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.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
2R01AI076059-07A1
Application #
8731533
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Conley, Tony J
Project Start
Project End
Budget Start
Budget End
Support Year
7
Fiscal Year
2014
Total Cost
Indirect Cost
Name
George Washington University
Department
None
Type
Schools of Medicine
DUNS #
City
Washington
State
DC
Country
United States
Zip Code
20052
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
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
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
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
Tandon, Ravi; SenGupta, Devi; Ndhlovu, Lishomwa C et al. (2011) Identification of human endogenous retrovirus-specific T cell responses in vertically HIV-1-infected subjects. J Virol 85:11526-31
Jha, Aashish R; Nixon, Douglas F; Rosenberg, Michael G et al. (2011) Human endogenous retrovirus K106 (HERV-K106) was infectious after the emergence of anatomically modern humans. PLoS One 6:e20234
Jha, Aashish R; Pillai, Satish K; York, Vanessa A et al. (2009) Cross-sectional dating of novel haplotypes of HERV-K 113 and HERV-K 115 indicate these proviruses originated in Africa before Homo sapiens. Mol Biol Evol 26:2617-26