In 2013 the Retroviral Immunology Section continued investigation into host mechanisms of genetic resistance and susceptibility to retroviral infection. Following is a brief summary of five publications in peer-reviewed journals describing our discoveries in this area. These findings have implications for the design of therapeutics and vaccines to treat and prevent infections with viruses such as HIV. 1. Although interferon gamma is generally considered to be a cytokine beneficial to the development of immune responses to viral infections, we found that IFN-gamma production can have detrimental effects on early adaptive immune responses and virus control. first, IFN-gamma signaling indirectly modulated Friend virus-specific CD8(+) T cell responses. Second, intrinsic IFN-gamma signaling in B cells promoted polyclonal B cell activation and enhanced early FV infection, despite promotion of germinal center formation and neutralizing Ab production. 2. The in vivo protective effect of tetherin was investigated using mice infected with Friend virus. Tetherin is a membrane protein that tethers enveloped virus particles on the surface of infected cells. However, it was previously not known whether this 'tethering'activity promoted or restricted retroviral spread in vivo. We found that Tetherin cell surface expression was a key parameter for retroviral restriction in vivo. 3. In an experimental evolution approach, we collaborated with the Potts lab to examine the role of the major histocompatibility complex (MHC) in the evolution of retroviruses to adapt and become more virulent in host animals. We found that although the MHC complex comprises only about 0.1% of the genome, its influence on the viral fitness of retroviruses was orders of magnitude stronger than all other genes combined. 4. CD4(+) T cells are known to play an important role in viral immunity, especially in providing essential help for antiviral B and T cell responses. In this study we collaborated with the Dittmer lab to examine the effects of immunosuppressive regulatory T cells (Tregs) on virus-specific CD4(+) T cell responses in vitro. Using the Friend virus model, we found that Tregs reduced the number of virus-specific CD4(+) T cells and suppressed their cytokine production. Interestingly we also found that CD8+ T cells also affected CD4+ T cell function, in particular the cytolytic capacity to kill virus-infected cells. These findings highlight the important role of Tregs in retroviral infections and point to avenues of therapeutic intervention. 5. In collaboration with the Santiago lab, a study of the therapeutic administration of IFN-alpha during Friend virus infection was undertaken. The effects of IFN-alpha on several virus restriction factors was analyzed including Apobec3, Tetherin/BST2, SAMHD1, Viperin, ISG15, OAS1, and IFITM3. We found that IFN-alpha inhibited acute Friend retrovirus infection primarily through the antiviral effector Apobec3 in vivo. This study highlights the potential of the APOBEC3 proteins as therapeutic targets against pathogenic retrovirus infections.

Project Start
Project End
Budget Start
Budget End
Support Year
18
Fiscal Year
2013
Total Cost
$356,827
Indirect Cost
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Messer, Ronald J; Lavender, Kerry J; Hasenkrug, Kim J (2014) Mice of the resistant H-2(b) haplotype mount broad CD4(+) T cell responses against 9 distinct Friend virus epitopes. Virology 456-457:139-44
Halemano, Kalani; Guo, Kejun; Heilman, Karl J et al. (2014) Immunoglobulin somatic hypermutation by APOBEC3/Rfv3 during retroviral infection. Proc Natl Acad Sci U S A 111:7759-64
Lavender, Kerry J; Messer, Ronald J; Race, Brent et al. (2014) Production of bone marrow, liver, thymus (BLT) humanized mice on the C57BL/6 Rag2(-/-)?c(-/-)CD47(-/-) background. J Immunol Methods 407:127-34
Thorborn, Georgina; Ploquin, Mickael J; Eksmond, Urszula et al. (2014) Clonotypic Composition of the CD4+ T Cell Response to a Vectored Retroviral Antigen Is Determined by Its Speed. J Immunol 193:1567-77
Joedicke, Jara J; Myers, Lara; Carmody, Aaron B et al. (2014) Activated CD8+ T cells induce expansion of V?5+ regulatory T cells via TNFR2 signaling. J Immunol 193:2952-60
Li, Sam X; Barrett, Bradley S; Heilman, Karl J et al. (2014) Tetherin promotes the innate and adaptive cell-mediated immune response against retrovirus infection in vivo. J Immunol 193:306-16
Joedicke, Jara J; Zelinskyy, Gennadiy; Dittmer, Ulf et al. (2014) CD8+ T cells are essential for controlling acute friend retrovirus infection in C57BL/6 mice. J Virol 88:5200-1
Kubinak, J L; Ruff, J S; Cornwall, D H et al. (2013) Experimental viral evolution reveals major histocompatibility complex polymorphisms as the primary host factors controlling pathogen adaptation and virulence. Genes Immun 14:365-72
Manzke, Nora; Akhmetzyanova, Ilseyar; Hasenkrug, Kim J et al. (2013) CD4+ T cells develop antiretroviral cytotoxic activity in the absence of regulatory T cells and CD8+ T cells. J Virol 87:6306-13
Pike, Rebecca; Filby, Andrew; Ploquin, Mickael J-Y et al. (2009) Race between retroviral spread and CD4+ T-cell response determines the outcome of acute friend virus infection. J Virol 83:11211-22

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