Where has HIV been hiding?

NEWS AND VIEWS AIDS----------------------------------------------library. The initial ARIA peptide sequence suggested, and the eDNA sequence indeed confirmed, that ARIA is also a product of the NDF/heregulin/GGF gene 2 . Both purified GGF 1 and purified ARIA 2 ·11 stimulate tyrosine phosphorylation of a 185K protein, which may be neu or HER4. In situ hybridization experiments performed by both Marchionni et at. and Falls et at. indicate the NDF/GGF/ARIA messenger RNAs are products of neurons, that expression is particularly high in motor neurons of the embryonic spinal cord, and that the mRNAs are expressed at relatively early stages of embryonic neural development. These expression patterns might be expected for a protein that mediates the stimulatory effects of axons on Schwann cell proliferation and gene expression; they are demanded of a protein that mediates the observed trophic effects of motor neurons and their terminals on muscle development; and they are consistent with the hypothesis that released GGF accounts for the nerve dependence of amphibian limb regeneration 12 • So at least some of the interactions between neurons and their targets seem to be mediated directly by exogenous agents released or presented by neurons, rather than through indirect regulation of the expression of endogenous target cell trophic factors. The great diversity of biological responses to NDF/GGF/ARIA is not unusual. Indeed, a broad spectrum of activities now seems to be the rule, rather than the exception, for several trophic factors, and it is a real possibility that the isoforms generated by the NDF/ GGF/ARIA gene have distinct functions and activities. Sorting out which activity is associated with which protein variant, as well as how the various isoforms may differentially bind to neu or related receptors, is certain to provide still further insights into the biological properties of this expanding trophic-factor family. D Greg Lemke is at the Molecular Neurobiology Laboratory, The Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, California 92037, USA. 1. Marchionni, M.A. et at. Nature 362. 312-318 (1993). 2. Falls, D. L., Rosen. K. M., Corfas. G., Lane. W. S. & Fischbach, G. D. Ce//72, 801-815 (1993). 3. Lemke, G. E. & Brockes, J. P. J. Neurosci. 4, 75 (1984). 4. Bunge, R. P. & Griffen, J. W. in Diseases of the Nervous System. Clinical Neurobiology 87-100 (W. B. Saunders, Philadelphia, 1992). 5. Raff, M. C. eta/. Ce/115, 813--822 (1978). 6. Holmes, W. F. et at. Science 256, 1205-1210 (1992). 7. Wen, D. eta/. Ce/169, 55~572 (1992). 8. Plowman, G. D. eta/. Proc. natn. Acad. Sci. U.S.A. 90, 1746--1750 (1993). 9. Jessell, T. M., Siegel, R. E. & Fischbach, G. D. Proc. natn. Acad. Sci. U.S.A. 76, 5397-5401 (1979). 10. Hall, Z. W. & Sanes, J. R. Ce//72, Neuron (Suppl.) 9~121 (1993). 11. Corfas, G., Falls, D. L. & Fischbach, G. D. Proc. natn. Acad. Sci. U.S.A. 90, 1624-1628 (1993). 12. Brockes, J.P. & Kintner, C. R. Ce//45, 301 (1986). Where has HIV been hiding? Howard M. Temin and Dani P. Bolognesi ONE major question about HIV disease has been "Where is the virus?". Early in the epidemic it was difficult to find infectious HIV-1, even in people suffering from AIDS, but as techniques have improved it has been possible to demonstrate the virus in more and more infected people. Now pa~ers on pages 355 and 359 of this issue 1• show that large amounts of virus are present even during the asymptomatic stage of the disease, although it is not always in the form that might have been expected. The key to these latest developments is the polymerase chain reaction (PCR), which can measure a mere 1-10 HIVinfected cells present in a total of 100,000 uninfected cells. Pantaleo et at. 1 use PCR to show that in asymptomatic HIV -infected patients there are many infected cells in the lymph nodes, more than in the blood, and that these lymphnode cells are more likely to be virusproductive than cells in the blood. Embretson et at. 2 extend their earlier work combining PCR and in situ hybridization with autoradiographl to demonstrate that a high fraction of cells, around a quarter, in germinal centres of lymph nodes are infected, and that these cells tend not to be expressing viral RNA. In some sense these cells with viral DNA and no viral RNA can be called latently infected (see figure). At first sight, the. reader might have difficulty in rationalizing these results. Pantaleo et al. stress the point that there is much virus expression in secondary lymphoid organs, whereas Embretson et at. tell us that the overwhelming infection in lymph nodes is of a latent nature. Is there an inconsistency here? We believe not. Pantaleo et at. did not attempt to determine the fraction of cells that were latently infected versus those expressing RNA at a quantitative single cell level, as Embretson et at. did. Indeed, similar measurements of cells of the blood would render these analyses more complete. The issue of the percentage of latently infected cells notwithstanding, one can conclude from both reports that secondary lymphoid organs are solidly infected with HIV. Both also point out that virus particles are carried, probably passively, by follicular dendritic cells but in a form that is likely to be infectious for other HIV target cells, especially T-cells, that circulate through these organs. Many questions arise from these data. One in particular is the proportion of cells with viral DNA and no viral RNA that carry infectious as opposed to defective proviruses (see figure). The high rate of errors in retrovirus replication could result in many defective proviruses4 . If so, cells infected by defective proviruses might not be killed by virus replication nor be subject to host immune surveillance. They might also be protected from infection by nondefective viruses. It is now clear that there are many cells harbouring virus in an HIV-infected individual, even early after infection, and that the infection takes many different forms including one in which the virus is completely latent. One implication is that, for a preventive vaccine to be effective against HIV-1, the vaccine must block the virus from ever estab- - Activation Virions or defective virions The differences between a latently infected (a) and a virus-producing cell (b). and between an infectious (b) and a defective (c) provirus. In all of the cells there is an HIV-1 provirus, depicted as integrated HIV-1 DNA in the cell nucleus. In the latently infected cell, the provirus is not transcribed. Thus, there is no viral RNA nor protein. The latently infected cell can be activated to become virus-producing; after activation, early and then late transcription starts, producing viral proteins and ultimately infectious virus. By contrast in the cell infected with a defective provirus, there is a defect (deletion or lethal mutation) in the provirus such that it either makes no viral RNA or viral protein or, as shown, make (...truncated)