In prior posts I’ve written about research from the laboratories of Mario Ostrowski and Doug Nixon looking at the effect of HIV infection on human endogenous retrovirus (HERV) protein expression. This work, led by Brad Jones and Keith Garrison, has shown that the liberating effects of the HIV Vif protein can cause normally inactive HERV genetic sequences to produce proteins in cells infected by HIV. These proteins can then be processed and presented as antigens and, as a consequence, HERV-specific CD8 T-cell responses are detectable in some individuals with HIV. However, up until now there has been no direct evidence that HERV-specific CD8 T-cell responses can actually recognize and kill HIV-infected CD4 T cells. A paper just published in the Journal 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).
Based on their findings, 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.
J Clin Invest. 2012 Nov 12. pii: 64560. doi: 10.1172/JCI64560. [Epub ahead of print]
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.
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.