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Immune clearance of highly pathogenic SIV infection

An Addendum to this article was published on 21 June 2017

A Corrigendum to this article was published on 29 October 2014

This article has been updated


Established infections with the human and simian immunodeficiency viruses (HIV and SIV, respectively) are thought to be permanent with even the most effective immune responses and antiretroviral therapies only able to control, but not clear, these infections1,2,3,4. Whether the residual virus that maintains these infections is vulnerable to clearance is a question of central importance to the future management of millions of HIV-infected individuals. We recently reported that approximately 50% of rhesus macaques (RM; Macaca mulatta) vaccinated with SIV protein-expressing rhesus cytomegalovirus (RhCMV/SIV) vectors manifest durable, aviraemic control of infection with the highly pathogenic strain SIVmac239 (ref. 5). Here we show that regardless of the route of challenge, RhCMV/SIV vector-elicited immune responses control SIVmac239 after demonstrable lymphatic and haematogenous viral dissemination, and that replication-competent SIV persists in several sites for weeks to months. Over time, however, protected RM lost signs of SIV infection, showing a consistent lack of measurable plasma- or tissue-associated virus using ultrasensitive assays, and a loss of T-cell reactivity to SIV determinants not in the vaccine. Extensive ultrasensitive quantitative PCR and quantitative PCR with reverse transcription analyses of tissues from RhCMV/SIV vector-protected RM necropsied 69–172 weeks after challenge did not detect SIV RNA or DNA sequences above background levels, and replication-competent SIV was not detected in these RM by extensive co-culture analysis of tissues or by adoptive transfer of 60 million haematolymphoid cells to naive RM. These data provide compelling evidence for progressive clearance of a pathogenic lentiviral infection, and suggest that some lentiviral reservoirs may be susceptible to the continuous effector memory T-cell-mediated immune surveillance elicited and maintained by cytomegalovirus vectors.

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Figure 1: Virological analysis of early RhCMV/SIV vector-mediated protection.
Figure 2: Longitudinal analysis of RhCMV/SIV vector-mediated protection after intravaginal challenge.
Figure 3: Virological analysis of medium- to long-term RhCMV/SIV vector-mediated protection.

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Data deposits

New SIVmac239 sequences reported in this manuscript are accessible in GenBank under accessions KF439057, KF439058 and KF439059.

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This work was supported by the AIDS Vaccine Research in Nonhuman Primates Consortium of the National Institute of Allergy and Infectious Diseases (NIAID; U19 AI095985), as well as other NIAID grants (RO1 AI060392, R37 AI054292, P01 AI094417 and U19 AI096109); the Bill & Melinda Gates Foundation-supported Collaboration for AIDS Vaccine Discovery (CAVD); the International AIDS Vaccine Initiative (IAVI) and its donors, particularly the US Agency for International Development (USAID); the National Center for Research Resources (P51 OD011092); and the National Cancer Institute (contract HHSN261200800001E). We thank A. Sylwester, A. Okoye, C. Kahl, S. Hagen, R. Lum, Y. Fukazawa, S. Shiigi and L. Boshears for technical or administrative assistance; C. Miller, N. Miller and T. Friedrich for provision of SIV stocks; K. Reimann for provision of the CD8-depleting monoclonal antibody; D. Watkins for MHC typing; D. Montefiori for neutralizing antibody assays; and A. Townsend for figure preparation. We acknowledge the contribution of M. A. Jarvis to the design, construction and initial in vitro characterization of all the strain 68.1-derived RhCMV vectors used in this study, including both previously published RhCMV/SIV vectors and a previously unpublished vector expressing an Mycobacterium tuberculosis Ag85B–ESAT6 fusion protein, used as a negative control in this study.

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Authors and Affiliations



S.G.H. planned and performed animal experiments, and analysed immunological and virological data, assisted by A.B.V., C.M.H., R.M.G., J.C.F., M.S.L., A.N.G., G.X. and N.W. M.P. and J.D.L. planned and performed SIV quantification, assisted by K.O., R.S. and Y.L. B.J.B. and J.B.S. performed infected cell recognition assays. B.F.K. performed sequencing analysis. J.D.E. performed immunohistological studies. S.L.P., J.M.T., A.W.L. and M.K.A. managed the animal protocols. J.A.N. and K.F. supervised CMV vector design and development. J.D.L. planned and supervised SIV quantification and immunohistological experiments. P.T.E. performed all statistical analyses. L.J.P. conceived the RhCMV vector strategy, supervised all experiments, analysed data, and wrote the paper, assisted by S.G.H., J.D.L. and J.B.S.

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Correspondence to Jeffrey D. Lifson or Louis J. Picker.

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Competing interests

Oregon Health & Science University, and authors L.J.P., S.G.H., K.F. and J.A.N. have a considerable financial interest in TomegaVax, Inc., a company that may have a commercial interest in the results of this research and technology. The potential individual and institutional conflicts of interest have been reviewed and managed by Oregon Health & Science University.

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Hansen, S., Jr, M., Ventura, A. et al. Immune clearance of highly pathogenic SIV infection. Nature 502, 100–104 (2013).

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