Passive Immunization with Neutralizing Antibodies Interrupts the Mouse Mammary Tumor Virus Life Cycle

Abstract

Mouse mammary tumor virus (MMTV) infects the host via mucosal surfaces and exploits the host immune system for systemic spread and chronic infection. We have tested a neutralizing rat monoclonal antibody specific for the retroviral envelope glycoprotein gp52 for its efficiency in preventing acute and chronic mucosal and systemic infection. The antibody completely inhibits the superantigen response and chronic viral infection following systemic or nasal infection. Surprisingly however, the antibody only partially inhibits the early infection of antigen-presenting cells in the draining lymph node. Despite this initially inefficient protection from infection, superantigen-specific B-and T-cell responses and systemic viral spread are abolished, leading to complete clearance of the retroviral infection and hence interruption of the viral life cycle. In conclusion, systemic neutralizing monoclonal antibodies can provide an efficient protection against chronic retroviral amplification and persistence.The retrovirus mouse mammary tumor virus (MMTV) is transmitted from infected mothers to offspring via milk during the first 2 weeks after birth. MMTV targets three major cell types for infection: dendritic cells (DC) (33, 42) and B lymphocytes (9, 22) early in infection and epithelial cells of exocrine secretory organs later on (for a review see reference 31). Once MMTV has crossed the mucosa it infects DC and B cells in the Peyer's patches (PP) before spreading to peripheral organs (27). Chronic infection of the mammary gland leads to viral transmission via milk and to mammary tumor development after retroviral insertion next to proto-oncogenes (34). Adult mice can be chronically infected by subcutaneous (s.c.) injection (23) or by nasal administration of the virus (44). After entry into the cell, viral RNA is reverse transcribed and the resulting viral DNA is integrated into the genome in target DC and B cells. This leads to expression of a viral superantigen (SAg) at the cell surface (22). Oral, s.c., and nasal routes of infection proceed with similar kinetics, which are dominated by efficient priming of a SAg T-cell response via an interaction between infected B cells and DC-primed SAg-reactive cognate T cells. SAg-activated T cells are slowly deleted from the peripheral T-cell repertoire. This deletion represents one of the most sensitive readouts for chronic infection and systemic spread of MMTV. While the virus persists in all lymphoid and nonlymphoid organs, MMTV establishes a chronic immune response with germinal centers, persisting antigen (Ag), and virus-specific B and T cells only in the draining lymph node (LN). This leads to a weak life-long neutralizing antibody (Ab) response against the viral envelope (Env) protein gp52 (32). Although in susceptible mice this chronic Ab response is unable to clear the virus infection, resistant mouse strains such as I/LnJ have evolved a strong neutralizing Ab response that controls chronic infection and prevents infection of the progeny (39). This is in agreement with the r...

Oncogenic Viruses and Breast Cancer: Mouse Mammary Tumor Virus (MMTV), Bovine Leukemia Virus (BLV), Human Papilloma Virus (HPV), and Epstein–Barr Virus (EBV)

“…Although premature at this stage of research, it is of interest that the development of preventive and therapeutic vaccines against MMTV in humans is a practical proposition. MMTV-associated mouse mammary tumors can be prevented from developing by immunization with purified mammary tumor virus ( 194 – 196 ). MMTV virus envelope peptides have also been used to prevent MMTV-associated mouse breast cancers ( 197 ).…”

Catching viral breast cancer

“…Mouse mammary tumour virus: studies conducted several decades ago on experimental mice indicate the possibility of developing preventive vaccines [ 86 ]. More recently Braitbard et al working in Israel have shown the possibility of MMTV derived proteins used to prevent and treat MMTV breast infections [ 87 ].…”