Mouse mammary tumor viruses with functional superantigen genes are selected during in vivo infection
T V Golovkina1, J P Dudley, A B Jaffe
1Department of Microbiology/Cancer Center, University of Pennsylvania, Philadelphia 19104-6142, USA.
Abstract:
Mouse mammary tumor virus (MMTV) encodes a superantigen that is important for viral infectivity in vivo. To determine whether superantigen function was required for infection by milk-borne MMTV, we created HYB PRO/Cla transgenic mice. These mice produced a full-length, packaged viral RNA with a frameshift mutation that caused premature termination of the superantigen protein. Young HYB PRO/Cla mice showed no deletion of their cognate V beta 14+ T cells, although they shed virus in their milk. The nontransgenic offspring of the HYB PRO/Cla mice were infected with this virus, since transgene-specific viral transcripts were detected in their mammary glands. Surprisingly, these offspring demonstrated the progressive deletion of V beta 14+ T cells characteristic of exogenous MMTV (C3H) infection. Sequence analysis demonstrated that these newly acquired viruses had reconstituted superantigen open reading frames resulting from recombination between the HYB PRO/Cla and endogenous Mtv-1 proviral RNAs. Thus, there is selection during the infection process for MMTVs with functional superantigen genes.
Insights
Mouse mammary tumor virus (MMTV) infection requires a functional superantigen. Recombination in milk-borne MMTV can restore the superantigen gene, demonstrating selection for functional MMTV during infection.
Area of Science:
- Virology
- Immunology
- Genetics
Background:
- Mouse mammary tumor virus (MMTV) is a retrovirus known to cause mammary tumors in mice.
- MMTV encodes a superantigen crucial for viral infectivity and T cell deletion in vivo.
- The role of superantigen function in milk-borne MMTV infection and transmission remained unclear.
Purpose of the Study:
- To investigate the necessity of MMTV superantigen function for infection via milk.
- To analyze the genetic mechanisms of MMTV transmission and adaptation in offspring.
Main Methods:
- Generation of HYB PRO/Cla transgenic mice producing MMTV RNA with a non-functional superantigen.
- Monitoring of T cell populations (V beta 14+ T cells) in transgenic mice and their offspring.
- Sequence analysis of MMTV isolates from infected offspring to identify genetic alterations.
Main Results:
- HYB PRO/Cla mice shed MMTV in milk but did not exhibit V beta 14+ T cell deletion.
- Nontransgenic offspring were infected by milk-borne MMTV and showed progressive V beta 14+ T cell deletion.
- Recombination between transgenic and endogenous proviral RNAs reconstituted functional MMTV superantigen genes in offspring.
Conclusions:
- Functional MMTV superantigen is not required for initial milk-borne transmission but is selected for during infection.
- Recombination events are critical for restoring MMTV superantigen function and infectivity in vivo.
- This study highlights the adaptive evolution of MMTV to ensure its propagation through the selection of functional superantigen genes.
