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Plasmacytoid dendritic cells (pDCs), a primary source of interferon α (IFN-α), provide a first line of innate immune defense against human immunodeficiency virus infection. However, their kinetics and functions during acute infection are poorly understood. In mucosal tissues of normal rhesus macaques, we found CD4(+) pDCs to be the subset responsible for most IFN-α and tumor necrosis factor α (TNF-α) production in response to Toll-like receptor (TLR) 7/8 stimulation, compared with relatively anergic CD4(-) pDCs. During acute simian immunodeficiency virus (SIV) infection, gut homing was imprinted on pDCs in the bone marrow, resulting in a decline in pDCs from circulation and secondary lymphoid tissues. Although the accumulated pDCs in the gut mucosae had robust cytokine responses to TLR7/8 stimulation in vitro, pDC gut migration occurred after infection and detection of SIV in plasma. Our data suggest that innate pDC responses do not control initial SIV seeding and dissemination but instead may contribute to ongoing immune activation in the gut.

Cytomegalovirus (CMV) is a herpesvirus establishing life-long persistence after primary infection. CMV infection can cause severe manifestations in immunocompromised subjects and fetuses but is usually asymptomatic in immunocompetent hosts. Data from several studies support an important role for CD4+ T lymphocytes in the control of human CMV infection. Early appearance of functional CMV-specific CD4+ T cells is associated with asymptomatic infections after kidney transplantation [1] and with a lower risk of viremia after hematopoietic stem cell transplantation [2]. In chronic infection, CMV-specific CD4+ T cells acquire direct antiviral functions and are pivotal for optimal B and CD8+ T-lymphocyte responses [3]. CMV-specific CD4+ T cells produce multiple cytokines, including interferon γ (IFN-γ), tumor necrosis factor α (TNF-α), and interleukin 2 (IL-2), have potent proliferative capacity and can display major histocompatibility complex class II–restricted cytotoxicity [4, 5]. Asymptomatic primary CMV infection in immunocompetent hosts, particularly children, often leads to virus shedding in bodily secretions for a prolonged duration, suggesting incomplete immune control [6, 7]. Following primary infection, CMV-specific CD4+ T cells emerge rapidly but acquire the capacity to proliferate in vitro in response to viral antigens only several months after seroconversion [1, 7, 8]. While the delayed acquisition of functional CD4+ T-lymphocyte responses in primary infection is likely to contribute to the incomplete control of CMV replication, the etiology of functional CD4+ T-lymphocyte exhaustion remains uncertain. We recently observed that the slow acquisition of proliferative responses in primary CMV infection is associated with a reduced capacity to produce cytokines, including IL-2, IFN-γ, and TNF-α [9]. Clinical studies suggest that this functional impairment is a risk factor for mother-to-fetus transmission of CMV and for CMV retinitis in human immunodeficiency virus (HIV)–infected patients [10–13]. Thus, development of therapeutic strategies to prevent the clinical complications associated with primary CMV infection will require a better understanding of the mechanisms compromising its immune control. Rhesus macaques are currently the best available animal model of human CMV infection [14]. CMV infection is widely prevalent among captive group-housed rhesus macaques, and rhesus CMV shares close genetic similarity to human CMV [15–17]. Similar to humans, rhesus CMV infection is asymptomatic in immunocompetent macaques, and CMV reactivation-associated disease manifests only in the setting of immunosuppression [18–20]. In contrast to chronic infection, there are limited data on the virologic and immunologic events in naturally acquired primary rhesus CMV infection. We and others have shown that maternal antibodies to CMV wane around 1 year of age and that seroconversion following natural infection occurs soon thereafter [15, 18]. Furthermore, hand-reared newborn macaques separated at birth from their mothers remain CMV seronegative after loss of maternal CMV antibodies [18], suggesting that natural CMV acquisition occurs in the postnatal period. In this study, we investigated the relationship between viral load and CMV-specific CD4+ T-lymphocyte responses at different time points following natural CMV acquisition in rhesus macaques.