REJECTED LETTER TO EDITOR OF NATURE (1998)
gp120 AND HIV INFECTION
Sir - The work on the structure of the "HIV gp120 envelope glycoprotein" by the groups of Sodroski and Hendrickson (Nature 393, 648-659; 705-710, 1998) was conducted in the belief that "The entry of HIV into host cells is mediated by the viral envelope glycoproteins, which are organized into oligomeric, probably trimeric spikes displayed on the surface of the virion". However, every single electron microscopy or immune electron microscopy study published to date on the HIV particles has shown that: "The outer lipid membrane was frequently broken or absent in places and there was no evidence of surface spikes".(1) Suffice to mention the work (undoubtedly the best so far published re HIV particles) by Hans Gelderblom and his colleagues from the Koch-Institute in Berlin. In 1985 they wrote: "When we looked closely at the ultrastructure of HTLV-III we noted that cell-released HTLV-III had lost most of its surface projections", spikes.
In 1987 they wrote: "The outer env gp120 of HIV, representing the viral surface knobs [spikes], are only loosely attached to the viral envelope and easily shed. This observation is in agreement with further biochemical and EM investigations from which an extremely labile anchorage of the HIV gp120 was deduced".(2) In yet another 1987 study they wrote: "Shedding of envelope proteins is a common phenomenon of retroviruses. The extent and velocity of loss of surface proteins in case of HIV, however, appears extraordinary. Our observations are confirmed by biochemical studies. The loss of surface knobs apparently correlates morphologically with virus maturation. Immature and/or budding HIV particles are "spiked", but they are rarely observed".(3)
In a study published in 1992 they tried to quantify the number of spikes. From one of the many evaluations "that was particularly successful" they reported that immediately after release there were, on the average, 0.5 spikes per particle. But they also added "it was possible that structures resembling knobs might be observed even when there was no gp120 present, i.e., false positives".(4)
Regarding infection by retroviruses, as far back as 1983, Gallo pointed out that "the viral envelope which is required for infectivity is very fragile. It tends to come off when the virus buds from infected cells, thus rendering the particles incapable of infecting new cells". Because of this, Gallo said, "cell-to-cell contact may be required" for retroviral infection.(5) As far back as 1987 the researchers from the Koch-Institute wrote: "It is well established that CD4 serves as the receptor for HIV and that the CD4 gp120 interaction is the first step in HIV replication. On the other hand, the association of the MHC antigens with the virion and the spontaneous loss of the virus specific gp120 from the surface of the virion implies speculations on the infectivity of HIV…Whether such virions are infectious for certain cells and MHC antigens alone or in connection with the transmembrane glycoprotein gp41 might serve as receptors has to be elucidated".(6)
One cannot consider the findings by the two groups to "have important implications for virology, immunology and vaccine development" as Moore and Binley (Nature 393, 630-631, 1998) state unless the following questions are first answered:
1. Is gp120 fundamentally necessary or not for HIV infectivity?
2. If it is, then given that even today there is no proof for the existence of spikes (gp120) on the cell-free particles , how can they be infectious?
Eleni Papadopulos-Eleopulos (1) Valendar F.Turner (2) John M. Papadimitriou (3) Bruce Hedland-Thomas (1) Barry Page (1) David Causer (1)
(1) Department of Medical Physics, (2) Department of Emergency Medicine, Royal Perth Hospital, Perth, Western Australia; (3) Department of Pathology, University of Western Australia.
1. Hockley, D.J., Wood, R.D. & Jacobs, J.P. Journal of General Virology 69, 2455-2469 (1988).
2. Hausmann, E.H.S., Gelderblom, H.R., Clapham, P.R., Pauli, G. & Weiss, R.A. Journal of Virological Methods 16, 125-137 (1987).
3. Gelderblom, H.R., Hausmann, E.H., Ozel, M., Pauli, G. &
Koch, M.A. Fine structure of human immunodeficiency virus (HIV) and
immunolocalization of structural proteins. Virology 156, 171-6
4. Layne, S.P., et al. Virology 189, 695-714 (1992).
5. Marx, J.L. Science 220, 806-809 (1983).
6. Gelderblom, H., Reupke, H., Winkel, T., Kunze, R. & Pauli, G. Zeitschrift fur Naturforschung 42C, 1328-1334 (1987)