Igor M. Belyakov, M.D., Ph.D., D.Sc.
Research Assistant Professor,
Department of Internal Medicine, Division of Allergy
Michigan Nanotechnology Institute for Medicine and Biological Sciences
ibelyako@umich.edu

Current Research

My primary interest in research is the immunology of host-pathogen interactions and the host immune responses to pathogens at mucosal sites. One major focus of my studies is mucosal immune responses against viral and bacterial infections, innate immunity at mucosal sites, and mucosal inflammation (IBD model). I am interested in clinical and basic research in immunology with the application to the pathogenesis of infectious disease and vaccines. My future studies will focus primarily on mucosal immune responses against viral and bacterial infections that are transmitted through mucosal surfaces (such as HIV-1, HSV, influenza, RSV, smallpox, Salmonella, and others), innate immunity, mucosal adjuvants, CD8+ T cells, MHC class I,  mucosal DC and epithelial cells, and the mechanism of T cell trafficking to and among different mucosal sites. I will work on the development of novel nanoemulsion-based recombinant vaccines for viral and bacterial pathogens and will characterize immune correlates of protection. My laboratory will be developing targeted delivery of pharmaceuticals to inflamed mucosal tissue (IBD) and to cancerous cells. My research will be concentrated in basic research in immunology with applications to the pathogenesis of infectious disease and to vaccine development against viral and bacterial pathogens and cancer.
           
In my previous studies, I have shown that mucosal immunization with a synthetic, multideterminant HIV peptide construct plus cholera toxin adjuvant induced long-lasting, antigen-specific memory in both the inductive (Peyer’s patch) and effector (lamina propria) mucosal sites, as well as in systemic sites. We showed that mucosal CTL responses are both IL-12 and IFN- dependent  (Belyakov et al., Proc. Natl. Acad.Sci., 1998, Vol.95, pp.1709-1714). We presented the first direct demonstration of the importance of mucosal cytotoxic T lymphocytes in the protection against mucosal transmission of a virus (Belyakov et al., J. Clin. Invest. 1998. Vol.102, pp.2072-2081).  We also found that the choice of mucosal adjuvant affects the cytokine enviroment, and the mucosal response and protection can be enhanced by manipulating the cytokine environment with synergistic cytokine combinations incorporated in the vaccine (Belyakov et al., J.Immunol., 2000, Vol.165, p.6454-6462). Our results studying viral vectors indicate that nonreplicating recombinant MVA may be at least as effective for mucosal immunization as replicating recombinant vaccinia virus (Belyakov et al.,  J. Virol.,  1998, Vol 72, N10, p.8264-8272). We took advantage of an asymmetry we observed between mucosal and systemic compartments to show that intrarectal immunization can circumvent the problem of pre-existing vaccinia immunity.  Intrarectal immunization of already vaccinia-immune animals with recombinant vaccinia virus expressing HIV gp 160 induced specific serum antibody and strong HIV-specific cytotoxic T lymphocyte responses, whereas subcutaneous immunization was ineffective in vaccinia-immune animals (Belyakov et al., Proc. Natl. Acad. Sci., 1999, Vol. 96, p.4512-4517). Extending these studies to primates, we found that induction of mucosal CTL with a mucosal AIDS vaccine ameliorates SHIV infection in primates. After intrarectal challenge of macaques with pathogenic SHIV-Ku2, viral titers were eliminated more completely (to undetectable levels) both in the blood and the intestine, a major reservoir for virus replication, in intrarectally immunized animals than in subcutaneously immunized or control macaques. Moreover, CD4+ T cells were better preserved in intrarectally immunized macaques than in subcutaneously immunized animals (Belyakov et al.,  Nat. Medicine.,  2001, Vol 7, N12, p.1320-1326). We recently found that a CTL avidity compartmentalization to the site of the mucosal immunization contributes to the protection of the macaques against SHIV depletion of mucosal CD4+ T cells (Belyakov et al., 2007, Journal of Immunology, Vol.178, pp.7211-7221). We recently demonstrated that amplification of the CTL responses by a synergistic combination of cytokines and CpG oligonucleotides together with a mucosal peptide prime-viral boost strategy may improve the efficacy of mucosal vaccination in Rhesus macaques. There was a significant delay in the peak of viremia in the immunized animals which was inversely correlated with the level of high-avidity SIV-specific CD8+ CTL in the mesenteric lymph nodes prior to the challenge (Belyakov et al., 2006, Blood, Vol.107(8), pp. 3258-3264). Recently we showed that activated DCs carrying skin-derived antigen also migrated from the skin to immune inductive sites in the gut mucosa and presented antigen directly to the resident lymphocytes (Belyakov et al., J. Clin. Invest. 2004. Vol.113, pp.998-1007). We demonstrated that a protective adjuvant effect of CpG ODN for a live viral vector vaccine that is mediated predominantly by CD8+ T cells responses, but not neutralizing antibody production. Protective adjuvant effect of CpG ODN may overcome CD4 deficiency in the induction of protective CD8+ T-cell mediated immunity (Belyakov et al., Journal of Immunology, 2006,Vol.177, pp. 6336-6343).           

Representative Publications

Belyakov I.M., Derby M.A., Ahlers J.D., Kelsall B.L., Earl P., Moss B., Strober W., & Berzofsky J.A., 1998. Mucosal Immunization with HIV-1 peptide vaccine induces mucosal and systemic T lymphocytes and protective immunity in mice against intrarectal recombinant HIV-vaccinia challenge. Proc. Natl. Acad. Sci. USA, Vol.95, pp.1709-1714.

Belyakov I.M., Wyatt L.S., Ahlers J.D., Earl P., Pendleton C.D., Kelsall B.L., Strober W., Moss B., & Berzofsky J.A., 1998. Induction of mucosal CTL response by intrarectal immunization with a replication-deficient recombinant vaccinia virus expressing HIV 89.6 envelope protein. Journal of Virology, Vol.72 (10), pp. 8264-8272.

Belyakov I.M., Ahlers J.D., Brandwein B.Y., Earl P., Kelsall B.L., Strober W., Moss B., & Berzofsky J.A., 1998. Local mucosal HIV-specific CD8+ cytotoxic T lymphocytes protect against mucosal transmission of recombinant virus expressing HIV-1 gp160. Enhancement of protection by local administration of IL-12. Journal of Clinical Investigation, Vol.102, pp.2072-2081.

Belyakov I.M., Moss B., Strober W., & Berzofsky J.A., 1999. Mucosal vaccination overcomes the barrier to recombinant vaccinia immunization caused by preexisting poxvirus immunity. Proc. Natl. Acad. Sci. USA, Vol.96, pp.4512-4517.

Belyakov I.M., Ahlers J.D., Clements J.D., Strober W., & Berzofsky J.A., 2000. Interplay of cytokines and adjuvants in the regulation of mucosal and systemic HIV-specific CTL. Journal of Immunology, Vol.165, pp.6454-6462.

Belyakov I.M., Hel Z, Kelsall B, Kuznetsov V., Ahlers J.D., Nacsa J., Watkins D.I., Altman J, Woodward R, Markham P., Clements J.D., Franchini G., Strober W., & Berzofsky J.A., 2001. Mucosal AIDS Vaccine Reduces Disease and Viral Load in Gut Reservoir and Blood After Mucosal Infection of Macaques. Nature Medicine, Vol.7, pp.1320-1326.

Belyakov I.M., Wang J., Koka R., Ahlers J.D., Snyder J.T., Tse R., Cox J., Gibbs J.S., Margulies D., & Berzofsky J.A., 2001. Activating CTL precursors to reveal CTL function without skewing the repertoire by in vitro expansion. European Journal of Immunology, Vol.31, pp. 3557-3566.

Berzofsky J.A., Ahlers J.D., & Belyakov I.M., 2001. Strategies for Designing and Optimizing New Generation Vaccines. Nature Reviews: Immunology, Vol.1 (3), pp.209- 219.

Belyakov I.M., Earl P., Dzutsev A., Kuznetsov V.A., Lemon M., Wyatt L.S., Snyder J.S., Ahlers J.D., Franchini G., Moss B., & Berzofsky J.A., 2003. Shared modes of protection against poxvirus infection by attenuated and conventional smallpox vaccine viruses. Proc. Natl. Acad. Sci. USA, Vol.100 (16), pp.9458-9463.

Snyder J.T., Alexander-Miller M.A., Berzofsky J.A., & Belyakov I.M., 2003. Molecular mechanisms and biological significance of CTL avidity. Current HIV Research, Vol.1, pp.287-294.

Belyakov I.M., Hammond S.A., Ahlers J.D., Glenn G.M. & Berzofsky J.A., 2004. Transcutaneous immunization induces mucosal CTL and protective immunity by migration of primed skin dendritic cells. Journal of Clinical Investigation, Vol.113 (7), pp.998- 1007.

Belyakov I.M., & Berzofsky J.A., 2004. Immunobiology of mucosal HIV infection and the basis for development of a new generation of mucosal AIDS vaccines. Immunity, Vol.20 (3), pp.247-253.

Berzofsky J.A., Ahlers J.D., Janik J., Morris J., Oh SK., Terabe M., & Belyakov I.M., 2004. Progress on new vaccine strategies for chronic viral infections. Journal of Clinical Investigation, Vol.114 (4), pp.450-462.

Belyakov I.M., Kuznetsov V.A., Kelsall B., Klinman D., Moniuszko M., Lemon M., Markham P.D., Pal P., Clements J.D., Lewis M.G., Strober W., Franchini G., & Berzofsky J.A., 2006. Impact of Vaccine-induced Mucosal High Avidity CD8+ CTL in Delay of AIDS-viral Dissemination from Mucosa. Blood, Vol.107 (8), pp. 3258-3264.

Belyakov I.M., Isakov D., Zhu Q., Dzutsev A., Klinman D., & Berzofsky J.A., 2006. Enhancement of CD8+ T cell Immunity in the Lung by CpG ODN Increases Protective Efficacy of a Modified Vaccinia Ankara Vaccine Against Lethal Poxvirus Infection Even in a CD4-Deficient Host. Journal of Immunology, Vol.177, pp. 6336-6343.

Belyakov I.M., Isakov D., Zhu Q., Dzutsev A. & Berzofsky J.A., 2007. A Novel Functional CTL Avidity/Activity Compartmentalization to the Site of Mucosal Immunization Contributes to Protection of Macaques Against Simian/Human Immunodeficiency Viral Depletion of Mucosal CD4+ T cells. Journal of Immunology, Vol.178, pp.7211-7221.

Belyakov I.M., Kozlowski S., Mage M., Ahlers J.D., Boyd L.F., Margulies D.H. & Berzofsky J.A., 2007. Role of á3 domain of class I MHC molecules in the activation of high and low avidity of CD8+ cytotoxic T lymphocytes. International Immunology, Vol.19 (12); pp.1413-1420.

Belyakov I.M. & Ahlers J.D., 2008. Functional CD8+ CTL in Mucosal Sites and HIV Infection: Moving Forward toward a Mucosal AIDS Vaccine. Trends in Immunology, Vol.29(11), pp.574-585.

Belyakov I.M., Ahlers J.D., Nabel G.J., Moss B., & Berzofsky J.A., 2008.Generation of functionally active HIV-1 specific CD8+ CTL in intestinal mucosa following mucosal, systemic or mixed prime-boost immunization. Virology, Vol.381(1); pp.106-115.

Belyakov I.M., & Ahlers J.D., 2009. What Role Does the Route of Immunization Play in Generation of Protective Immunity Against Mucosal Pathogens? Journal of Immunology, Vol.183(11), pp.6883-6892.

Belyakov I.M. & Ahlers J.D., 2011. Simultaneous approach using systemic, mucosal and transcutaneous routes of immunization for induction of protective mucosal immune responses. Current Medical Chemistry, Vol.18(26), pp.3953-3962. 

Isakov D, Dzutsev A, Berzofsky JA, & Belyakov IM., 2011.  Lack of IL-7 and IL-15 signaling affects interferon-gamma production more than survival of small intestinal intraepithelial CD8 T cells.  European Journal of Immunology (in press).