Microbiology and Immunology
Uniformed Services University of the Health Sciences
Department of Microbiology and Immunology
4301 Jones Bridge Road
Bethesda, Maryland 20814-4799
Phone: (301) 295-3737
FAX: (301) 295-3773
Joseph Mattapallil, B.V.Sc., M.S., Ph.D.
Ph.D., University of California Davis
Research: Cellular and Molecular Mechanisms of HIV Pathogenesis and HIV Vaccine Development
Memory CD4 T cells is the primary target of HIV infection. Mucosal tissues are enriched for these memory CD4 T cells thereby making these tissues a central player in the immunopathogenesis and persistence of HIV infection. Mucosal CD4 T cells are the first to get infected as HIV breaches the mucosal barrier and serve to actively amplify infection. As the infection explodes out of the mucosa it ravages all of the memory CD4 T cells that are present in the entire immune system very early during the acute phase. This early phase of infection is accompanied by a massive loss of memory CD4 T cells. The cells that are lost represent the entire memory CD4 T cell repertoire that an individual has accumulated over his lifetime. Given the central importance of these cells in the development of immune responses onset of immunodeficiency occurs very early during infection. Protecting the mucosal CD4 T cells from infection thereby is a central goal for the development of HIV vaccines and therapy. Using state of the art technologies such as multi-color flow cytometry, real time qPCR and microarray based approaches we hope to gain a better understanding of the correlate of protection in the mucosa, and develop strategies that can better protect the mucosal CD4 T cell compartment. Research in my laboratory is focused on:
- Understanding and delineating the correlates of immunity in mucosal tissues.
- Developing vaccine based strategies to protect the mucosal CD4 T cell compartment.
- Understanding why CD8 T cells fail to control viral infection.
- Developing strategies aimed at reducing the viral reservoir in mucosal and other lymphoid tissues.
- Understanding the mechanisms underlying the reactivation of secondary viral infections such as EBV and CMV in mucosal tissues during immunodeficiency.
Understanding and delineating the correlates of immunity in mucosal tissues
Protecting the mucosal CD4 T cell from infection is critical to stop the dissemination of infection. However the exact nature of protective immunity required in the mucosal tissue compartment is not clearly known. Studies in non-human primates using either CD8 depletion or passive immunization suggest that both arms of the immune system may be required. Though both T and B cell responses may be critical very little is known about the nature and magnitude of these responses that may be required to either prevent or contain infection. We are using the non-human primate model of HIV infection to address this question either using T/B cell depletion or specific vaccination strategies. We hope to get better insights into the role played by T and B cells in protecting the mucosal CD4 T cell compartment. This will allow us to design better vaccination and therapeutic approaches to control HIV.
Developing vaccine based strategies to protect the mucosal CD4 T cell compartment
Previous studies have shown that systemic vaccination induced immune responses in mucosal tissues of non-human primates that were challenged with pathogenic SIV (Simian immunodeficiency virus). However these responses were lower than those induced in the peripheral tissues. As a consequence the extent of protection was dramatically lower in mucosal tissues than in the periphery. One of our major objectives to explore the concept of mucosal immunizations to induce immune responses in the mucosa that are potent and larger in magnitude, and clarify the role these responses play in protection following challenge.
Understanding why CD8 T cells fail to control viral infection
HIV and SIV infections are associated with an early and massive loss of memory CD4 T cells. Our studies and others have shown these early changes were accompanied by a loss of SIV specific CD4 T cells. Studies in small animal models have demonstrated that CD4 T cell help is critical for the development and maintenance of adaptive CD8 T and B cell responses to viral infections. We hypothesize that the early loss of HIV specific CD4 T cells leads to the generation of defective T and B cell responses in HIV infection. These defects eventually lead to a failure of immune responses to control HIV infection. We are addressing this question in SIV infected non-human primates by using strategies that can protect their SIV specific CD4 T cells. By evaluating the effect of protecting SIV specific CD4 T cells on the phenotype and differentiation of CD8 T cells we hope to better understand the role of CD4 T cell help in anti-viral control of HIV infection.
Developing strategies aimed at reducing the viral reservoir in mucosal and other lymphoid tissues
HIV latency is associated with the generation of viral reservoir that appears to play a critical role in viral persistence. The inability to reduce the viral reservoir has been a major reason for the failure of anti-retroviral therapy. A critical requirement for developing strategies aimed at reducing the viral reservoir it to first clarify and understand where and how the viral reservoir evolves over time. We propose to develop SIV that has been fluorescently tagged to address this question. Using this approach we hope to be able to study the effects of infection, therapy and vaccination on the viral reservoir burden in the mucosa and other tissues.
Understanding the mechanisms underlying the reactivation of secondary viral infections such as EBV in mucosal tissues during immunodeficiency
HIV infection causes an extensive loss of CD4 T cells and severely disables the capacity of the immune system to mount secondary immune responses to previously encountered pathogens. This progressive loss of CD4 T cells leads to immunodeficiency and AIDS, and is accompanied by the reemergence of various opportunistic viral infections in the mucosal tissues such as EBV and CMV. The exact mechanisms leading to the reactivation of these opportunistic viral infections are not known. It is possible the both immune and non-immune related mechanisms may be playing a role in this process. Research is currently underway to delineate the mechanisms at a cellular and molecular level using the non-human primate model for HIV infection. These studies will provide valuable insights into the mechanisms of EBV and CMV reactivation that will aid in the development of novel therapeutic intervention strategies to control HIV infection associated opportunistic viral infections.
Peer Reviewed Publications
Taylor, B. C., Mattapallil, J., Scibienski, R and Stott, J. L. 1994. Characterization of a novel bovine cell-cell adhesion protein. Tissue Antigens. 44: 252-60.
Smit-McBride, Z., Mattapallil, J., Villinger, F., Ansari, A. A and Dandekar, S. 1998. Intracellular cytokine expression in the CD4+ and CD8+ T cells from intestinal mucosa of simian immunodeficiency virus infected macaques. J. Med. Primatol. 27: 129-140.
Smit-McBride, Z., Mattapallil, J., D. A. Ferrick and Dandekar, S. 1998. Gastrointestinal T lymphocytes retain high potential for cytokine responses but have severe CD4 (+) T-cell depletion at all stages of simian immunodeficiency virus infection compared to peripheral lymphocytes. J. Virol. 72: 6646-56.
Mattapallil, J., Smit-McBride, Z., McChesney, M and Dandekar, S. 1998. Intestinal intraepithelial lymphocytes are primed for gamma interferon and MIP-1beta expression and display antiviral cytotoxic activity despite severe CD4 (+) T-cell depletion in primary simian immunodeficiency virus infection. J. Virol. 72: 6421-9.
Mattapallil, J., Smit-McBride, Z and Dandekar, S. 1999. Intestinal epithelium is an early extra-thymic site for the increased prevalence of CD34+ progenitor cells during primary SIV infection. J. Virol. 73: 4518-23.
Mattapallil, J., Smit-McBride, Z., Dailey, P and Dandekar, S. 1999. Activated memory CD4+ T cells repopulate the intestinal mucosa early after anti-retroviral therapy but exhibit a decreased potential to produce IL-2. J. Virol: 73. 6661-9.
Mattapallil, J., Dandekar, S., Canfield, D. R and Solnick, J. V. 2000. A predominant Th-1 type of immune response is induced early during acute H.pylori infection in rhesus macaques. Gastroenterology. 118. 307-315.
Mattapallil, J., Reay, E and Dandekar, S. 2000. Early expansion of CD8ab+ T cells is observed in the intestinal epithelium in contrast to the depletion CD8aa+ T cells during primary simian immunodeficiency virus infection of rhesus macaques. AIDS. 14: 637-46.
Mattapallil, J., Letvin, N. L and Roederer, M. 2004. T cell dynamics in acute SIV infection. AIDS. 18: 13-23.
Song, K., Rabin, R. L., Hill, B. J., De Rosa, S., Perfetto, S. P., Zhang, H. H., Foley, J. F., Reiner, J. S., Liu, J., Mattapallil, J., Douek, D. C., Roederer, M and Farber, J. M. 2005. Novel subsets of CD4+ memory T cells reveal early-branched pathways of T cell differentiation in humans. PNAS. 102: 7916-21.
Mattapallil, J., Douek, D. C., Hill, B., Nishimura, Y., Martin, M. A and Roederer, M. 2005. Massive infection and loss of memory CD4 T-cells in multiple tissues during acute SIV Infection. Nature. 434: 1093-97.
Nishimura, Y., Brown, C. R., Mattapallil, J., Igarashi, T., Buckler-White, A., Lafont, B., Hirsch, V., Roederer, M and Martin, M. A. 2005. Resting na?ve CD4+ T cells are massively infected and eliminated by X4-tropic SHIVs in Macaques. PNAS. 102: 8000-5.
Wille, U., Flynn, B. J., Lore, K., Koup, R. A., Kedl, R. M., Mattapallil, J., Nason, M., Roederer, M., Weiss, W. R and Seder, R. A. 2005. HIV Gag protein conjugated to a TLR7/8 agonist elicits Th1 and CD8+ T cell responses in monkeys. PNAS 102. 15190-4.
Kuwata, T., Dehghani, H., Plishka, R., Buckler-White, A., Igarashi, T., Mattapallil, J., Roederer, M and Hirsch, V. M. 2005. Characterization of Infectious Molecular Clones from a Simian Immunodeficiency Virus-infected Rapid Progressor (RP) Macaque: Differential Selection of RP-Specific Envelope Mutations in vitro and in vivo. J. Virol. 80: 1463-75.
Wille, U., Flynn, B. J., Lore, K., Koup, R. A., Miles, A.P., Saul, A., Kedl, R. M., Mattapallil, J., Weiss, W.R., Roederer, M and Seder, R. A. 2006. TLR agonists influence the magnitude and quality of Th1 and CD8+ T cell responses following prime-boost immunization in non-human primates. J. Exp. Med. 203: 1249-58.
Mattapallil, J., Douek, D.C., Buckler-White, A., Montefiori, D., Letvin, N. L., Nabel, G. J and Roederer, M. 2006. Vaccination prevents the destruction of CD4 memory T cells during acute SIV infection. J. Exp. Med. 203: 1533-41.
Mattapallil, J., Hill, B., Douek, D.C and Roederer, M. 2006. Systemic vaccination prevents the total destruction of mucosal CD4 T cells during acute SIV challenge. J. Med. Primatol. 35: 217-24.
Seggewiss, R., Lore, K., Guenaga, F.J., Pittaluga, S., Mattapallil, J., Chow, C. K., Koupm, R. A., Camphausen, K., Nason, M. C., Meier-Schellersheim, M., Donahue, R. E., Blazar, B. R., Dunbar, C. E and Douek, D. C. 2007. Keratinocyte growth factor augments immune reconstitution after autologous hematopoietic progenitor cell transplantation in rhesus macaques. Blood. 110: 441-9.
Petrovas, C., Price, D. A., Mattapallil, J., Ambrozak, D. R., Geldmacher, C., Cecchinato, V., Vaccari, M., Tryniszewska, E., Gostick, E., Roederer, M., Douek, D. C., Morgan, S. H., Davis, S. J., Franchini, G and Koup, R. A. 2007. SIV-specific CD8+T-cells express high levels of PD1 and cytokines but have impaired proliferative capacity in acute and chronic SIVmac251 infection. Blood. 110: 928-36.
Wilson, D.P., Mattapallil, J., Zhang, L., Roederer, M and Davenport, M. P. 2007. Estimating the infectivity of CCR5-tropic SIVmac251 in the gut: implications for HIV vaccination. J. Virol. 81: 8025-9.
Mattapallil, M. J., Augello, A., Cheadle, C., Teichberg, D., Becker, K., Chan, C. C., Mattapallil, J., Pennesi, G and Caspi, R. R. 2008. Differentially expressed genes in MHC-compatible rat strains that are susceptible or resistant to experimental autoimmune uveitis. Invest Ophthalmol Vis Sci. 49:1957-70.
Vaccari, M., Mattapallil, J., Song, K., Tsai, W.P., Hryniewicz, A., Venzon, D., Zanetti, M., Reimann, K.A., Roederer, M and Franchini, G. 2008. Reduced protection from SIVmac251 afforded by memory CD8+ T-cells induced by vaccination in condition of CD4+ T-cell deficiency. J. Virol. 82: 9629-38.
Kader, M., Hassan, W., Eberly, M., Piatak, M., Lifson, J., Roederer, M and Mattapallil, J. J. 2008. Anti-retroviral therapy prior to acute viral replication preserves CD4 T cells in the periphery but not in the rectal mucosa during acute simian immunodeficiency virus infection. J. Virol. 82: 11467-71. (Faculty of 1000 Medicine citation in 2008).
Petravic, J., Ribeiro, R. M., Casimiro, D. R., Mattapallil, J., Roederer. M., Shiver, J. W and Davenport, M. P. 2008. Estimating the impact of vaccination on acute simian-human immunodeficiency virus/simian immunodeficiency virus infections. J. Virol. 82: 11589-98.
Eberly, M. D., Kader, M., Hassan, W., Rogers, K. A., Zhou, J., Mueller, Y.M., Mattapallil, M. J., Piatak, M., Lifson, J. D., Katsikis, P. D., Roederer, M., Villinger, F and Mattapallil, J.J. 2009. Increased IL-15 production is associated with higher susceptibility of memory CD4 T cells to SIV during acute infection. J. Immunology. 182: 1439-48.
Nishimura, Y., Sadjadpour, R., Mattapallil, J., Igarashi, T., Lee, W., Buckler-White, A., Roederer, M., Chun, T. W and Martin, M. A. 2009. High frequencies of resting CD4+ T cells containing integrated viral DNA are found in rhesus macaques during acute lentivirus infection. PNAS: 106: 8015-20.
Kader, M., Wang, X., Piatak, M., Lifson, J., Roederer, M., Veazy, R and Mattapallil, J. J. 2009. a4+?7hiCD4+ memory T cells harbor most Th-17 cells and are preferentially infected during acute SIV infection. Mucosal Immunology: 2: 439-49. (Faculty of 1000 Medicine citation in 2010).
Kader, M., Bixler, S., Piatak, M., Lifson, J. D. and Mattapallil, J. 2009. Antiretroviral therapy fails to restore the severe Th-17: Tc-17 imbalance observed in peripheral blood during simian immunodeficiency virus infection. J Medical Primatol: 38: 24-31.
Kader, M., Bixler, S., Roederer, M., Veazey, R. and Mattapallil, J. 2009. CD4 T cell subsets in the mucosa are CD28+Ki-67?HLA-DR?CD69+ but show differential infection based on a4b7 receptor expression during acute SIV infection. J Medical Primatol: 38: 32-38.
Mueller, Y. M, Do, D. H., Boyer, J. D., Kader, M., Mattapallil, J., Lewis, M. G., Weiner, D. B., and Katsikis, P. D. 2009. CD8-depletion of SIV-infected macaques induces CD4+ T cell proliferation that contributes to increased viral loads. J. Immunology: 183: 5006-12.
Geisbert, T. W., Daddario-DiCaprio, K. M., Hickey, A. A., Smith, M. A., Chan, Y., Wang, L., Mattapallil, J.,Geisbert, J. B., Bossart, K. N., and Broder, C. C. 2010. Development of an acute highly pathogenic nonhuman primate model of Nipah virus infection. PLOS One: 18: e10690.
Song, K., Bolton, D., Wilson, R., Bao, S., Mattapallil, J., Andrews, C., Sadoff, G., Goudsmit, J., Pau, M., Seder, R. A., Kozolowski, P., Nabel, G. J., Roederer, M., and Rao, S. S. 2010. Potent local and systemic immunogenicity of finely -aerosolized adenoviral vaccines. PNAS: 107: 22213-8.
Grorge, J., Cofano, E., Lybarger, E., Louder, M., Lafont, B. A., Mascola, J. R., Robert-Guroff, M and Mattapallil, J. 2011. Alterations in Homeostatic Balance of CD4 and CD8+FoxP3+ T cells is Associated with Higher Viral Loads in SIV Infection. AIDS Research & Hum Retroviruses: 27: 763-75.
Teran, R., Mitre, E., Vaca, M., Erazo, S., Oviedo, G., Hubner, M. P., Quinzo, I., Chico, M. E., Mattapallil, J., Bickle, Q., Rodrigues, L. C., and Cooper, P. J. 2011. Immune system development during early childhood in tropical Latin America: evidence for the age-dependent down regulation of the innate immune response. Clinical Immunology: 138: 299-310.
Uchida, N., Bonifacino, A., Krouse, A. E., Metzger, M. E., Csako, G., Fasano, R. M., Leitman, S. F., Mattapallil, J. Hsieh, M. M., Tisdale, J. F and Donahue, R. E. 2011. Long-Term Reconstitution of Transduced Rhesus CD34+ Cells Mobilized by G-CSF and Plerixafor. Experimental Hematology: 39: 795-805.
Mattapallil, M. J., Silver, P. B., Mattapallil, J., Horai, R., Karabekian, Z., McDowell, H., Chan, C., James, E. A., Kwok, W. W., Sen, N., Nussenblatt., R. B., David, C, S., and Caspi, R. R. 2011. Uveitis-associated epitopes of retinal antigens are pathogenic in the humanized mouse model of EAU and identify autoagressive cells. Journal of Immunology: 187: 1977-85.
Kean, L. S., Sen, S., Singh, K., Robertson, J., Onabajo, O. O., Bonifacino, A. C., Metzger, M. E., Promislow, D. E. L., Mattapallil, J and Donahue, R. E. 2011. Significant mobilization of both conventional and regulatory T cells with AMD3100. Blood: 118: 6580-90.
Moore, A. C., Bixler, S. L., Lewis, M. G., Verthelyi, D and, Mattapallil, J. 2011. Mucosal and Peripheral Lin?HLA-DR+CD11c/123?CD14? Mononuclear cells are preferentially infected very early during simian immunodeficiency virus infection. J. Virology: 86: 1069-78.
Mattapallil, J., and Roederer, M. 2006. Acute HIV pathogenesis: it takes more than guts. Current opinion in HIV/AIDS. 1(1): 10-15.
Mattapallil, J., and Roederer, M. 2006. HIV Vaccines: can mucosal CD4 T cells be preserved? Current opinion in HIV/AIDS. 1(4): 272-276.
Roederer M and Mattapallil, J. 2007. CCR5 vs HIV: the less the better!. Blood. 109 (3): 854.
Mattapallil, J and Roederer M. 2008. The mucosa and vaccine induced immune protection in nonhuman primates. Current Opinion in HIV/AIDS. 3:387-92.
Mattapallil, J and Roederer M. 2011. Commentary on ?Massive infection and loss of memory CD4 T cells in multiple tissues during acute SIV infection. HIV Global HIV Vaccine Enterprise electronic resource for HIV vaccine research community