HIVs controlled by HERVs specific CTLs

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J Clin Invest. 2012 Nov 12. pii: 64560. doi: 10.1172/JCI64560. [Epub ahead of print] HERV-K-specific T cells eliminate diverse HIV-1/2 and SIV primary isolates. Jones RB, Garrison KE, Mujib S, Mihajlovic V, Aidarus N, Hunter DV, Martin E, John VM, Zhan W, Faruk NF, Gyenes G, Sheppard NC, Priumboom-Brees IM, Goodwin DA, Chen L, Rieger M, Muscat-King S, Loudon PT, Stanley C, Holditch SJ, Wong JC, Clayton K,Duan E, Song H, Xu Y, Sengupta D, Tandon R, Sacha JB, Brockman MA, Benko E, Kovacs C, Nixon DF, Ostrowski MA. Abstract The genetic diversity of HIV-1 represents a major challenge in vaccine development. In this study, we establish a rationale for eliminating HIV-1-infected cells by targeting cellular immune responses against stable human endogenous retroviral (HERV) antigens. HERV DNA sequences in the human genome represent the remnants of ancient infectious retroviruses. We show that the infection of CD4+ T cells with HIV-1 resulted in transcription of the HML-2 lineage of HERV type K [HERV-K(HML-2)] and the expression of Gag and Env proteins. HERV-K(HML-2)-specific CD8+ T cells obtained from HIV-1-infected human subjects responded to HIV-1-infected cells in a Vif-dependent manner in vitro. Consistent with the proposed mode of action, a HERV-K(HML-2)-specific CD8+ T cell clone exhibited comprehensive elimination of cells infected with a panel of globally diverse HIV-1, HIV-2, and SIV isolates in vitro. We identified a second T cell response that exhibited cross-reactivity between homologous HIV-1-Pol and HERV-K(HML-2)-Pol determinants, raising the possibility that homology between HIV-1 and HERVs plays a role in shaping, and perhaps enhancing, the T cell response to HIV-1. This justifies the consideration of HERV-K(HML-2)-specific and cross-reactive T cell responses in the natural control of HIV-1 infection and for exploring HERV-K(HML-2)-targeted HIV-1 vaccines and immunotherapeutics. A paper just published in theJournal of Clinical Investigation addresses this information gap, demonstrating that CD8 T cells specific for a HERV-K(HML-2) epitope are able to recognize and kill CD4 T cells infected with an array of HIV-1, HIV-2, and SIV isolates (albeit with varying levels of effectiveness depending on the specific isolate). The researchers suggest that induction of HERV-K(HML-2)-specific CD8 T-cell responses using vaccines may offer a way to target HIV-infected cells without having to deal with the problem of HIV’s genetic variability. One serious concern with this approach is that, if HERV-K(HML-2) proteins are ever expressed by healthy cells, autoimmunity could ensue. But so far, the authors note, “expression of HERV-K(HML-2)-Gag and -Env protein has not been convincingly demonstrated in any healthy adult human tissue, despite extensive screening.” Additional studies are now planned to assess whether targeting HERV-K(HML-2) might have potential in the context of both therapeutic and preventive HIV vaccine strategies. http://www.jci.org/articles/view/64560