HIV Awakens Retroviral Zombies from Cellular Slumber

Back in February the blog covered two conference presentations relating to interactions between HIV and endogenous retroviruses. The gist of the story is that cells infected with HIV appear to also produce fragments of ancient endogenous retroviruses; these remnants of past retroviral infections litter the human genome but cannot replicate or, under normal conditions, transcribe their genetic material into proteins. The HIV protein Vif seems to allow these retroviral zombies to awaken by facilitating the transcription of their genetic material. The production of endogenous retrovirus proteins by HIV-infected cells may thus provide an additional means for the immune system to recognize and target these cells for elimination. Because endogenous retroviruses cannot replicate, they also cannot mutate. So while the rapidly-mutating HIV typically represents a moving target for the immune system,  targeting proteins from endogenous retroviruses may offer an additional, easier means for immune responses to recognize HIV-infected cells.

Keith Garrison and colleagues have now published their data showing that T cell responses to human endogenous retroviruses (HERVs) can be detected in people with HIV and, furthermore, that these T cell responses show a correlation with control of HIV replication during acute HIV infection (the data were also mentioned by senior author Doug Nixon in a recently published interview with TAG). The researchers suggest that the finding may lead to novel HIV vaccine strategies targeting HERVs. However, more study of the circumstances under which otherwise healthy cells might express HERV proteins is needed in order to ascertain the safety and practicality of this idea (so far, HERV expression has been primarily reported in people with HIV and people with certain cancers such as seminoma and breast cancer). A new study looking at this question has also just been published, in the journal AIDS (see second abstract and link, below).

PLoS Pathogens Vol. 3, No. 11, e165 doi:10.1371/journal.ppat.0030165

T Cell Responses to Human Endogenous Retroviruses in HIV-1 Infection

Keith E. Garrison1, R. Brad Jones2, Duncan A. Meiklejohn3, Naveed Anwar2, Lishomwa C. Ndhlovu1, Joan M. Chapman1, Ann L. Erickson1, Ashish Agrawal3, Gerald Spotts4, Frederick M. Hecht4, Seth Rakoff-Nahoum5, Jack Lenz6, Mario A. Ostrowski2,7, Douglas F. Nixon1

1 Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, California, United States of America, 2 Department of Immunology, University of Toronto, Toronto, Ontario, Canada, 3 Gladstone Institute of Virology and Immunology, University of California San Francisco, San Francisco, California, United States of America, 4 Positive Health Program, Department of Medicine, San Francisco General Hospital, University of California San Francisco, San Francisco, California, United States of America, 5 Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America, 6 Department of Molecular Genetics, Albert Einstein College of Medicine, Bronx, New York, United States of America, 7 St. Michael's Hospital, Toronto, Ontario, Canada

Human endogenous retroviruses (HERVs) are remnants of ancient infectious agents that have integrated into the human genome. Under normal circumstances, HERVs are functionally defective or controlled by host factors. In HIV-1-infected individuals, intracellular defense mechanisms are compromised. We hypothesized that HIV-1 infection would remove or alter controls on HERV activity. Expression of HERV could potentially stimulate a T cell response to HERV antigens, and in regions of HIV-1/HERV similarity, these T cells could be cross-reactive. We determined that the levels of HERV production in HIV-1-positive individuals exceed those of HIV-1-negative controls. To investigate the impact of HERV activity on specific immunity, we examined T cell responses to HERV peptides in 29 HIV-1-positive and 13 HIV-1-negative study participants. We report T cell responses to peptides derived from regions of HERV detected by ELISPOT analysis in the HIV-1-positive study participants. We show an inverse correlation between anti-HERV T cell responses and HIV-1 plasma viral load. In HIV-1-positive individuals, we demonstrate that HERV-specific T cells are capable of killing cells presenting their cognate peptide. These data indicate that HIV-1 infection leads to HERV expression and stimulation of a HERV-specific CD8+ T cell response. HERV-specific CD8+ T cells have characteristics consistent with an important role in the response to HIV-1 infection: a phenotype similar to that of T cells responding to an effectively controlled virus (cytomegalovirus), an inverse correlation with HIV-1 plasma viral load, and the ability to lyse cells presenting their target peptide. These characteristics suggest that elicitation of anti-HERV-specific immune responses is a novel approach to immunotherapeutic vaccination. As endogenous retroviral sequences are fixed in the human genome, they provide a stable target, and HERV-specific T cells could recognize a cell infected by any HIV-1 viral variant. HERV-specific immunity is an important new avenue for investigation in HIV-1 pathogenesis and vaccine design.

AIDS: Volume 21(18), 30 November 2007, p2417-2424

The replicative activity of human endogenous retrovirus K102 (HERV-K102) with HIV viremia

Laderoute MP, Giulivi A, Larocque L, Bellfoy D, Hou Y, Wu HX, Fowke K, Wu J, Diaz-Mitoma F.

OBJECTIVE:: To address the activation and replicative activity of HERV-K102 in vivo associated with HIV viremia. DESIGN AND METHODS:: Initially serology was performed on HERV-K102 specific envelope peptides to determine if HERV-K102 may become activated with HIV viremia. Before developing a quantitative PCR (qPCR) assay, we first determined whether plasma associated particles contained DNA or RNA genomes in a pilot study which surprisingly revealed predominantly DNA genomes. A relative, ddCt qPCR ratio method was then devised to detect excess levels of HERV-K102 pol DNA templates over genomic levels which served as a surrogate marker to reliably index the level of particles found in plasma. RESULTS:: Both the peptide serology and ddCt qPCR excess ratio methods suggested the activation of HERV-K102 in about 70-80% of HIV viremic cases whereas only 2-3% of normal healthy adults had marginally activated HERV-K102 (P < 0.0001). Moreover, by digestion with dUTPase we were able to confirm that the vast majority of excess DNA template in plasma related to cDNA production rather than representing genomic copies. CONCLUSIONS:: Our work uniquely suggests the common activation of HERV-K102 with HIV viremia and may be first to directly demonstrate HERV-K102 cDNA production in vivo. The potential implications of the induction of HERV-K102 activation and replication for the prevention and control of HIV are discussed.

Comments

[Michael Linde]

I feel like this is a really exciting prospect for a therapeutic vaccine. I suppose one of the key questions, though, is the timing of HERV protein expression compared with HIV release. If infected cells express HERV sequences and these are presented within the first 24 hours after fusion, then a cellular response against the HERV sequences might kill the infected cell prior to HIV budding. If HERV sequences are delayed for some reason (which would be surprising if the transcription factors activating HIV also activate HERVs), then a cell-medicated response might be too late.

The other concern would obviously be if an anti-HERV response resulted in an unintended autoimmune reaction. HERV sequences may be activated in other conditions. Given the state of therapeutic vaccines, though, I would think this is worth the risk.

[Richard Jefferys]

Good question, I'd imagine Doug Nixon's group is looking at the issue of the timing of expression. I guess the lack of apparent ill-effects in the people with HERV-specific T cell responses may offer some reassurance in terms of safety but it would be useful if any therapeutic interventions could be explored in animal models first (I think macaques do have some HERVs but I'm not sure if their expression has been studied in SIV). The second paper, from AIDS, reports that HERV-K102 activity can also be detected in people with herpes and hepatitis B&C viremia, not just in people with HIV viremia, which complicates the story somewhat.

[Dr. Marian Laderoute]

HERV-K102 particle production was detected in the plasma from 2 of 4 normal cord blood samples. Also in this paper we showed particle production with disease activity and not when recovered (CFS-ME, MS, and acute EBV infection). HERV-K102 replication occurs in human monocytes and can be regulated by cytokines. It is unlikely that permanent T cell and antibody responses could be induced by vaccines. But there may be protection in the short term (a few months?). We suggested protection by HERV-K102 might relate to its foamy retrovirus like properties and ability to undergo lytic infections in virally infected cells or in transformed cells.