Reverse transcriptase-dependent and -independent phases of infection with mouse mammary tumor virus: implications for superantigen function.
Mouse mammary tumor virus (MMTV) encodes a superantigen (SAg) that promotes stable infection and virus transmission. Upon subcutaneous MMTV injection, infected B cells present SAg to SAg-reactive T cells leading to a strong local immune response in the draining lymph node (LN) that peaks after 6 d. We have used the reverse transcriptase inhibitor 3'-azido-3'-deoxythymidine (AZT) to dissect in more detail the mechanism of SAg-dependent enhancement of MMTV infection in this system. Our data show that no detectable B or T cell response to SAg occurs in AZT pretreated mice. However, if AZT treatment is delayed 1-2 d after MMTV injection, a normal SAg-dependent local immune response is observed on day 6. Quantitation of viral DNA in draining LN of these infected mice indicates that a 4,000-fold increase in the absolute numbers of infected cells occurs between days 2 and 6 despite the presence of AZT. Furthermore MMTV DNA was found preferentially in surface IgG+ B cells of infected mice and was not detectable in SAg-reactive T cells. Collectively our data suggest that MMTV infection occurs preferentially in B cells without SAg involvement and is completed 1-2 d after virus challenge. Subsequent amplification of MMTV infection between days 2 and 6 requires SAg expression and occurs in the absence of any further requirement for reverse transcription. We therefore conclude that clonal expansion of infected B cells via cognate interaction with SAg-reactive T cells is the predominant mechanism for increasing the level of MMTV infection. Since infected B cells display a memory (surface IgG+) phenotype, both clonal expansion and possibly longevity of the virus carrier cells may contribute to stable MMTV infection.
Held
W
W
Ludwig Institute for Cancer Research, University of Lausanne, Epalinges, Switzerland.
Waanders
G A
GA
Acha-Orbea
H
H
MacDonald
H R
HR
D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D004279:DNA, Viral / Q000032:analysis / Q000096:biosynthesis; D007700:Kinetics; D008198:Lymph Nodes / Q000276:immunology / Q000821:virology; D008324:Mammary Tumor Virus, Mouse / Q000187:drug effects / Q000472:pathogenicity / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D010641:Phenotype; D016133:Polymerase Chain Reaction; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism*; D018089:Superantigens / Q000096:biosynthesis*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000821:virology; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000494:pharmacology
D004279:DNA, Viral; D018089:Superantigens; D015215:Zidovudine; D012194:RNA-Directed DNA Polymerase