Todd M. Allen, Ph.D.

Associate Professor in Medicine
Ragon Institute of MGH, MIT, and Harvard
Massachusetts General Hospital
Harvard Medical School
Bldg. 149, 13th Street, Rm 6625
Charlestown, MA 02129
Tel: 617-726-7846
Fax: 617-724-8586
tallen2@partners.org
6 postdoctoral fellows

RESEARCH INTERESTS:

My laboratory at the Ragon Institute of MGH, MIT and Harvard (formerly Partners AIDS Research Center) focuses on characterizing genetic changes in HIV and hepatitis C virus (HCV) in response to host immune pressures. These viruses can rapidly evade host immune responses through sequence evolution (mutation) which we use as a powerful tool to measure the ability of immune responses to influence these pathogens in the host. This work has lead to a greater understanding of the interplay between these highly variable pathogens and the host cellular immune response. My laboratory has 3 major areas of interest designed to aid in the development of more effective vaccines against HIV and HCV: 

Impact of immune pressures on HIV evolution:  A critical issue to HIV vaccine design is determining which cellular immune responses are dictating immune control. Recent studies indicate that viral evolution is uniquely linked to host genetic markers and immune control. Therefore, longitudinal assessment of viral evolution following acute HIV infection is helping us pinpoint those immune responses exerting the greatest selective pressure on HIV, and thus most critical to its control. Viral sequencing from larger cohorts of genetically typed HIV-infected subjects is also enabling us to reveal very distinct evolutionary patterns on the population level correlating with control of HIV. In parallel we are examining the evolution of a distinctly different clade of HIV (CRF01_AE) in Thailand to examine how different clades of HIV evolve under different host genetic backgrounds.

HIV-1 viral replicative fitness: The replicative capacity (or fitness) of different HIV strains is also contributing to immune control and disease progression. Both drug- and immune-driven mutations have been shown to dramatically impair HIV fitness. As such, we have begun to address the question of whether the ability of particular cellular immune responses to control HIV is due to their ability to induce uniquely deleterious mutations that cripple HIV’s ability to replicate effectively. Thus far these studies have revealed a substantial impact of immune-driven escape mutations in Gag on capsid structure and viral replication. Moreover, this work has revealed critical structural interactions between viral proteins and host proteins such as cyclophilin A and Trim5-alpha that may be critical to HIV replication and also highly susceptible to the effects of immune driven mutations.

Impact of immune pressures on HCV evolution: Recent work has illustrated immune escape through viral evolution in HCV, but difficulties in detecting immune responses in HCV-infected subjects has hampered this work. Our recent work illustrates that viral sequence evolution in HCV may serve as an excellent surrogate marker for identifying unique cellular immune responses correlating with immune control. In collaboration with the Broad Institutes we have now begun to extend these efforts to larger cohorts to more broadly identify correlates of immune control with host genetics in order to guide vaccine design.

References:

Allen TM, O'Connor DH, Jing P, Dzuris JL, Mothé BR, Vogel TU, Dunphy E, Liebl ME, Emerson C, Wilson N, Kunstman KJ, Wang X, Allison DB, Hughes AL, Desrosiers RC, Altman JD, Wolinsky SM, Sette A, Watkins DI.   Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia.  Nature 2000;407:386-90.

O'Connor DH*, Allen TM*, Vogel TU, Jing P, DeSouza IP, Dodds E, Dunphy EJ, Melsaether C, Mothé B, Yamamoto H, Horton H, Wilson N, Hughes AL, Watkins DI. Acute phase cytotoxic T lymphocyte escape is a hallmark of simian immunodeficiency virus infection.  Nature Medicine 2002; 8:493-9. (*shared 1st author)

Altfeld M*, Allen TM*, Yu XG, Johnston MN, Agrawal D, Korber BT, Montefiori DC, O'Connor DH, Davis BT, Lee PK, Maier EL, Harlow J, Goulder PJ, Brander C, Rosenberg ES, Walker BD.  HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus.  Nature 2002; 420:434-9.

Timm J, Lauer GM, Kavanagh DG, Sheridan I, Kim AY, Lucas M, Pillay T, Ouchi K, Reyor LL, Zur Wiesch JS, Gandhi RT, Chung RT, Bhardwaj N, Klenerman P, Walker BD, Allen TM.  CD8 epitope escape and reversion in acute HCV infection.  Journal of Experimental Medicine 2004;200:1593-604.

Schneidewind A, Brockman MA, Yang R, Adam RI, Li B, Le Gall S, Rinaldo CR, Craggs SL, Allgaier RL, Power KA, Kuntzen T, Tung CS, LaBute MX, Mueller SM, Harrer T, McMichael AJ, Goulder PJR, Aiken C, Brander C, Kelleher AD, Allen TM.  Escape from the Dominant HLA-B27 Restricted CTL Response in Gag is Associated with a Dramatic Reduction in HIV-1 Replication.  Journal of Virology, 2007 81(22): 12382-93.

Streeck S, Li B, Poon AFY, Schneidewind A, Gladden AD, Power KA, Daskalakis D, Bazner S, Zuniga R, Brander C, Rosenberg E, Frost SDW, Altfeld M, Allen TM.  Immune Driven Recombination and Loss of Control Following HIV Superinfection.  Journal of Experimental Medicine. 2008 Aug 4;205(8):1789-96