The primary goal of my laboratory is to understand how the innate immune system detects retroviral infection and initiates virus-neutralizing adaptive immune responses. In addition, we are also interested in mechanisms evolved by retroviruses to overcome host protective responses. To investigate these important questions, we employ virus-resistant mice capable of controlling retroviruses from distinct genera. As is the case with other researchers who utilize mouse models to study either human or mouse pathogens, we trust that the data we generate will ultimately further our understanding of the progression and resolution of human disease. Using mice from retrovirus-resistant strains, we found that endosomal Toll-like receptor 7 (TLR7) is an innate immune receptor that detects mouse retroviruses and signals to stimulate the production of virus- neutralizing antibodies (Kane et al, Immunity 2011). The same innate mechanism was shown to detect Human Immunodeficiency Virus 1 (HIV-1).
Most viruses enter the host through surfaces exposed to the microbiota that protect the host from incoming pathogens. We performed pioneering work showing that orally transmitted retroviruses exploit the microbiota for their own benefit (Kane et al, Science 2011). The enveloped retrovirus, MMTV acquires host Lipopolysaccharide (LPS)-binding factors during budding to bind LPS produced by Gram-negative commensal bacteria (Wilks et al, Cell Host and Microbe 2015). Virion-associated LPS activates Toll-like receptor 4 (TLR4), stimulating production of the immunosuppressive cytokine IL-10 and virus evasion of the host immune response (Kane et al, Science, 2011). Julie Pfeiffer’s group simultaneously showed that picornavirus and reovirus transmission also depends on the gut microbiota. Noroviruses and rotaviruses have been recently added to the list of viruses known to require the gut microbiota for successful transmission, further supporting the idea that mouse models lead to fundamental discoveries.
Retroviruses earned their notoriety by inducing a broad range of tumors in vertebrates. Whereas some retroviruses carry oncogenes in their genome, the vast majority of retroviruses do not encode such elements and thus, must integrate near cellular proto-oncogenes and up-regulate them to induce tumors. Many cellular genes involved in tumorigenesis were first identified as viral oncogenes (v-onc) or genes up-regulated upon retroviral insertion. They are now known to be involved in various types of spontaneous tumors in humans. Up-regulation of cellular protooncogenes via insertional mutagenesis or insertion of v-oncs constitutes a necessary step for tumor induction. However, up-regulation of an oncogene alone is not sufficient for tumor induction and other events are required for tumor development. We have found that the gut commensal bacteria serve as an epigenetic factor that contributes to virally-induced cancer. Using well-defined animal models of virally-induced leukemogenesis we are searching for the mechanism(s) by which the commensal microbiota promotes virally-induced tumorigenesis.
All animals, including humans, show different susceptibility to infectious retroviruses. Mice of the I/LnJ strain control both gamma- and betaretroviruses via the same recessive immune mechanism, which involves production of virus-neutralizing antibodies (Abs)
(Purdy et al, J Exp Med 2003; Case et al, J Immunol 2005; Case et al, J Virol 2007). Even though I/LnJ mice become infected with both viruses, they produce anti-virus Abs which coat virions, rendering them uninfectious. As a consequence, retroviruses are eliminated from infected mice. The retrovirus resistance mechanism in I/LnJ mice is controlled by a single locus, virus infectivity controller 1 (vic1), that we mapped to Chromosome 17 (Case et a., J Virol, 2007). A non-classical major histocompatibility class II (MHCII) gene, H2-Ob (Ob), an inhibitor of antigen presentation was identified as the gene encoding for Vic1 (Denzin et. al, 2017, Immunity 47, 310-322). Subsequent bioinformatics and functional analyses of the human H2-Ob homologue, HLA-DOB revealed both loss- and gain-of-function alleles, which could affect the ability of their carriers to control infections with Human Hepatitis B (HBV) and C (HCV) viruses. Thus, understanding of the previously unappreciated role of H2-O (HLA-DO) in immunity to infections may suggest new approaches in achieving neutralizing immunity to viruses.
Moscow State University
Moscow, Former USSR
PhD - Biochemistry, Virology
MHC Class II Presentation Is Affected by Polymorphism in the H2-Ob Gene and Additional Loci.
Cullum E, Graves AM, Tarakanova VL, Denzin LK, Golovkina T. MHC Class II Presentation Is Affected by Polymorphism in the H2-Ob Gene and Additional Loci. J Immunol. 2021 Jun 16.
Genetic Control of Neonatal Immune Tolerance to an Exogenous Retrovirus.
Cullum E, Dikiy S, Beilinson HA, Kane M, Veinbachs A, Beilinson VM, Denzin LK, Chervonsky A, Golovkina T. Genetic Control of Neonatal Immune Tolerance to an Exogenous Retrovirus. J Virol. 2020 11 23; 94(24).
Human Hepatitis B Viral Infection Outcomes Are Linked to Naturally Occurring Variants of HLA-DOA That Have Altered Function.
Graves AM, Virdis F, Morrison E, Álvaro-Benito M, Khan AA, Freund C, Golovkina TV, Denzin LK. Human Hepatitis B Viral Infection Outcomes Are Linked to Naturally Occurring Variants of HLA-DOA That Have Altered Function. J Immunol. 2020 08 15; 205(4):923-935.
An Immunologic Mode of Multigenerational Transmission Governs a Gut Treg Setpoint.
Ramanan D, Sefik E, Galván-Peña S, Wu M, Yang L, Yang Z, Kostic A, Golovkina TV, Kasper DL, Mathis D, Benoist C. An Immunologic Mode of Multigenerational Transmission Governs a Gut Treg Setpoint. Cell. 2020 06 11; 181(6):1276-1290.e13.
Polymorphic Immune Mechanisms Regulate Commensal Repertoire.
Khan AA, Yurkovetskiy L, O'Grady K, Pickard JM, de Pooter R, Antonopoulos DA, Golovkina T, Chervonsky A. Polymorphic Immune Mechanisms Regulate Commensal Repertoire. Cell Rep. 2019 10 15; 29(3):541-550.e4.
Mapping Viral Susceptibility Loci in Mice.
Kane M, Golovkina TV. Mapping Viral Susceptibility Loci in Mice. Annu Rev Virol. 2019 09 29; 6(1):525-546.
A Single Locus Controls Interferon Gamma-Independent Antiretroviral Neutralizing Antibody Responses.
Kane M, Deiss F, Chervonsky A, Golovkina TV. A Single Locus Controls Interferon Gamma-Independent Antiretroviral Neutralizing Antibody Responses. J Virol. 2018 08 15; 92(16).
Neutralizing Antibody Responses to Viral Infections Are Linked to the Non-classical MHC Class II Gene H2-Ob.
Denzin LK, Khan AA, Virdis F, Wilks J, Kane M, Beilinson HA, Dikiy S, Case LK, Roopenian D, Witkowski M, Chervonsky AV, Golovkina TV. Neutralizing Antibody Responses to Viral Infections Are Linked to the Non-classical MHC Class II Gene H2-Ob. Immunity. 2017 08 15; 47(2):310-322.e7.
Lessons Learned from Mouse Mammary Tumor Virus in Animal Models.
Dudley JP, Golovkina TV, Ross SR. Lessons Learned from Mouse Mammary Tumor Virus in Animal Models. ILAR J. 2016; 57(1):12-23.
Mammalian Lipopolysaccharide Receptors Incorporated into the Retroviral Envelope Augment Virus Transmission.
Wilks J, Lien E, Jacobson AN, Fischbach MA, Qureshi N, Chervonsky AV, Golovkina TV. Mammalian Lipopolysaccharide Receptors Incorporated into the Retroviral Envelope Augment Virus Transmission. . 2015 Oct 14; 18(4):456-62.
The KT Jeang Retrovirology prize
University of Chicago
Fellow of American Association for the Advancement of Science
Fellow of the American Academy of Microbiology
Cancer Research Institute (CRI) 2000 Hillsdale Fund, Inc. Greensboro, N.C.
Oliver and Jennie Donaldson Charitable Trust
V Foundation Scholar
Cancer Research Institute Postdoctoral Fellowship Award
1993 - 1995
Prize of All-Union Young Scientists competition (together with S.V. Litvinov)