NEWS AND VIEWS AIDS------the syndrome showed that a profound Defective to blame? suppression of humoral and cellular immunity soon follows the lympho­ Robin A. Weiss proliferative phase. Both the B-cell hyper­ plasia and the immune suppression seem THREE new papers on an acquired immune retroviral env derived from to be T-cell dependent, because the deficiency syndrome in mice caused by a exogenous, 'ecotropic' and endogenous, affects nude mice much Jess severely''. strain of murine leukaemia virus suggest 'xenotropic' sequences. This new form of However, it is not clear that the that a defective is responsible for glycoprotein probably interacts with virus infects T-helper cells, and the the immunodeficiency. Janet Hartley, specific 'dual-tropic' receptors on erythroid macrophage reservoir and neurotropism Sandy Morse and colleagues' at the precursor cells to trigger their proli­ characteristic of HIV have not been National Institutes of Health have found feration'. As the term 'viral ' is examined in murine AIDS. In my view. an unusual pattern of genetic susceptibility usually restricted to gene sequences of the diseases induced by HIV-relatcd, to murine AIDS consistent with a defec­ mainly cellular origin, and of course per­ T-lymphotropic of cats (FIV), tive genome being carried by different tains to those inducing neoplastic cattle (BIV) and monkeys (SIV) will replication-competent 'helper' viruses. transformation, we need a new term for prove to be more proximate models ot This has been followed up by the molec­ retroviral genes of viral origin specifying human AIDS. ular identification, also by Hartley and particular disease forms - I would colleagues', of the defective virus. And an offer as a suggestion 'pathogenes' with Role in human AIDS apparently identical genome has been path as the generic equivalent to one. Nonetheless, the discovery of defective independently identified by Paul The SFFV gene determining erythro­ inducing severe immuno­ Jolicoeur and colleagues in Montreal, as leukaemia is derived from env sequences', suppression in cats and mice raises the they report on page 505 of this issue'. as is the gene inducing feline AIDS in question whether defective HIV After cloning of the defective virus, which defective feline leukaemia virus'. A recent might play a role in human AIDS. Rep­ retains gag sequences in its 4.8-kilobase paper by Poss et at. 9 indicates that the prop­ lication-competent, molecularly cloned genome, and rescue by non-pathogenic erty of the env protein of the defective HIV and SIV genomes have not yet been helper viruses, inoculation into mice feline AIDS virus which makes it cyto­ shown to induce AIDS, and even if they leads to the induction of AIDS'·'. These pathic for T cells lies in its post-trans­ do, that might require the generation findings supplement that from Jim lational glycosylation pattern. With murine of defective, variant genomes during the Mullins's group' which shows that in cats, AIDS, however, it appears that the func­ long incubation period between immunodeficiency can be caused by a tional path gene in the defective virus is and manifestations of disease. defective feline leukaemia virus. derived from the gag gene. Aziz, Hanna Several HIV laboratories are finding a Many classes of animal RNA virus and Jolicoeur' have sequenced the 4.8- myriad of viral forms when sequences are accumulate defective variants when pro­ kilobase genome and found four open amplified directly from infected tissues, pagated serially at high multiplicities of reading frames, two corresponding to rather than selecting for replication­ infection. This was first observed by von portions of gag, one to part of pol and one competent viruses in cell culture. Simon Magnus with virus'. Such defec­ to part ofpol-env. Wain-Hobson (personal communication) tive viruses frequently interfere with the The pl2 region of the largest open refers to such HIV populations as 'quasi­ replication of full-length, non-defective reading frame (586 amino acids) has only species' because they represent greater genomes and they may play a role in 40-50-per-cent identity with Gag p12 of diversity than might be expected from pathogenesis and persistent infection'. other murine , and it is this classical population variability. The mix­ Defective retroviruses, however, do not product that the authors suspect is respon­ ture of defective oncoviruses and the typically interfere with their helper viruses sible for inducing AIDS. Chattopadhyay helper viruses required for their generation and are not simply truncated forms of the et al.' also implicate a gag-related product and transmission represents a special case competent virus; they contain recom­ because Gag antisera including anti-p12, of quasi-species genome dynamics. No binant viral or cellular sequences that can but not anti-Pol and anti-Env sera, doubt defective forms of HIV will be care­ directly influence the pathogenesis of the immunoprecipitate a 60-kilodalton pro­ fully scrutinized at the molecular level. 0 virus population. tein from a murine cell line carrying the defective genome in the absence Robin A. Weiss is at the Chester Beatty Labora• Retroviral of . tories, Institute of Research, London The notion that defective variants of The study of defective murine and SW36JB, UK. retroviruses cause specific disease was feline leukaemia viruses causing immune 1. Hartley, J.W., Frederickson. T.N., Yetter. RA. Makino. raised more than 25 years ago, when deficiency syndromes should enhance our M. & Morse, H.C. I Viral. 63, 1223-1231 (1989) 7 Hanafusa et al. showed that the Bryan understanding of the various ways retro­ 2. Chattopadhyay, S.K., Morse, H.C., Makino. M, Ruscetti, SK & Hartley, J.W. Proc. natn. Acad. Sc1. U.S.A. (in the strain of Rous virus was defec­ viruses induce disease. Being oncoviruses press). tive. This classical study led eventually to rather than Jentiviruses and therefore less 3. Aziz, D.C., Hanna, Z. & Jolicoeur, P. Nature 338. 505- the identification of oncogenes derived closely related to the human immuno­ 508 (1989). 4. Overbaugh, J., Donahue. P.R .. Quackenbush, S.L. from cellular genes, usually by insertion at deficiency virus (HIV), their use in Hoover, EA & Mullins. J.l. Science 239. 906--910 the expense of viral genes, thereby ren­ screening anti-viral drugs is doubtful; if (1988). 5. Von Magnus, P. Acta path. microbial. immun. scand. 28. dering the viral genome replication­ one wishes to use an for this 278--293 (1951). defective. Nearly all retroviral oncogenes purpose, induces disease in 6. Huang, A.S. & Baltimore, D. Nature 226. 325-327 (1970) are carried in defective viruses requiring mice more quickly with a more quanti­ 7 Hanafusa, H., Hanafusa, T. & Rubin, H. Proc. natn. Acad. helper viruses for transmission. fiable endpoint. Sci. U.S.A. 49, 572-580 (1963). That defective retroviruses can carry Aziz et 3 cite striking similarities of 8. Li, J.-P .. Bestwick, R. K., Spiro, C. & Kabat. D.J. Viral. 61. at. 2782-2792 (1987) 'scrambled' viral genes determining new murine AIDS to human AIDS, though 9 Pass, M.L .. Mullms.J.I. &Hoover. EAJ. Viral. 63,189-- disease patterns, rather than cellular genes, there are striking differences too. The dis­ 195 (1989) 10 Haas. M. & Reshef, T. Eur. I Cancer 16, 909--913 was first seen with the spleen-focus-for­ ease was first described as '", (1980) ming virus (SFFV) component of Friend owing to what is now believed to be a 11 Mosier. D E , Yetter, RA & Morse. H.C. I exp Med 161, 766-784 (1985) erythroid leukaemia virus. The defective polyclonal B-cell rapidly 12. Mosier, D.E., Yetter. RA & Morse. H.C. J exp. Med. SFFV genome encodes an incomplete induced by the virus. A detailed study'' of 165,1737-1741 (1987) 458 NATURE · VOL 338 · 6 APRIL 1989 © 1989 Nature Publishing Group