Immunotherapeutic strategies to boost natural immunity against HIV-1 in those who are infected have largely been disappointing, with a few exceptions. Recently, however, the power of the natural immune response has been shown in human and nonhuman primate models. The """"""""Visconti"""""""" patients in France received early antiretroviral drug therapy and then stopped taking their drugs. Their own immune systems appeared to suppress viral replication below detection. In a vaccine model of SIV infection, generation of powerful immunity through a rhCMV-vector approach led to animals with undetectable viral loads after infection. However, viral variation and immune escape is still a major impediment to vaccine induced or natural immunity, and major efforts have been made to determine which immunogens might lead to conserved immunity. As the field moves towards the dream of elimination of HIV from infected persons, combination approaches appear to be needed. More intensive HAART therapy, strategies to """"""""flush"""""""" virus out of the latent reservoir, boosting of immune responses are all important in the goal of a functional cure. Over the past two years, excitement has built with the first patients apparently """"""""cured"""""""" of their HIV infection. n our current grant, a resubmission of a competitive renewal of an R01 grant, we have developed a novel paradigm. Human endogenous retroviruses (HERVs) HERVs are fixed in our DNA, and represent conserved, immutable targets (in contrast to the highly diverse and rapidly changing antigens produced by HIV) for cellular lysis when reactivated in the context of HIV-1 infection. We recently showed that HERV-K-specific CD8+ T cell clones can eliminate cells infected with diverse HIV-1, HIV-2 and SIV strains. This indicates that reactivated HERVs may serve as conserved, host-encoded targets on HIV-1-infected cells, leading to their cytotoxic lysis, and that they can potentially be exploited in a therapeutic vaccine strategy. This grant proposes 3 specific aims. In the 1st specific aim we will identify which HERV sequences are expressed in HIV-1 infection. In the 2nd specific aim we will identify HERV specific T cell clones with anti-HIV activity in vitro. In the 3rd specific aim we will test HERV specific T cells for their ability to ontrol or eliminate HIV-1 infection in the humanized mouse model. Our previous grant produced data that showed that HIV-1 infection leads to HERV expression and stimulates a HERV-specific immune response, which could eliminate HIV-1 infection in vitro. This renewal application builds on the previous grant to address which HERVs are expressed after HIV-1 infection, and thus which HERV specific T cells are most likely to be functional. We will test functionality in a humanized mouse model of HIV-1 infection. The work proposed in this grant has a direct route to a future human trial of HERV specific T cells to eliminate HIV-1 infection.

Public Health Relevance

The goal of this proposal is to identify which endogenous retroviruses, the fossil viruses in our genome, are woken up in HIV-1 infection. This information will be used to develop and test fossil virus specific white blood cells which can eliminate HIV-1 in a mouse model of HIV-1 infection.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Conley, Tony J
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George Washington University
Schools of Medicine
United States
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Michaud, Henri-Alexandre; SenGupta, Devi; de Mulder, Miguel et al. (2014) Cutting edge: An antibody recognizing ancestral endogenous virus glycoproteins mediates antibody-dependent cellular cytotoxicity on HIV-1-infected cells. J Immunol 193:1544-8
Michaud, Henri-Alexandre; de Mulder, Miguel; SenGupta, Devi et al. (2014) Trans-activation, post-transcriptional maturation, and induction of antibodies to HERV-K (HML-2) envelope transmembrane protein in HIV-1 infection. Retrovirology 11:10
Jones, R Brad; Song, Haihan; Xu, Yang et al. (2013) LINE-1 retrotransposable element DNA accumulates in HIV-1-infected cells. J Virol 87:13307-20
Jones, R Brad; Leal, Fabio E; Hasenkrug, Aaron M et al. (2013) Human endogenous retrovirus K(HML-2) Gag and Env specific T-cell responses are not detected in HTLV-I-infected subjects using standard peptide screening methods. J Negat Results Biomed 12:3
Sacha, Jonah B; Kim, In-Jeong; Chen, Lianchun et al. (2012) Vaccination with cancer- and HIV infection-associated endogenous retrotransposable elements is safe and immunogenic. J Immunol 189:1467-79
Lai, Olivia Y; Chen, Haoyan; Michaud, Henri-Alexandre et al. (2012) Protective effect of human endogenous retrovirus K dUTPase variants on psoriasis susceptibility. J Invest Dermatol 132:1833-40
Ormsby, Christopher E; Sengupta, Devi; Tandon, Ravi et al. (2012) Human endogenous retrovirus expression is inversely associated with chronic immune activation in HIV-1 infection. PLoS One 7:e41021
Jones, R Brad; Garrison, Keith E; Mujib, Shariq et al. (2012) HERV-K-specific T cells eliminate diverse HIV-1/2 and SIV primary isolates. J Clin Invest 122:4473-89
Jones, R Brad; John, Vivek M; Hunter, Diana V et al. (2012) Human endogenous retrovirus K(HML-2) Gag- and Env-specific T-cell responses are infrequently detected in HIV-1-infected subjects using standard peptide matrix-based screening. Clin Vaccine Immunol 19:288-92
SenGupta, Devi; Tandon, Ravi; Vieira, Raphaella G S et al. (2011) Strong human endogenous retrovirus-specific T cell responses are associated with control of HIV-1 in chronic infection. J Virol 85:6977-85

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