Oral bacteria induce a differential activation of human immunodeficiency virus-1 promoter in T cells, macrophages and dendritic cells.

Infection with the human immunodeficiency virus (HIV) results in a compromised immune system, and increased incidence of opportunistic infections with fatal consequences (28). The HIV targets and destroys CD4+ T cells, as well as infecting antigen-presenting cells such as macrophages and dendritic cells (DC) resulting in a continuous viremia and exacerbated acquired immunodeficiency syndrome (AIDS) outcomes. The advent of highly active antiretroviral therapies (HAART) has successfully transformed HIV infection from a progressive loss of immune function with associated morbidity into a chronic infection that generally manages the viremia and restores substantial T-cell immune function (27, 40). The persistence of HIV-1 latently infecting select host cells, e.g. CD4+ T cells, macrophages and DC, remains a significant obstacle in the elimination of HIV-1 infections (1). As a critical part of the HIV-1 life cycle, reactivation of the provirus results in the production of new virions. The reactivation phase of HIV transitions from a state with no replicating virus to the production of new virions. Latency is considered a dynamic process and is likely reflected by viral activity through these processes (9). Various exogenous stimuli have been shown to reactivate HIV-1 infections (18, 22, 31). Microbial coinfections have been associated with transient bursts of HIV-1 viremia in patients. This can result from microbial activation of proinflammatory cytokines with subsequent induction of HIV-1 production by infected T cells, macrophages and/or DC (36, 47). In addition to being a substantial viral reservoir, infected macrophages may also transfer HIV-1 to uninfected T cells (48). Although CD4+ T cells appear to be the main targets of HIV, other immune and non-immune cells with or without CD4 molecules on their surfaces can also be infected. The monocyte/macrophage has been identified to be a source of virus in infected tissues, a basis for viral transmission to target cells, and able to produce a range of cytokines/chemokines that affect both cell function and virus replication (15). It has been suggested that DC are potential first target cells in HIV-1 infections (38). These cells are also considered to be central in activating naive T cells, which can become permissive for HIV-1 infection (38, 46). DC are innate immune cells that constitute the link between innate and adaptive immunity by recognizing pathogen-associated molecular patterns (PAMPs) on bacteria to enable uptake, processing and presentation of antigens to T cells (30). The immune function of these DC depends upon their stage of maturation, with immature dendritic cells (iDC) considered as part of the innate phase of the immune response. Mature dendritic cells (mDC) provide the linkage to the adaptive phase of the immune response, whereby they present the captured and processed antigens to prime naive T cells for clonal expansion (2). Although it is clear that DC can engage a diverse array of microorganisms, there are minimal data concerning how HIV-latency in DC can be reactivated, and if oral bacteria or bacterial complexes have the capacity to perform this function. Lipopolysaccharide challenge of HIV-1-infected DC results in increased levels of tumor necrosis factor-α and interleukin-1β (IL-1β), as well as various β-chemokines (34). Periodontitis is a polymicrobial disease with pathological changes that result from a complex inflammatory and immune host response generated by resident gingival cells and inflammatory cells that migrate into the infected tissues (25, 44). It has been suggested that bacterial infections and mucosal-associated bacterial translocation in HIV-1-infected individuals may reactivate HIV-1 in bystander CD4+ T cells, macrophages and DC (8, 31). This report describes studies that delineate the characteristics of HIV promoter activation in T cells, macrophages and DC in response to challenge of these cells with oral bacteria or bacterial products. We hypothesize that these cell types will demonstrate a differential response to the microbial stimuli, and that the characteristics of the oral bacteria will dictate the patterns of HIV reactivation with the different host cell reservoirs.