lactoferrin and Cytomegalovirus-Infections

Human cytomegalovirus is the most common cause of congenital and perinatal infections throughout the world. Primary infection with human cytomegalovirus usually follows a benign course, but the virus remains latent or persistent in the host cell thereafter. Understanding the epidemiology of human cytomegalovirus is a key element in the development of strategies for prevention of infection. Although the actual sites of latency or persistence of human cytomegalovirus infections are still controversial, peripheral blood mononuclear cells and endothelial cells appear to be major sites of infection. Persistent infections caused by human cytomegalovirus could be augmented by a decrease in major histocompatibility complex expression as well as by virus-mediated immune dysfunction. It is possible that specific cellular interactions as well as production of several cytokines are necessary for the reactivation of human cytomegalovirus. Breast-fed infants are susceptible to human cytomegalovirus infection from breast milk. Human cytomegalovirus was isolated more frequently from breast milk at more than 1 month after delivery than from colostrum or early breast milk. Human cytomegalovirus DNA was also not detected in colostrum, but was found in breast milk samples 1 month after delivery. To clarify the role of milk cells and whey in vertical infection by breast feeding, we separated breast milk into milk cells and whey and examined each fraction. Human cytomegalovirus was isolated more frequently from milk whey samples than from cell samples. Human cytomegalovirus particle shedding into whey may be more important in vertical infection by breast milk than cell-to-cell transmission. The supernatant of colostrum did not exert an inhibitory effect on human cytomegalovirus-infected cells. Serum levels of cell free soluble interleukin-2 receptor of mothers with DNA-positive milk at 1 month after delivery were significantly higher than those of mothers with DNA-negative milk. It is likely that levels of factors such as soluble interleukin-2 receptor in serum are related to the reactivation of human cytomegalovirus which occurs locally in the mammary gland of the lactating mother after delivery. This minireview focuses on recent advances in the study of human cytomegalovirus infection of breast milk.

Topics: Antiviral Agents; Breast Feeding; Carrier State; Colostrum; Cytokines; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; Female; Humans; Infant; Infant, Newborn; Infectious Disease Transmission, Vertical; Lactoferrin; Milk, Human; Pregnancy

Lactoferrin is an antimicrobial agent, that, amongst other viruses, inhibits cytomegalovirus (CMV). In this study, we addressed the mechanism(s) by which lactoferrin interacts with CMV and its target cells to inhibit infection. We also studied the antiviral activity of lactoferrin in vivo in rat CMV models with and without immune suppression. We cationized a protein of similar molecular weight, i.e. human serum albumin (HSA), as well as a protein with a smaller molecular weight (beta-lactoglobulin). While HSA itself displayed no anti-CMV activity in vitro, cationic HSA inhibited CMV replication to a similar extent as lactoferrin. Time-of-addition assays indicated that all cationic proteins interacted with an early event in the infection and pre-incubation of cells rather than of virus significantly reduced CMV replication. Rats were treated with lactoferrin (4, 40 or 160 mg/kg, intravenously), beginning at 6h after CMV administration. Subsequently, the rats were treated three times a week. As a positive control, CMV-infected rats were treated with cidofovir, and this agent proved to be highly active in the rat models for CMV. Treatment with lactoferrin was beneficial when infection was initiated with cell-free virus, but not with virus-infected leukocytes. Lactoferrin treatment led to a 10-fold reduction in the final virus titers (salivary glands) at 4 weeks after infection in the immunocompromised rats. Lactoferrin exerted its effects via inhibition of cell entry rather than via stimulation of the immune system.

Topics: Animals; Antiviral Agents; Cell Line; Cytomegalovirus; Cytomegalovirus Infections; Lactoferrin; Rats; Spleen

In vitro, lactoferrin (LF) strongly inhibits human cytomegalovirus (HCMV), which led us to hypothesize that in vivo HCMV might also be inhibited in secretions with high LF concentrations. In breast milk, high viral loads observed as high viral DNA titers tended to coincide with higher LF levels. However, the LF levels did not correlate to virus transmission to preterm infants. The viral load in the transmitting group was highest compared to the nontransmitting group. We conclude that viral load in breast milk is an important factor for transmission of the virus.

Topics: Breast Feeding; Cytomegalovirus; Cytomegalovirus Infections; Data Interpretation, Statistical; DNA, Viral; Female; Humans; Infant, Newborn; Infant, Premature; Infectious Disease Transmission, Vertical; Lactoferrin; Milk, Human; Polymerase Chain Reaction; Prospective Studies; Viral Load

Human lactoferrin (hLF) as well as bovine lactoferrin (bLF) inhibited infection of tissue culture cells with human cytomegalovirus (HCMV) and human herpes simplex virus-1 (HSV-1). The addition of lactoferrin (LF) inhibited both in vitro infection and replication of HCMV and HSV-1 in human embryo lung host cells. The maximum inhibition by more than six exponentials of TCID50 for HCMV and four exponentials for HSV-1 was obtained at a concentration in a range from 0.5 to 1 mg of LF per ml of medium. The antiviral activity of LF was associated with its protein moiety, but not with its iron molecule or sialic acid. None of other transferrin gene family members bound to ferrous ions or sialic acid possessed significant antiviral activity. Additionally, we found that LF prevented virus adsorption and/or penetration into host cells, indicating an effect on the early events of virus infection. Preincubation of host cells with LF for 5 to 10 min was sufficient to prevent HCMV infection, even when LF was removed after addition of virus. These results suggest that LF possesses a potent antiviral activity and may be useful in preventing HCMV and HSV-1 infection in humans.

Topics: Adsorption; Animals; Antiviral Agents; Cattle; Cell Line; Conalbumin; Cytomegalovirus; Cytomegalovirus Infections; Herpes Simplex; Herpesvirus 1, Human; Humans; Lactoferrin; Milk Proteins; Polymerase Chain Reaction; Transferrin; Trypsin; Virus Replication