Profiles of Pioneers: Class of 2004–2009
Joseph (Mike) McCune, M.D., Ph.D.
Division of Experimental Medicine, University of California at San Francisco
San Francisco, CA
“[Pioneer funding] has allowed me to carry out a number of high-stakes and risky experiments.”
Fewer than half of all babies born to HIV-positive mothers are infected themselves, and of those, only a small fraction become infected in the womb. Why can some be exposed to HIV and resist infection, or become infected and either clear the virus or live with it without developing AIDS?
Dr. Mike McCune’s research aims to enable an HIV-infected host to keep the infection under control. With his Pioneer Award, McCune wanted to explore the reasons behind unexplained differences in the control of HIV and the progression to AIDS. This was a new area of research and one that would have not been easily funded by traditional means.
McCune has approached this problem by evaluating three naturally occurring scenarios:
- Nonhuman primates infected with SIV (the simian version of HIV) that do not get sick
- HIV-infected humans who control the virus without treatment
- Babies born to HIV-infected mothers who do not become infected
McCune’s Pioneer Award research uncovered something unexpected—that a pregnant mother’s immune cells “teach” those of her growing fetus how to balance the need for self-defense and the requirement for immune tolerance, suggesting that proper balance is critical. Too much immune restraint might lead to a deadly infection in the newborn; too little could lead to autoimmunity.
Research in this area has offered McCune and others a rare glimpse into the development of the human adaptive immune system. His work shows that the mother’s cells cross the placenta, enter the fetus’ body and teach it to tolerate her cells. This permits the mother and the fetus to co-exist during pregnancy, even though the two have DNA differences.
The work could have relevance to conditions beyond mother-to-child transmission of HIV, including other fetal infections, organ transplantation and autoimmune disorders like Type 1 diabetes.
McCune has also used his Pioneer Award to focus on the observation that chronic immune activation and progression to AIDS occur after SIV infection in macaques, but not in natural host primate species. This work has identified gene expression patterns specific to disease susceptibility, tissue compartmentalization and infection duration. McCune’s findings indicate that a change in the balance of different T cell types impacts the course of SIV disease progression.
Mold JE, Michaëlsson J, Burt TD, Muench MO., et al. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science 2008;322:1562-5.
Favre D, Lederer S, Kanwar B, Ma ZM, et al. Critical loss of the balance between Th17 and T regulatory cell populations in pathogenic SIV infection. PLoS Pathog 2009;5:e1000295.
Lederer S, Favre D, Walters KA, Proll S, et al. Transcriptional profiling in pathogenic and non-pathogenic SIV infections reveals significant distinctions in kinetics and tissue compartmentalization. PLoS Pathog 2009;5:e1000296.
Schweneker M, Favre D, Martin JN, Deeks SG, et al. HIV-induced changes in T cell signaling pathways. J Immunol 2008;180:6490-500.
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