- Email: [email protected]
Lymphocyte dynamics, apoptosis and HIV infection
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19 Iguchi-Ariga,8.M.M. and Schaffner,W. (1989) Genes Dev. 3, 612-619 20 Karlin,S., Ladunga, I. and Blaisdell,B.E. (1994)Proc. Natl Acad. Sci. USA 91, 12837-12841 21 Karlin,S., Doerfler,W. and Cardon, L.R. (1994)J. Virol. 68, 2889-2897 22 Shpaer,E.G. and Mullins,J.I. (1990)Nucleic Acids Res. 18, 5793-5797 23 Tate, P.H. and Bird, A.P. (1993) Curr. Opin. Genet. Dev. 3, 226-231 24 Cardon, L.R. et al. (1994) Proc. Natl Acad. Sci. USA 91, 3799-3803
25 Bains,W. and Bains,J. (1987)Mutat. Res. 179, 65-74 26 Krieg,A.M. (1995)J. Clin. Immunol. 15,284-292 27 Sano,H. and Morimoto, C. (1982)J. lmmunol. 128, 1341-1345 28 Van Helden,P.D. (1985)J. Immunol. 134, 177-179 29 Sano, H. etal. (1989)Scand. J. Immunol. 30, 51-63 30 Krapf,F. et al. (1989) Clin. Exp. Immunol. 75, 336-342 31 Richardson,B. et al. (1990)Arthritis Rheum. 33, 1665-1673 32 Yung, Ri. etal. (1995)J. Immunol. 154, 3025-3035 33 Kataoka, T. et al. (1992)Jpn. J. Cancer Res. Gann 83, 244-247 34 Azad, R.F. et al. (1993) Antimicrob. Agents Chemother. 37, 1945-1954 35 Bran&, R.F. et al. (1993) Biocbem. PharmacoI. 45, 2037-2043
Lymphocyte dynamics, apoptosis and HIV infection Simon D.W. Frost and Colin A. Michie he hallmark defect in H W Death of HIV-infected CD4 ÷ cells and gp120 when it binds to the CD4 + infection is a gradual HIV-induced death of uninfected CD4 ÷ receptor on the T cell. Additiondecline of CD4 + T cells cells by apoptosis have been suggested to ally, the viral protein Tat upin the peripheral blood from be important factors in causing the gradual regulates the CD95 (also known about 1000 per mm 3 of blood to progressive decline of CD4 ÷ cells in the as the APO-1/Fas receptor) about 200 per mm 3 at the onset blood of HIV-positive patients. Recent protein on the T cell, which of AIDS over a period that advances in our knowledge of the increases the rates at which varies from several months dynamics of infection and the mechanism TCR-mediated and g p 1 2 0 to more than 10 years 1. CD4 + of apoptosis are reviewed with the aid CD4-mediated apoptosis take T cells can be infected by HIV place 11,12 It has been suggested of a mathematical model. and may die, owing to a comthat, by inducing apoptosis in S.D.W. Frost* is in the Dept of Zoology, bination of the cytopathicity uninfected cells, HIV could Oxford University, South Parks Road, Oxford, of the virus (although the virus cause CD4 + T cell decline. UK OXI 3PS. C.A. Micbie is in the Dept of is not believed to be very cytoTwo main points have yet to Paediatrics, Ealing Hospital NHS Trust, London, pathic) and immune clearance be addressed; first, how the proUK UB1 3HW. *tel: +44 1865 271 160, fax: +44 1865.310 447, e-maih [email protected] by cytotoxic T cells 2. Whatever cesses of infection and apopthe mechanism, two recent studtosis of CD4 + T cells interact ies 3,4suggest a very high death rate of virus-producing with each other in vivo; and second, how the rates of CD4 +T cells. Even though at any one time a very low these processes translate into the overall decline of number of CD4 +T cells are actually producing virus s, CD4 + T cells in the blood. It is difficult to answer if HIV is very infectious, this high death rate could these questions as (1) the processes of infection and translate into a large decline in CD4 + T cells. apoptosis are likely to depend on the density of CD4 ÷ Uninfected CD4+T cells may also die in the presence cells and of HIV, and these so-called 'nonlinear' interof HIV. Several mechanisms have been proposed: HIV actions often give rise to counterintuitive results; and may act as a superantigen 6, activating CD4 +T cells, ulti(2) our knowledge of many immune parameters (such mately resulting in their death; HIV may induce autoas cell lifetime) is sparse. Mathematical models of the immunity against CD4 + T cellsT; or HIV may induce immune system are very useful in such circumstances, syncytia formation, where clumps of infected and unas they allow us to investigate nonlinear interactions infected CD4 + cells form, and subsequently dieL The under a wide range of assumptions. In this article, we mechanism that has received the most attention recently review recent advances in our understanding of infecis that HIV may induce apoptosis in uninfected CD4 ÷ tion dynamics and mechanisms of apoptosis in HIV T cells 9,1°. Apoptosis, unlike necrosis, is an active proinfection using a mathematical model. cess where the cell is 'told' to die, and is very important in the control of lymphocyte populations in normal A simple mathematical model healthy individuals. HIV may induce apoptosis by acA mathematical model of CD4 ÷T cell infection by HW, tivating the CD4 ÷ T cell via the T cell receptor (TCR) based upon one previously published 13, is illustrated complex, or by the effect of the HIV envelope protein in Fig. 1. In the absence of HIV infection, we assume
T
Copyright © 1996 Elsevier Science Ltd. All rights reserved. 0966 842X/96/S15.00
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Fig. 1. A simple model of HIV infection of CD4 + cells. The boxes represent the densities of CD4- cells and virus, the arrows represent flows. Notation: X, the density of uninfected CD4* T cells; L, the density of latently infected CD4 + cells; E, the density of actively infected CD4* cells; V, the density of free virus; A, the rate of supply of uninfected CD4÷ cells; p, the per capita death rate of uninfected CD4 ÷ cells; cq the apoptosis rate per virion per uninfected cell; ~, the infection rate per virion per uninfected cell; 8, the proportion of infections that result directly in an actively infected cell; (y, the per capita activation rate of latently infected cells; t, the per capita mortality rate due to active infection; p, the rate of virion production per actively infected cell; m, the clearance rate of free virus; t, time. The assumptions of the model are discussed in the text. The set of ordinary differential equations describing the rates of change of population densities are: dX/dt= A-pX-czXV-~XV; d L / d t = ( 1 - 8 ) ~ X V - ( p + (~)L; dE/dt=8[JXV + ~ L - ( p + ~)E; dV/dt= pE-mV.
that the density of uninfected CD4 + T cells, which we denote X, increases at a constant rate A, and decreases at a constant per capita rate p. The increase is likely to be due mainly to proliferation of T cells rather than input from the thymus, which is degenerate in adults. Although extremely simple, the assumed constant input of CD4 ÷cells mimics the higher rate of increase of T cells seen in v i v o when T cell counts are low 3,s. Uninfected cells can also be infected or undergo apoptosis in the presence of HIV. The infection rate and the apoptosis rate are likely to increase with the density of uninfected CD4 ÷cells and the density of HIV. We assume that apoptosis occurs at a rate 0tXV, i.e. apoptosis increases at a rate proportional both to the density of uninfected cells, X, and to the density of virus, V. Both empirical data and the behaviour of the model suggest that this may be a reasonable first approximation. (1) Westendorp et al.LZ found that the apoptosis rate increased in proportion to concentrations of the viral protein Tat over a range of concentrations similar to those found in vivo. (2) Finkel et al. TM found that the number of apoptotic cells in sections of HIV-infected lymphoid tissue increased with the number of productively infected cells. (3) The model exhibits unrealistic oscillatory behaviour over time (not shown) if apoptosis is assumed to act at a rate saturated by virus. In a similar fashion, uninfected cells are assumed to be infected at a rate [8XV, i.e. the rate is proportional both to the density of uninfected cells and to that of free virus. It seems reasonable that were we to increase the density of uninfected cells or virus, the infection rate would increase. However, some degree of saturation of the apoptosis or infection rates at high levels of virus and/or uninfected cells cannot be ruled out, and the implications of this are discussed later. A proportion of infections (which we shall call 'fast' infections), 8,
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result directly in producing actively infected cells, the density of which is denoted by E, while the remainder of infections (which we shall call 'slow' infections), 1-8, enter a latently infected cell class, the density of which is denoted by L. Latently infected cells are assumed not to suffer mortality as a consequence of their infection, and so die at the same rate, It, as uninfected cells. Latently infected cells are assumed not to undergo apoptosis in the presence of HIV, although dropping this assumption does not affect any of the conclusions drawn here. Latently infected cells can be activated at a per capita rate (5 to become active virus-producing cells. Actively infected cells produce free virus at a per capita rate P, and die at a per capita rate bt + ~. Finkel et al. 14 have observed that productively infected CD4 + cells do not undergo apoptosis. Free virus, V, is assumed to decay at a per virion rate m. Our knowledge of the values of the model parameters is extremely poor, and over the long period of HIV infection, the parameters are likely to change. However, there are some data on the model parameters, and some model predictions are robust to parameter estimates. We use the model to investigate the factors setting the rate of CD4 + cell decline and the role of apoptosis in CD4 + cell decline.
The rate of CD4 ÷ T cell decline The densities of uninfected, latently infected, actively infected cells and free virus over time head towards a steady state, which we can write in terms of the parameters of the model, and are denoted by the superscript ..... (see Box 1). These steady states are time dependent, as we allow the parameters of the model to change. In Box I an expression for the overall replicative ability of H1V, R, is defined; the higher R is, the higher the replicative ability of HIVIL The steady-state populations can be rewritten in terms of R, which makes them easier to inspect. Two recent studies 3,4have shown that the 'fast' infections described here are more important in producing plasma virus than are 'slow' infections, where virus is produced by activation of the latently infected cell pool, and that the lifespan of actively infected cells (here denoted by E) and plasma virus (denoted by V) are very short (about a day or two). In this scenario, the CD4 + cell count and virus density rapidly approach their steady states, at a rate much faster than the rate at which the model parameters are likely to change. In mathematical terms, the uninfected cell and viral density are in a quasisteady state with respect to the parameters. The population densities quickly reach a quasisteady state, and then change in response to a changing replication rate, R. Changes in many model parameters could change R; a higher viral infectivity (modelled by the parameter 18),a higher proportion of fast infections (higher 6), higher viral production (higher p), and lower clearance rates of actively infected cells (lower ~) and free virus (lower m). These immunological parameters may change because of many biological processes, which might include activation of the immune system (by other pathogens 16, HIV or HIV products), a weakening immune response (e.g. caused by antigen-presenting cell
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Box 1. The replicative ability of HIV, R It would be useful to have a standard measure of the replicative ability of HIV within an individual at any one time. We define such a measure, R, as the number of virions produced by one virion during its lifetime if it were the only virion present, such that uninfected CD4 ÷ cells are not limiting. These virions could be produced either directly from infection of uninfected cells (the 'fast' route) or by activation of latent cells (the 'slow' route). Hence R is the sum of virions produced by the two routes: R=
R fast +
Rs~°~
The vast majority of the virus in the plasma is produced by the fast route, that is: R = R fast
In terms of the parameters of the model: R=
;513PA o~p(p+T)
which written in words is: R-
Proportion of fast infections x infectivity × virus production × uninfected cell supply Death rate of virus x death rate of uninfected cells x death rate of actively infected cells Factors that increase virus production Factors that decrease viral production
The quasisteady state densities of uninfected cells and free virus (X* and V*, respectively) can be written in terms of R: A X * ~ - -
pR In words: Uninfected cell supply Death rate of uninfected cell supply x replication rate of HIV
V*=
g (R-l) y+13
In words: Death rate of uninfected cells x replication rate of HIV-1 V*
-
Apoptosis rate constant x infection rate constant
destruction 17, increasing viral diversity ~8,19or decreasing nutritional status) or a shift to more-virulent strains 2°. An increase in replicative ability, R, results in a higher viral density (see Box 1). This result is independent of parameter estimates (although the extent to which V* rises with R does depend on parameter estimates and the underlying cause of increasing R). A gradual increase in R can result in a gradual increase in viral density and generally a gradual decline of the quasisteady state density of uninfected CD4 ÷cells, X* (see Fig. 2a), with one important exception. If the replicative ability of HIV, R, changes due to changes in the input or death rate of uninfected CD4 + cells (the parameters A and p respectively), then X* remains unchanged (see Fig. 2b), as changes in the supply or death of uninfected cells are compensated for by changes in the infection rate. This is independent of the assumed parameter values, and stems from our assumption that the infection rate
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rises in proportion to both uninfected cell density, X, and virus density, V. If we assume that the infection rate rises less than in proportion to X and/or V, then increasing proliferation (or decreasing death) of uninfected cells would increase both uninfected cell and virus density. As long as the infection rate is not completely saturated, however, changes in the dynamics of uninfected cells may be compensated for, at least in part, by changing infection rates, and the possibility remains that changing the supply or death of uninfected cells may affect viral density more than uninfected cell density. The effect of apoptosis Increasing the apoptosis rate in the model decreases the viral density (Fig. 3), as uninfected cells are more likely to die than be infected, and does not affect uninfected cell density, as an increasing apoptosis rate is compensated for by a decreasing infection rate. This result is
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A more general conclusion is that increasing apoptosis may have more of an effect on viral density than uninfected cell density because the infection rate compensates for the higher death rate of uninfected cells by apoptosis. The mechanism that causes apoptosis of uninfected cells may have effects on other model parameters. (1) Although Tat may eventually induce apoptosis of uninfected cells, it may also increase T cell proliferation (A), compensating for the higher death rate of uninfected cells. Li e t a l . ' 1 found that before peripheral blood mononuclear cells underwent apoptosis in response to the Tat protein, they showed signs of activation. In the murine (mouse) model of AIDS, where CD4 ÷cells are not infected, apoptosis of CD4 +cells is associated with raised levels of CD4 + T cells21. (2) Lymphocyte proliferation may increase the efficiency of infection by increasing the susceptibility of cells to infection (increasing 13) or by decreasing the proportion of infections that become latent (increasing 6). There is some evidence to suggest that activated cells are preferentially infected22,23. (3) The mechanism underlying apoptosis of uninfected cells may also result in a weaker immune response, so apoptosis is compensated for by the longer life of infected cells (smaller "c) so that they can produce more virus.
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Fig. 2. The effect of increasing the replication rate on the densities of virus and uninfected cells depends upon which parameter(s) are causing the change. The densities of uninfected cells and virus are assumed to reach a quasisteady state with respect to the parameters of the model on a timescale much faster than that of the timecourse of infection. The graphs show the change in the quasisteady state densities of uninfected CD4 ÷ T cells, X* (squares), and of free virus, V* (triangles), per mm 3 of blood over time, assuming R (circles), the measure of HIV replication defined in Box 1, increases exponentially from (just over) i to 10 over 10 years. (a) The increase in R is assumed to be caused by changes in 6, the proportion of infections that result directly in an actively infected cell; (~, the per capita activation rate of latently infected cells; ~, the per capita mortality rate due to active infection; p, the rate of virion production per actively infected cell; or ~o, the clearance rate of free virus. Note that X* decreases and V* increases with R. A similar graph is obtained if R is assumed to increase due to increasing ~, the infectivity of the virus. (b) The increase in R is assumed to be caused by an increase in A, the supply rate of uninfected cells. Note that X* is constant whilst V* increases with R. A similar graph is obtained if the increase in R is assumed to be caused by a lower death rate of uninfected cells, ~. The initial conditions are X* = 1000, V* = 1 and are chosen purely for illustrative purposes; the qualitative conclusions remain unchanged with different parameter values.
independent of the parameter estimates, and holds true even if apoptosis rates are saturated by virus or are constant. This result stems from the assumption that the infection rate rises in proportion to both uninfected cell density, X, and virus density, V. If there was some degree of saturation in the infection rate, it is possible that increasing apoptosis rates would result in both a lower viral density and a lower uninfected cell density.
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The underlying cause of the slow progression of HIV infection to AIDS is still controversial. Although millions of virus particles are produced and cleared every day 3,4, for some reason this highly dynamic balance of power between HIV and the immune system slowly swings in favour of HIV, eventually resulting in AIDS after years of the immune system controlling the virus is. We have examined just one aspect of HIV pathogenesis, the gradual decline of CD4+ cells in the peripheral blood and, using a simple mathematical model, we derive a measure for the overall replicative ability of HIV, R. An increase in the replicative ability of HIV, not surprisingly, always results in an increase in viral density, robust to model assumptions, although many processes could contribute to this change. The numerical contribution of each process to HIV replication and how this changes over time is as yet unknown, but is likely only to be important in determining the extent to which
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viral burden increases with repli-¢ --" ¢ ,¢ ¢¢ ~5 cation rate. 800 "~ The effect of increasing HIV repli~ ~, cation rate, R, on uninfected cell deno -4m sity is more difficult to establish, as an ~ >= ~ 600 increasing R in the model may be as~ ~ ..~ sociated with a decrease, no change ~ .~ -3"~ or even an increase in uninfected cell 0~ , density depending on why R is increas~ ~ 400 ind. If R increases as a result of an in>, g creasing supply of uninfected cells "~ "lD relative to the death rate of uninfected ~ 0~ cells, uninfected cell density remains ~ ~ 200 unchanged (if the infection rate in~ creases in proportion to uninfected cell = density) or may increase (if the infecI 0 tion rate increases less than propor0 0 0.02 0.04 0.06 0.08 0.10 tionately with uninfected cell density, Apoptosis rate i.e. there is some saturation of the inFig. 3. Increasing the apoptosis rate decreases viral density and leaves uninfected cell density fection rate). If R increases because of unchanged. Quasisteady state densities of uninfected CD4+ T cells, X* (squares), and of reasons other than a relative increase free virus, V* (triangles), per mm 3 of blood and the replication rate of HIV, R (circles), over a in the supply of uninfected cells, unrange of apoptosis rates (per virion per year). The parameter values used (see text) are: infected cell density falls with increasA = 2000 cells year 1, p=2year 1, i~=0.01pervirionyear 1, R=5, and are chosen purely for illustrative purposes. The qualitative results depend only on the assumption that the infection ing R. With broad generality, changes rate is proportional to both uninfected cell and viral density. The implications of dropping this in the turnover of uninfected cells are assumption are discussed in the text. 'mopped up' by changes in the infection rate, and the extent to which this occurs depends on how the proliferQ u e s t i o n s for f u t u r e r e s e a r c h ation and infection rates of CD4 +cells change with viral and uninfected cell • What is the single most important factor in increasing the replicative ability of HIV density. over the long period of infection? Assessing the overall role that apop• Why do productively infected cells not undergo apoptosis14? Perhaps HIV produces tosis of uninfected cells plays is also a protein that prevents apoptosis of the infected cell, analogous to those produced by Epstein-Barr virus 25 and adenovirus2% difficult, as changes in the death rate of • Much of our knowledge of infection dynamics in HIV comes from studies of the uninfected cells may also be 'mopped peripheral blood, yet lymphoid tissues are likely to be more important as sites of up' by changes in the infection rate. HIV replication. What do studies of HIV infection dynamics in the blood reveal about Consequently, apoptosis of uninfected the dynamics in lymphoid tissues? cells may have more of a role in de• In the lymphoid tissues, how does infection and apoptosis of CD4 + cells occur creasing viral burden than in CD4 +cell - from contact with free virus, with infected T cells or macrophages, or by virus decline. If the infection rate increases attached to follicular dendritic cells14.~7? in proportion to viral and uninfected • CD4 + cell decline in the blood is not the only immunological defect seen in HIV cell density, then apoptosis of unininfection. How important is the contribution of CD4 ÷ cell decline to the slow progression to AIDS17? fected cells is perfectly compensated for by the infection rate, and uninfected cell density remains unchanged. In addition, the mechanism that causes apoptosis of uninTo assess how CD4 ~ cell turnover affects CD4 ÷ cell fected cells may also have effects on other parameters, count and viral density, further study is required of how such as increasing proliferation of uninfected cells. the densities of CD4 + cells and HIV interact to set inIndeed, apoptosis of uninfected cells may simply be a fection, apoptosis and proliferation rates. The study of side effect of HIV manipulating other immunological lymphocyte dynamics in HIV infection may reveal not parameters. It is possible that the virus gains more in only how HIV causes CD4 +cell decline (and so provide terms of replication by increasing proliferation of unbetter models of CD4+ cell infection), but also how the infected cells than it loses by death of these cells by apopimmune system is regulated. tosis. Unless the individual effects of the mechanism that Acknowledgements causes apoptosis are quantified, the overall effect on Wethank Drs AngelaMcLean,ClaireParkerand MichaelGravenorfor CD4 ÷cell count and viral density cannot be established. usefuldiscussion.S.D.W.F.is fundedbythe IVledicalResearchCouncil. The turnover of uninfected CD4 + cells 3,4 is much higher than that seen in individuals recovering from References radiotherapy treatment 24, where CD4 +cell count is also 1 Levy,J.A. (1993)Microbiol.Rev. 57, 183-289 reduced. This is likely to reflect both a normal homeo2 Zinkernagel,R.M. and Hengartner,H. (1994) ImmunoL Today static response by the body to restore the number of 15, 262-268 CD4 +cells and the disruption of this response by HIV. 3 Ho, D.D. etal. (1995)Nature 373, 123-126 A
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4 Wei,X. etal. (1995) Nature 373, 117-122 5 McLean,A.R.and Michie,C.A. (1993) Nature 365, 301 6 lmberti,L. et al. (1991) Science 254, 860-862 7 Kion,T.A. and Hoffman,G.W.(1991) Science 253, 1138-1140 8 Yoffe,B. et al. (1987) Proc. Natl Acad. Sci. USA 84, 1429-1433 9 Gougeon,M.L. et al. (1993) AIDS Res. Hum. Retroviruses 9, 553-563 10 Ascher,M.S. and Sheppard,H.W. (1990) Lancet 336, 507 11 Li, C.J. et al. (1995) Science 268, 429-43l 12 Westendorp,M.O. et al. (1995) Nature 375, 497-500 13 McLean,A.R. et al. (1991) AIDS 5, 485-489 14 Finkel,T.H. et al. (1995) Nature Med. 1,129-134 15 McLean,A.R. (1993) Trends Microbiol. 1, 9-13 16 McLean,A.R.and Nowak,M.A. (1992)J. Theor. Biol. 155, 69-86
Inject and hope for the best? Combined Vaccines and Simultaneous Administration: Current Issues and Perspectives
edited by J.C. Williams, K.L. Goldenthal, D.L. Burns and B.P. Lewis Jr Annals of the New York Academy of Sciences Vol. 754, 1995. $140.00 pbk (xv + 404 pages) ISBN 0 89766 862 6 he development of the 'supershot in which vaccilaation against all childhood diseases is administered in a single injection is the main objective of the Children's Vaccine Initiative. The ease of record keeping and the reduction in costs and discomfort to children provide a powerful impetus behind vaccine combination or simultaneous administration at different sites. The book contains a balanced mixture of philosophical essays that deal with the overwhelming difficulties associated with the evaluation of the plethora of potential new vaccine products that have been developed and down-to-earth discussions with actual data on safety, lot consistency and vaccine interference. Combination vaccines require the absence of interference between the various components. This can be a problem. The surprising effect of a Hib vaccine on the titres of antibodies to the pertussis c o m p o n e n t of the DTP vaccine would not have been predicted from first principles, nor can it be explained. In other cases interference did not occur where it might be expected, for
T
17 Frost, S.D.W.and McLean,A.R. (1994)J. AIDS 7, 236-244 18 Nowak,M.A. et al. (1991) Science 254, 963-969 19 Nowak,M.A.et al. {1995}Nature 375, 606-611 20 Fenyo,E.M. et al. (1989)AIDS 3 (Suppl. 1), $5-S12 21 Cohen,D.A.et al. (1993) Cell. Immunol. 151,392-403 22 Schnittman,S.M. et al. (1990) Proc. Natl Acad. Sci. USA 87, 6058-6062 23 Romagnani,S. et al. (1994) AIDS Res. Hum. Retroviruses 10, iii-ix 24 McLean,A.R.and Michie,C.A. (1995) Proc. NatI Acad. Sci. USA 92, 3707-3711 25 Silins,S.L.and Sculley,T.B. (1995) Int. J. Cancer 60, 65-72 26 Farrow,S.N. et al. (1995) Nature 374, 731-733 27 Heath,S.L.et al. (1995) Nature 377, 740-744
example when immunosuppressive live-attenuated measles virus is combined with mumps and rubella virus. Few examples of interference were actually documented in the book and possibly it is not as large a problem as suspected. I was impressed by the myriad of new combinations of antigens, vectors, adjuvants and routes of administration described. The book explains lucidly how large studies would have to be to demonstrate slight changes in the rate of side effects and how large the number of study arms in vaccine trials would have to be to demonstrate interference between the various components. Obviously, not all new products can be evaluated in costly trials. However, straight commercial considerations ,viii limit the number of vaccine product combinations evaluated as few manufacturers will carry out trials with other manufacturer's products. The book also shows how little we know about how different immunological responses to vaccination confer protection and how we often do not have good surrogate markers for protection. Certain aspects of the immune response to vaccines, such as the T h l and Th2 biases associated with various antigens and mechanisms of antigen presentation, were discussed repeatedly. Importantly, a change from T h l to Th2 bias can change responses from protective to disease inducing. Differences in T h l and Th2 bias associated with various antigens and routes of administration may be of relevance when new combinations of antigens from different organisms are injected.
In his conclusion Barry Bloom remarked that all vaccines except for some bacterial toxins are already combination vaccines, but these contain 'natural' combinations of antigens from a single organism that has often had to reach an evolutionary accommodation with its human host. At present, it is impossible to predict responses to new combined vaccines. At the end of the day, the numbers of products that await evaluation is so large, the safety questions that can be formulated are so complex and the studies so costly that we may end up trying new vaccines in volunteers and hoping for the best. This is of course what was done at the introduction of the first generation of vaccines. We now have so much knowledge about immune responses that it is almost impossible to convince oneself that any new product is safe and should be used in non-life-threatening situations. The book describes most of the current vectors and adjuvants in scant detail. Despite it being a collection of papers delivered at a meeting of the New York Academy in 1993 and, as all books of this kind, repetitive, the various sections provide a good account of the subject. I found it thought provoking and well worth reading, but undoubtedly already out of date as its publication lagged 2 years behind the conference. Bert Rima
School of Biology and Biochemistry, The Queen's University of Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, UK BT9 7BL
Copyright © 1996 Elsevicr Science Ltd. All rights reserved. 0966 842X/96/$15.00
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19 Iguchi-Ariga,8.M.M. and Schaffner,W. (1989) Genes Dev. 3, 612-619 20 Karlin,S., Ladunga, I. and Blaisdell,B.E. (1994)Proc. Natl Acad. Sci. USA 91, 12837-12841 21 Karlin,S., Doerfler,W. and Cardon, L.R. (1994)J. Virol. 68, 2889-2897 22 Shpaer,E.G. and Mullins,J.I. (1990)Nucleic Acids Res. 18, 5793-5797 23 Tate, P.H. and Bird, A.P. (1993) Curr. Opin. Genet. Dev. 3, 226-231 24 Cardon, L.R. et al. (1994) Proc. Natl Acad. Sci. USA 91, 3799-3803
25 Bains,W. and Bains,J. (1987)Mutat. Res. 179, 65-74 26 Krieg,A.M. (1995)J. Clin. Immunol. 15,284-292 27 Sano,H. and Morimoto, C. (1982)J. lmmunol. 128, 1341-1345 28 Van Helden,P.D. (1985)J. Immunol. 134, 177-179 29 Sano, H. etal. (1989)Scand. J. Immunol. 30, 51-63 30 Krapf,F. et al. (1989) Clin. Exp. Immunol. 75, 336-342 31 Richardson,B. et al. (1990)Arthritis Rheum. 33, 1665-1673 32 Yung, Ri. etal. (1995)J. Immunol. 154, 3025-3035 33 Kataoka, T. et al. (1992)Jpn. J. Cancer Res. Gann 83, 244-247 34 Azad, R.F. et al. (1993) Antimicrob. Agents Chemother. 37, 1945-1954 35 Bran&, R.F. et al. (1993) Biocbem. PharmacoI. 45, 2037-2043
Lymphocyte dynamics, apoptosis and HIV infection Simon D.W. Frost and Colin A. Michie he hallmark defect in H W Death of HIV-infected CD4 ÷ cells and gp120 when it binds to the CD4 + infection is a gradual HIV-induced death of uninfected CD4 ÷ receptor on the T cell. Additiondecline of CD4 + T cells cells by apoptosis have been suggested to ally, the viral protein Tat upin the peripheral blood from be important factors in causing the gradual regulates the CD95 (also known about 1000 per mm 3 of blood to progressive decline of CD4 ÷ cells in the as the APO-1/Fas receptor) about 200 per mm 3 at the onset blood of HIV-positive patients. Recent protein on the T cell, which of AIDS over a period that advances in our knowledge of the increases the rates at which varies from several months dynamics of infection and the mechanism TCR-mediated and g p 1 2 0 to more than 10 years 1. CD4 + of apoptosis are reviewed with the aid CD4-mediated apoptosis take T cells can be infected by HIV place 11,12 It has been suggested of a mathematical model. and may die, owing to a comthat, by inducing apoptosis in S.D.W. Frost* is in the Dept of Zoology, bination of the cytopathicity uninfected cells, HIV could Oxford University, South Parks Road, Oxford, of the virus (although the virus cause CD4 + T cell decline. UK OXI 3PS. C.A. Micbie is in the Dept of is not believed to be very cytoTwo main points have yet to Paediatrics, Ealing Hospital NHS Trust, London, pathic) and immune clearance be addressed; first, how the proUK UB1 3HW. *tel: +44 1865 271 160, fax: +44 1865.310 447, e-maih [email protected] by cytotoxic T cells 2. Whatever cesses of infection and apopthe mechanism, two recent studtosis of CD4 + T cells interact ies 3,4suggest a very high death rate of virus-producing with each other in vivo; and second, how the rates of CD4 +T cells. Even though at any one time a very low these processes translate into the overall decline of number of CD4 +T cells are actually producing virus s, CD4 + T cells in the blood. It is difficult to answer if HIV is very infectious, this high death rate could these questions as (1) the processes of infection and translate into a large decline in CD4 + T cells. apoptosis are likely to depend on the density of CD4 ÷ Uninfected CD4+T cells may also die in the presence cells and of HIV, and these so-called 'nonlinear' interof HIV. Several mechanisms have been proposed: HIV actions often give rise to counterintuitive results; and may act as a superantigen 6, activating CD4 +T cells, ulti(2) our knowledge of many immune parameters (such mately resulting in their death; HIV may induce autoas cell lifetime) is sparse. Mathematical models of the immunity against CD4 + T cellsT; or HIV may induce immune system are very useful in such circumstances, syncytia formation, where clumps of infected and unas they allow us to investigate nonlinear interactions infected CD4 + cells form, and subsequently dieL The under a wide range of assumptions. In this article, we mechanism that has received the most attention recently review recent advances in our understanding of infecis that HIV may induce apoptosis in uninfected CD4 ÷ tion dynamics and mechanisms of apoptosis in HIV T cells 9,1°. Apoptosis, unlike necrosis, is an active proinfection using a mathematical model. cess where the cell is 'told' to die, and is very important in the control of lymphocyte populations in normal A simple mathematical model healthy individuals. HIV may induce apoptosis by acA mathematical model of CD4 ÷T cell infection by HW, tivating the CD4 ÷ T cell via the T cell receptor (TCR) based upon one previously published 13, is illustrated complex, or by the effect of the HIV envelope protein in Fig. 1. In the absence of HIV infection, we assume
T
Copyright © 1996 Elsevier Science Ltd. All rights reserved. 0966 842X/96/S15.00
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VX
t
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Fig. 1. A simple model of HIV infection of CD4 + cells. The boxes represent the densities of CD4- cells and virus, the arrows represent flows. Notation: X, the density of uninfected CD4* T cells; L, the density of latently infected CD4 + cells; E, the density of actively infected CD4* cells; V, the density of free virus; A, the rate of supply of uninfected CD4÷ cells; p, the per capita death rate of uninfected CD4 ÷ cells; cq the apoptosis rate per virion per uninfected cell; ~, the infection rate per virion per uninfected cell; 8, the proportion of infections that result directly in an actively infected cell; (y, the per capita activation rate of latently infected cells; t, the per capita mortality rate due to active infection; p, the rate of virion production per actively infected cell; m, the clearance rate of free virus; t, time. The assumptions of the model are discussed in the text. The set of ordinary differential equations describing the rates of change of population densities are: dX/dt= A-pX-czXV-~XV; d L / d t = ( 1 - 8 ) ~ X V - ( p + (~)L; dE/dt=8[JXV + ~ L - ( p + ~)E; dV/dt= pE-mV.
that the density of uninfected CD4 + T cells, which we denote X, increases at a constant rate A, and decreases at a constant per capita rate p. The increase is likely to be due mainly to proliferation of T cells rather than input from the thymus, which is degenerate in adults. Although extremely simple, the assumed constant input of CD4 ÷cells mimics the higher rate of increase of T cells seen in v i v o when T cell counts are low 3,s. Uninfected cells can also be infected or undergo apoptosis in the presence of HIV. The infection rate and the apoptosis rate are likely to increase with the density of uninfected CD4 ÷cells and the density of HIV. We assume that apoptosis occurs at a rate 0tXV, i.e. apoptosis increases at a rate proportional both to the density of uninfected cells, X, and to the density of virus, V. Both empirical data and the behaviour of the model suggest that this may be a reasonable first approximation. (1) Westendorp et al.LZ found that the apoptosis rate increased in proportion to concentrations of the viral protein Tat over a range of concentrations similar to those found in vivo. (2) Finkel et al. TM found that the number of apoptotic cells in sections of HIV-infected lymphoid tissue increased with the number of productively infected cells. (3) The model exhibits unrealistic oscillatory behaviour over time (not shown) if apoptosis is assumed to act at a rate saturated by virus. In a similar fashion, uninfected cells are assumed to be infected at a rate [8XV, i.e. the rate is proportional both to the density of uninfected cells and to that of free virus. It seems reasonable that were we to increase the density of uninfected cells or virus, the infection rate would increase. However, some degree of saturation of the apoptosis or infection rates at high levels of virus and/or uninfected cells cannot be ruled out, and the implications of this are discussed later. A proportion of infections (which we shall call 'fast' infections), 8,
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result directly in producing actively infected cells, the density of which is denoted by E, while the remainder of infections (which we shall call 'slow' infections), 1-8, enter a latently infected cell class, the density of which is denoted by L. Latently infected cells are assumed not to suffer mortality as a consequence of their infection, and so die at the same rate, It, as uninfected cells. Latently infected cells are assumed not to undergo apoptosis in the presence of HIV, although dropping this assumption does not affect any of the conclusions drawn here. Latently infected cells can be activated at a per capita rate (5 to become active virus-producing cells. Actively infected cells produce free virus at a per capita rate P, and die at a per capita rate bt + ~. Finkel et al. 14 have observed that productively infected CD4 + cells do not undergo apoptosis. Free virus, V, is assumed to decay at a per virion rate m. Our knowledge of the values of the model parameters is extremely poor, and over the long period of HIV infection, the parameters are likely to change. However, there are some data on the model parameters, and some model predictions are robust to parameter estimates. We use the model to investigate the factors setting the rate of CD4 + cell decline and the role of apoptosis in CD4 + cell decline.
The rate of CD4 ÷ T cell decline The densities of uninfected, latently infected, actively infected cells and free virus over time head towards a steady state, which we can write in terms of the parameters of the model, and are denoted by the superscript ..... (see Box 1). These steady states are time dependent, as we allow the parameters of the model to change. In Box I an expression for the overall replicative ability of H1V, R, is defined; the higher R is, the higher the replicative ability of HIVIL The steady-state populations can be rewritten in terms of R, which makes them easier to inspect. Two recent studies 3,4have shown that the 'fast' infections described here are more important in producing plasma virus than are 'slow' infections, where virus is produced by activation of the latently infected cell pool, and that the lifespan of actively infected cells (here denoted by E) and plasma virus (denoted by V) are very short (about a day or two). In this scenario, the CD4 + cell count and virus density rapidly approach their steady states, at a rate much faster than the rate at which the model parameters are likely to change. In mathematical terms, the uninfected cell and viral density are in a quasisteady state with respect to the parameters. The population densities quickly reach a quasisteady state, and then change in response to a changing replication rate, R. Changes in many model parameters could change R; a higher viral infectivity (modelled by the parameter 18),a higher proportion of fast infections (higher 6), higher viral production (higher p), and lower clearance rates of actively infected cells (lower ~) and free virus (lower m). These immunological parameters may change because of many biological processes, which might include activation of the immune system (by other pathogens 16, HIV or HIV products), a weakening immune response (e.g. caused by antigen-presenting cell
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Box 1. The replicative ability of HIV, R It would be useful to have a standard measure of the replicative ability of HIV within an individual at any one time. We define such a measure, R, as the number of virions produced by one virion during its lifetime if it were the only virion present, such that uninfected CD4 ÷ cells are not limiting. These virions could be produced either directly from infection of uninfected cells (the 'fast' route) or by activation of latent cells (the 'slow' route). Hence R is the sum of virions produced by the two routes: R=
R fast +
Rs~°~
The vast majority of the virus in the plasma is produced by the fast route, that is: R = R fast
In terms of the parameters of the model: R=
;513PA o~p(p+T)
which written in words is: R-
Proportion of fast infections x infectivity × virus production × uninfected cell supply Death rate of virus x death rate of uninfected cells x death rate of actively infected cells Factors that increase virus production Factors that decrease viral production
The quasisteady state densities of uninfected cells and free virus (X* and V*, respectively) can be written in terms of R: A X * ~ - -
pR In words: Uninfected cell supply Death rate of uninfected cell supply x replication rate of HIV
V*=
g (R-l) y+13
In words: Death rate of uninfected cells x replication rate of HIV-1 V*
-
Apoptosis rate constant x infection rate constant
destruction 17, increasing viral diversity ~8,19or decreasing nutritional status) or a shift to more-virulent strains 2°. An increase in replicative ability, R, results in a higher viral density (see Box 1). This result is independent of parameter estimates (although the extent to which V* rises with R does depend on parameter estimates and the underlying cause of increasing R). A gradual increase in R can result in a gradual increase in viral density and generally a gradual decline of the quasisteady state density of uninfected CD4 ÷cells, X* (see Fig. 2a), with one important exception. If the replicative ability of HIV, R, changes due to changes in the input or death rate of uninfected CD4 + cells (the parameters A and p respectively), then X* remains unchanged (see Fig. 2b), as changes in the supply or death of uninfected cells are compensated for by changes in the infection rate. This is independent of the assumed parameter values, and stems from our assumption that the infection rate
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rises in proportion to both uninfected cell density, X, and virus density, V. If we assume that the infection rate rises less than in proportion to X and/or V, then increasing proliferation (or decreasing death) of uninfected cells would increase both uninfected cell and virus density. As long as the infection rate is not completely saturated, however, changes in the dynamics of uninfected cells may be compensated for, at least in part, by changing infection rates, and the possibility remains that changing the supply or death of uninfected cells may affect viral density more than uninfected cell density. The effect of apoptosis Increasing the apoptosis rate in the model decreases the viral density (Fig. 3), as uninfected cells are more likely to die than be infected, and does not affect uninfected cell density, as an increasing apoptosis rate is compensated for by a decreasing infection rate. This result is
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A more general conclusion is that increasing apoptosis may have more of an effect on viral density than uninfected cell density because the infection rate compensates for the higher death rate of uninfected cells by apoptosis. The mechanism that causes apoptosis of uninfected cells may have effects on other model parameters. (1) Although Tat may eventually induce apoptosis of uninfected cells, it may also increase T cell proliferation (A), compensating for the higher death rate of uninfected cells. Li e t a l . ' 1 found that before peripheral blood mononuclear cells underwent apoptosis in response to the Tat protein, they showed signs of activation. In the murine (mouse) model of AIDS, where CD4 ÷cells are not infected, apoptosis of CD4 +cells is associated with raised levels of CD4 + T cells21. (2) Lymphocyte proliferation may increase the efficiency of infection by increasing the susceptibility of cells to infection (increasing 13) or by decreasing the proportion of infections that become latent (increasing 6). There is some evidence to suggest that activated cells are preferentially infected22,23. (3) The mechanism underlying apoptosis of uninfected cells may also result in a weaker immune response, so apoptosis is compensated for by the longer life of infected cells (smaller "c) so that they can produce more virus.
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Discussion
Fig. 2. The effect of increasing the replication rate on the densities of virus and uninfected cells depends upon which parameter(s) are causing the change. The densities of uninfected cells and virus are assumed to reach a quasisteady state with respect to the parameters of the model on a timescale much faster than that of the timecourse of infection. The graphs show the change in the quasisteady state densities of uninfected CD4 ÷ T cells, X* (squares), and of free virus, V* (triangles), per mm 3 of blood over time, assuming R (circles), the measure of HIV replication defined in Box 1, increases exponentially from (just over) i to 10 over 10 years. (a) The increase in R is assumed to be caused by changes in 6, the proportion of infections that result directly in an actively infected cell; (~, the per capita activation rate of latently infected cells; ~, the per capita mortality rate due to active infection; p, the rate of virion production per actively infected cell; or ~o, the clearance rate of free virus. Note that X* decreases and V* increases with R. A similar graph is obtained if R is assumed to increase due to increasing ~, the infectivity of the virus. (b) The increase in R is assumed to be caused by an increase in A, the supply rate of uninfected cells. Note that X* is constant whilst V* increases with R. A similar graph is obtained if the increase in R is assumed to be caused by a lower death rate of uninfected cells, ~. The initial conditions are X* = 1000, V* = 1 and are chosen purely for illustrative purposes; the qualitative conclusions remain unchanged with different parameter values.
independent of the parameter estimates, and holds true even if apoptosis rates are saturated by virus or are constant. This result stems from the assumption that the infection rate rises in proportion to both uninfected cell density, X, and virus density, V. If there was some degree of saturation in the infection rate, it is possible that increasing apoptosis rates would result in both a lower viral density and a lower uninfected cell density.
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The underlying cause of the slow progression of HIV infection to AIDS is still controversial. Although millions of virus particles are produced and cleared every day 3,4, for some reason this highly dynamic balance of power between HIV and the immune system slowly swings in favour of HIV, eventually resulting in AIDS after years of the immune system controlling the virus is. We have examined just one aspect of HIV pathogenesis, the gradual decline of CD4+ cells in the peripheral blood and, using a simple mathematical model, we derive a measure for the overall replicative ability of HIV, R. An increase in the replicative ability of HIV, not surprisingly, always results in an increase in viral density, robust to model assumptions, although many processes could contribute to this change. The numerical contribution of each process to HIV replication and how this changes over time is as yet unknown, but is likely only to be important in determining the extent to which
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viral burden increases with repli-¢ --" ¢ ,¢ ¢¢ ~5 cation rate. 800 "~ The effect of increasing HIV repli~ ~, cation rate, R, on uninfected cell deno -4m sity is more difficult to establish, as an ~ >= ~ 600 increasing R in the model may be as~ ~ ..~ sociated with a decrease, no change ~ .~ -3"~ or even an increase in uninfected cell 0~ , density depending on why R is increas~ ~ 400 ind. If R increases as a result of an in>, g creasing supply of uninfected cells "~ "lD relative to the death rate of uninfected ~ 0~ cells, uninfected cell density remains ~ ~ 200 unchanged (if the infection rate in~ creases in proportion to uninfected cell = density) or may increase (if the infecI 0 tion rate increases less than propor0 0 0.02 0.04 0.06 0.08 0.10 tionately with uninfected cell density, Apoptosis rate i.e. there is some saturation of the inFig. 3. Increasing the apoptosis rate decreases viral density and leaves uninfected cell density fection rate). If R increases because of unchanged. Quasisteady state densities of uninfected CD4+ T cells, X* (squares), and of reasons other than a relative increase free virus, V* (triangles), per mm 3 of blood and the replication rate of HIV, R (circles), over a in the supply of uninfected cells, unrange of apoptosis rates (per virion per year). The parameter values used (see text) are: infected cell density falls with increasA = 2000 cells year 1, p=2year 1, i~=0.01pervirionyear 1, R=5, and are chosen purely for illustrative purposes. The qualitative results depend only on the assumption that the infection ing R. With broad generality, changes rate is proportional to both uninfected cell and viral density. The implications of dropping this in the turnover of uninfected cells are assumption are discussed in the text. 'mopped up' by changes in the infection rate, and the extent to which this occurs depends on how the proliferQ u e s t i o n s for f u t u r e r e s e a r c h ation and infection rates of CD4 +cells change with viral and uninfected cell • What is the single most important factor in increasing the replicative ability of HIV density. over the long period of infection? Assessing the overall role that apop• Why do productively infected cells not undergo apoptosis14? Perhaps HIV produces tosis of uninfected cells plays is also a protein that prevents apoptosis of the infected cell, analogous to those produced by Epstein-Barr virus 25 and adenovirus2% difficult, as changes in the death rate of • Much of our knowledge of infection dynamics in HIV comes from studies of the uninfected cells may also be 'mopped peripheral blood, yet lymphoid tissues are likely to be more important as sites of up' by changes in the infection rate. HIV replication. What do studies of HIV infection dynamics in the blood reveal about Consequently, apoptosis of uninfected the dynamics in lymphoid tissues? cells may have more of a role in de• In the lymphoid tissues, how does infection and apoptosis of CD4 + cells occur creasing viral burden than in CD4 +cell - from contact with free virus, with infected T cells or macrophages, or by virus decline. If the infection rate increases attached to follicular dendritic cells14.~7? in proportion to viral and uninfected • CD4 + cell decline in the blood is not the only immunological defect seen in HIV cell density, then apoptosis of unininfection. How important is the contribution of CD4 ÷ cell decline to the slow progression to AIDS17? fected cells is perfectly compensated for by the infection rate, and uninfected cell density remains unchanged. In addition, the mechanism that causes apoptosis of uninTo assess how CD4 ~ cell turnover affects CD4 ÷ cell fected cells may also have effects on other parameters, count and viral density, further study is required of how such as increasing proliferation of uninfected cells. the densities of CD4 + cells and HIV interact to set inIndeed, apoptosis of uninfected cells may simply be a fection, apoptosis and proliferation rates. The study of side effect of HIV manipulating other immunological lymphocyte dynamics in HIV infection may reveal not parameters. It is possible that the virus gains more in only how HIV causes CD4 +cell decline (and so provide terms of replication by increasing proliferation of unbetter models of CD4+ cell infection), but also how the infected cells than it loses by death of these cells by apopimmune system is regulated. tosis. Unless the individual effects of the mechanism that Acknowledgements causes apoptosis are quantified, the overall effect on Wethank Drs AngelaMcLean,ClaireParkerand MichaelGravenorfor CD4 ÷cell count and viral density cannot be established. usefuldiscussion.S.D.W.F.is fundedbythe IVledicalResearchCouncil. The turnover of uninfected CD4 + cells 3,4 is much higher than that seen in individuals recovering from References radiotherapy treatment 24, where CD4 +cell count is also 1 Levy,J.A. (1993)Microbiol.Rev. 57, 183-289 reduced. This is likely to reflect both a normal homeo2 Zinkernagel,R.M. and Hengartner,H. (1994) ImmunoL Today static response by the body to restore the number of 15, 262-268 CD4 +cells and the disruption of this response by HIV. 3 Ho, D.D. etal. (1995)Nature 373, 123-126 A
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4 Wei,X. etal. (1995) Nature 373, 117-122 5 McLean,A.R.and Michie,C.A. (1993) Nature 365, 301 6 lmberti,L. et al. (1991) Science 254, 860-862 7 Kion,T.A. and Hoffman,G.W.(1991) Science 253, 1138-1140 8 Yoffe,B. et al. (1987) Proc. Natl Acad. Sci. USA 84, 1429-1433 9 Gougeon,M.L. et al. (1993) AIDS Res. Hum. Retroviruses 9, 553-563 10 Ascher,M.S. and Sheppard,H.W. (1990) Lancet 336, 507 11 Li, C.J. et al. (1995) Science 268, 429-43l 12 Westendorp,M.O. et al. (1995) Nature 375, 497-500 13 McLean,A.R. et al. (1991) AIDS 5, 485-489 14 Finkel,T.H. et al. (1995) Nature Med. 1,129-134 15 McLean,A.R. (1993) Trends Microbiol. 1, 9-13 16 McLean,A.R.and Nowak,M.A. (1992)J. Theor. Biol. 155, 69-86
Inject and hope for the best? Combined Vaccines and Simultaneous Administration: Current Issues and Perspectives
edited by J.C. Williams, K.L. Goldenthal, D.L. Burns and B.P. Lewis Jr Annals of the New York Academy of Sciences Vol. 754, 1995. $140.00 pbk (xv + 404 pages) ISBN 0 89766 862 6 he development of the 'supershot in which vaccilaation against all childhood diseases is administered in a single injection is the main objective of the Children's Vaccine Initiative. The ease of record keeping and the reduction in costs and discomfort to children provide a powerful impetus behind vaccine combination or simultaneous administration at different sites. The book contains a balanced mixture of philosophical essays that deal with the overwhelming difficulties associated with the evaluation of the plethora of potential new vaccine products that have been developed and down-to-earth discussions with actual data on safety, lot consistency and vaccine interference. Combination vaccines require the absence of interference between the various components. This can be a problem. The surprising effect of a Hib vaccine on the titres of antibodies to the pertussis c o m p o n e n t of the DTP vaccine would not have been predicted from first principles, nor can it be explained. In other cases interference did not occur where it might be expected, for
T
17 Frost, S.D.W.and McLean,A.R. (1994)J. AIDS 7, 236-244 18 Nowak,M.A. et al. (1991) Science 254, 963-969 19 Nowak,M.A.et al. {1995}Nature 375, 606-611 20 Fenyo,E.M. et al. (1989)AIDS 3 (Suppl. 1), $5-S12 21 Cohen,D.A.et al. (1993) Cell. Immunol. 151,392-403 22 Schnittman,S.M. et al. (1990) Proc. Natl Acad. Sci. USA 87, 6058-6062 23 Romagnani,S. et al. (1994) AIDS Res. Hum. Retroviruses 10, iii-ix 24 McLean,A.R.and Michie,C.A. (1995) Proc. NatI Acad. Sci. USA 92, 3707-3711 25 Silins,S.L.and Sculley,T.B. (1995) Int. J. Cancer 60, 65-72 26 Farrow,S.N. et al. (1995) Nature 374, 731-733 27 Heath,S.L.et al. (1995) Nature 377, 740-744
example when immunosuppressive live-attenuated measles virus is combined with mumps and rubella virus. Few examples of interference were actually documented in the book and possibly it is not as large a problem as suspected. I was impressed by the myriad of new combinations of antigens, vectors, adjuvants and routes of administration described. The book explains lucidly how large studies would have to be to demonstrate slight changes in the rate of side effects and how large the number of study arms in vaccine trials would have to be to demonstrate interference between the various components. Obviously, not all new products can be evaluated in costly trials. However, straight commercial considerations ,viii limit the number of vaccine product combinations evaluated as few manufacturers will carry out trials with other manufacturer's products. The book also shows how little we know about how different immunological responses to vaccination confer protection and how we often do not have good surrogate markers for protection. Certain aspects of the immune response to vaccines, such as the T h l and Th2 biases associated with various antigens and mechanisms of antigen presentation, were discussed repeatedly. Importantly, a change from T h l to Th2 bias can change responses from protective to disease inducing. Differences in T h l and Th2 bias associated with various antigens and routes of administration may be of relevance when new combinations of antigens from different organisms are injected.
In his conclusion Barry Bloom remarked that all vaccines except for some bacterial toxins are already combination vaccines, but these contain 'natural' combinations of antigens from a single organism that has often had to reach an evolutionary accommodation with its human host. At present, it is impossible to predict responses to new combined vaccines. At the end of the day, the numbers of products that await evaluation is so large, the safety questions that can be formulated are so complex and the studies so costly that we may end up trying new vaccines in volunteers and hoping for the best. This is of course what was done at the introduction of the first generation of vaccines. We now have so much knowledge about immune responses that it is almost impossible to convince oneself that any new product is safe and should be used in non-life-threatening situations. The book describes most of the current vectors and adjuvants in scant detail. Despite it being a collection of papers delivered at a meeting of the New York Academy in 1993 and, as all books of this kind, repetitive, the various sections provide a good account of the subject. I found it thought provoking and well worth reading, but undoubtedly already out of date as its publication lagged 2 years behind the conference. Bert Rima
School of Biology and Biochemistry, The Queen's University of Belfast, Medical Biology Centre, 97 Lisburn Road, Belfast, UK BT9 7BL
Copyright © 1996 Elsevicr Science Ltd. All rights reserved. 0966 842X/96/$15.00
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