The Discovery of SIV and Development of Monkey Models for the Study of HIV/AIDS. Ronald C Desrosiers University of Miami Miller School of Medicine

Transcription

1 The Discovery of SIV and Development of Monkey Models for the Study of HIV/AIDS Ronald C Desrosiers University of Miami Miller School of Medicine

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4 10 FEBRUARY 1984 Infectious Diseases Branch, National Institute for Neurological and Communicative Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20205, USA Feb. 10, 1984 Feb. 11, 1984 MANETH GRAVELL WILLIAM T. LONDON REBECCA S. HAMILTON JOHN L. SEVER THE LANCET, February 11, 1984 TRANSMISSION OF SIMIAN AIDS WITH TYPE D RETROVIRUS ISOLATE SIR,-Monkeys of the genus Macaca housed at two regional primate centres in the USA have acquired by natural means a highly fatal immunosuppressive disease which resembles human acquired immunodeficiency syndrome (AIDS).3,4 Like human AIDS, the simian disease (SAIDS) is characterised by profound immunosuppression, multiple opportunistic infections, chronic wasting, malignancy in some instances, and a high death rate.3-7 Laboratory of Infectious Diseases, National Institutes of Allergy and Infectious Diseases, Bethesda, Maryland Department of Virology, St Jude Children s Research Hospital, Memphis, Tennessee Frederick Cancer Research Facility, Frederick, Maryland California Primate Research Center; and Department of Medical Pathology University of California at Davis ALBERT Z. KAPIKIAN GOPAL MURTI LARRY O. ARTHUR RAYMOND V. GILDEN KENT G. OSBORN PRESTON A. MARX ROY V. HENRICKSON MURRAY B. GARDNER 2. Vetter H, Fischer M, Muller-Rensing R, Vetter W, Winterberg B. [131I]-metaiodobenzylguanidine in treatment of malignant phaeochromocytomas Lancet 1983; ii: Henrickson RV, Osborn KG, Madden DL, et al. Epidemic of acquired immunodeficiency in rhesus monkeys. Lancet 1983; i: Hunt RD, Blake BJ, Chalifoux LV, et al. Transmission of naturally occurring lymphoma in macaque monkeys. Proc Natl Acad Sci USA 1983; 80: London WT, Madden DL, Gravell M, et al. Experimental transmission of simian acquired immunodeficiency syndrome (SAIDS) and Kaposi-like skin lesions. Lancet 1983, ii Gravell M, London WT, Houff SA, et al. Transmission of simian acquired immunodeficiency syndrome (SAIDS) with blood or filtered plasma. Science 1984; 223: Litvin NL, King NW, Daniel MD, et al. Experimental transmission of macaque AIDS by means of inoculation of macaque lymphoma tissue. Lancet 1983; ii:

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7 Science June 7, 1985

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9 Mm Mm SIVmac251 Lymphoma and M. avium in rhesus macaques at NEPRC Mm Mm Mm Mm Mm ?? Mm SIVmac239 Natural SIVmac identified at NEPRC in 1987 serological survey Origins of SIV at NEPRC Keith Mansfield et al Epidemic of lymphoma and M. avium in rhesus macaques at CNPRC Cercocebus torquatus atys asymptomatically infected with SIVsm at CNPRC AIDS in M. arctoides at CNPRC Derivation and suspected origin of SIVmac at NEPRC

10 Induction of AIDS in Rhesus Monkeys by Molecularly Cloned Simian Immunodeficiency Virus HARRY KESTLER, TOSHIAKI KODAMA, DOUGLAS RINGLER, MARTA MARTHAS, NIELS PEDERSEN, ANDREW LACKNER, DEAN REGIER, PRABHAT SEHGAL, MUTHIAH DANIEL, NORVAL KING, RONALD DESROSIERS* Better understanding of the pathogenesis of acquired immunodeficiency syndrome (AIDS) would be greatly facilitated by a relevant animal model that uses molecularly cloned virus of defined sequence to induce the disease. Such a system would also be of great value for AIDS vaccine research. An infectious molecular clone of simian immunodeficiency virus (SIV) was identified that induces AIDS in common rhesus monkeys in a time frame suitable for laboratory investigation. These results provide another strong link in the chain of evidence for the viral etiology of AIDS. More importantly, they define a system for molecular dissection of the determinants of AIDS pathogenesis. Science June 1, 1990

11 The infectious, pathogenic SIVmac239 clone The first pathogenic clone to be defined for any lentivirus At the time, the viral etiology of AIDS in humans was being questioned (Duesberg). Induction of AIDS in monkeys by 10,279 base pairs of cloned DNA provided unambiguous evidence even for the skeptics SIVmac239, derivatives of it, and other such clones have proven enormously useful Homogeneous virus of defined sequence for a better controlled laboratory setting Any gene, any nucleotide, any amino acid can be changed and the effects on pathogenic potential, tropism, neut sensitivity, etc can be determined

12 One Application Relative Importance and Functional Role of the so-called Auxiliary Genes

13 Δvpr > Δvpx > ΔvprΔvpx Δnef > Δ3 > Δ3x > Δ4 >> Δvif > Δ5.

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16 A long, long time ago, in a pub not so far away Absence of intact nef sequences in a long-term survivor with nonprogressive HIV-1 infection. NEJM 332:228 Sully Uncle Ron

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25 1994 Idea squashed

26 Two important points regarding the concept of live attenuated vaccines for HIV 1. While SIVΔnef and SIVΔ3 provide strong protection against challenge by SIV strains identical or closely matched in sequence, these live attenuated vaccines do NOT provide very good protection against heterologous SIV strains. 2. This situation is probably analogous to the inability of infection by one HIV strain to routinely protect against superinfection by a different HIV strain

27 Estimated time of infection for the 10 cases of superinfection observed among 56 women in the Mombasa cohort Years PI Intersubtype Intrasubtype The intervals are variable due to differences in availability of samples for testing.

28 Current uses of SIV and SHIV models Better understanding of pathogenesis Inform and guide development of vaccine concepts for use in humans Investigation of novel therapy strategies, including cure strategies

29 Current Emphases in my Lab Pathogenesis Replication-competent recombinant herpesvirus as a preventive vaccine AAV vector for long-term delivery of monoclonal antibodies for prevention and therapy

30 Partial List of Trainees Past Jae Jung Frank Kirchoff Blossom Damania Welkin Johnson David Evans Michaela Gack Alexander Hahn Present Young Shin Sebastian Fuchs Jose Martinez-Navio Georg Bischof James Termini Shara Pantry Zach Silver

31 Critical Colleagues over the Years Bernhard Fleckenstein Larry Arthur Jeff Lifson John Sullivan David Watkins and Mario Stevenson

32 AAV Delivery of Monoclonal Antibodies for the Prevention and Treatment of HIV Infection

33 Need for alternate strategies Long-term delivery of mabs is one such alternate strategy Such antibody-based strategies are made possible by an incredible array of mabs with potent, broadly-neutralizing activity against HIV that have been isolated and characterized over the last several years

34 AAV as a long-term delivery vehicle - ideal in many respects The only protein expressed from AAV vector comes from the transgene put into it Proven ability to achieve long-term expression of the transgene product Outstanding safety record in human gene therapy trials Little or no integration of AAV vector DNA into host genome sequences

35 400 Week 187 (> 3.5 years) Concentration of 5L7 IgG1 in serum (µg/ml) Time (weeks) after AAV administration

36 Viral Loads by Jeff Lifson

37 Antibody µg/ml Monkey rh C9-LS 3BNC117-LS 10E8-LS SHIV-AD8 VL SHIV-AD8 Log10 copies/ml Weeks post-aav inoculation

38 Molecular Therapy Received 14 August 2015; accepted 1 October 2015; advance online publication 3 November doi: /mt

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40 SERIAL PASSAGE OF SIV sm : ACQUISITION / SELECTION OF A PATHOGENIC PHENOTYPE Adapted from K Mansfield, R Desrosiers and M Martin

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42 Fields Virology

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46 Keith Mansfield