Response from Deacon et al.

COMMENT

I

n cvety

person

infected

with

HIV-l

there are two major factors that influence the infection course and -ion to disease, namely, the fitness of the host protective response and the fitness (virulence and pdqgaaikity) of the virus. We agree with Michael Miller and Warner Greene that most cases of nonprogression to AIDS cannot be explained by the -ion of a defective ncfgene, and are probably due to strong Lost protective responses against the virus. HIV-1 virus load has been shown to be a good marker of disease severity, and increases in virus load predict disease progression’. However, high virus loads are not necessarily pathogenic. In both African green monkey-simian immunodefickcy virus (SIVagm) and sooty maogabey-SIVsm systew lifelong high virus loads are not pathogenic [P.R. Johnson (1995) International Workshop on Long-term Ncnproqression in HIV Infection, London. LJK, Abstr.]. Whik there is evidence from severe combined immi,nodeficient mice grafted with human peripheral blood lymphocytes and infected with HIV-1 that virulence is often associated with high virus load, some strains of HIV-1 replicate to high levels but fail to deplete CD4’ lymphocy&. The hypothesis that viral load is the sole factor in HIV-l and SIV pathogenesis could be tested by, for example, infecting adult macaques with SIV with a deleted Mfengineered to produce a high viral load, and asking whetber disease results. Althoogh one imponart function of Nef is to increase HIV infectivity (by an incompletely understood mechanism), we should not overlook tk immunoreguiatory effects of Nef in the infected lymphocyte. HIV-l Nef interacts with protems of the signal tmnsdtsction pathways and rltersT cell activation and proliferation~4, found efkts

as wd as having proon virus replication,

interkukin 2 receptor‘, and to interact with p56”‘, CD4, pS3 and p44mm4’ proteins’, so interfering with the ability of the infected cell to respond to antigen or cytokincs. and leading to immunodefiiiency. The failure of r&deleted SIV and HIV-1 to induce immunodeficiency in viw may be related to the lack of synthesis of a functional Nef protein. It must be remembered that the naturally occurring attenuated virus strain of the Sydney cohort is also defective in the Ion, terminal repeaf, which controls gene expression and so is important in virus replication. We agree that the findings of Baba etta/.‘cortceming the infection of newhom macaques with SIV A3 raises concerns about the use oi &deleted virus as a vaccine strain. While newborns inoculated with a high doti r!r nefdeleted virus may be a special case’, there is obviously a need to investigate further the ability of nefdekted virus to cause disease wku transmitted naturally from infected mother to offspring or to other immunocompromised individuals. However, a n&deleted HIV strain should not be rejected as a vaccine candidate simply hecause it can cause disease in some immunocompromised patients. Virtually all the live attenuated vaccines currently in use (including poliomyelitis and measles vaccines) cause disease in immunocompromised patients, yet they have resulted in dramatic reductions in morbidity and mortality.

l

IN

John

Mills

Natioual Centre for HIV Virology Research, Macfarlane Bumet Crntre for Medical Research, PO gox 254, Fairfield, Victoria 307’8, Australia Jennifer Learmont Look l%ack Unit, New South Wales Red Cross Blood Transfusion Service, 153 Clarence Street, Sydney. NSW 2000. Australia

2 hhier. D.E. d al. (1993) htw 260, 689-692 3 Grcmway. A. et af. I 19951j. Vi&. 69, 1842-1850 4 Baur, AS. da/. (1994) Immmhy 1, 373-384 5 Gmwaj, A.L. rt cd. (1994) \‘idqy 198.245-2.56 6 kacor.. N.J. et a/. ( 199.5) hnce 270. Wl-991 7 B&q T.W. et al. (1995) kiencr 267, 1820-1825

pmtelnr

invdved in natural vector transmissk5n,

GbleJofoel~rnotsoulesofB(wtomloesdemMtftMlshr lntmdhm. by B.S. ~+P@wm

Ml~OUCDLCiY

A. McPhee,

Suzanne Crowe and

among bacterial flagellar systems, by R.M. Ham*

ma rob of irun in plant 8yD.Gtpert.C.EnmdutdC.

-hI?NDS

Nicholas J. Deacon, Dale

Coming soon in Trends in Micmbiofogy

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*Plant tins

TllC ,,y of ,rc/-delr* *I! ’ * -~ ! ,. tlk k.lsi* 1c.r 3 pos,~l~l~~ 13~i’ ,a,.rltki ated virus vaccine against HIV-1 remains controversial, and further study is necessary. Less controversial, however, is the suggestion that the function of Nef might he a promising target for antiviral chemotherapy’, which could delay progression to AIDS.

173

VOL.

host-pmogm Msrcl#n

4

No.

5

KIM

and

S.L

lnteractbns,

MAY

4996

Newman

by S.M. Gray