegawa et al 2009;Burdo et al 2010;Cai et al 2015). In addition, those studies reported that the more rapid disease progression to AIDS in neonatal rhesus macaques correlated with earlier and sustained higher monocyte turnover following SIV infection (Merino et al 2017;Sugimoto et al 2017). This study attempts to unravel the paradox of a more rapid disease course, of high viral loads and yet no significant lesions in brains.…”

Visualizing the Immune System: Providing Key Insights into HIV/SIV Infections

“…Furthermore, pharmacological manipulation of monocyte activation results in reduced recruitment of activated monocytes to the LN and reduced viral replication ( 78 ). More recently, tissue imaging has shown that infected macrophages could contribute to the rapid disease progression in SIV-infected non-human primate (NHP) infants ( 79 ). While monocytes/macrophages can clearly become infected with HIV/SIV, the relative contribution of infected monocytes/macrophages as long-lived viral reservoirs in vivo is still an open question.…”