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]
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.
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