[Diagnostic image (287). A newborn with exanthema].
A 4-week-old girl presented with annular skin lesions caused by neonatal lupus syndrome.
Diagnosis, Differential↗
Biomedical subjects
R J de Boer
Publications and source records attributed to R J de Boer.
The race between initial T-helper expansion and virus growth upon HIV infection influences polyclonality of the response and viral set-point.
Infection with HIV is characterized by very diverse disease-progression patterns across patients, associated with a wide variation in viral set-points. Progression is a multifactorial process, but an important role has been attributed to the HIV-specific T-cell response. To explore the conditions under which different set-points may be explained by differences in initial CD4 and CD8 T-cell responses and virus inoculum, we have formulated a model assuming that HIV-specific CD4 cells are both targets for infection and mediators of a monoclonal or polyclonal immune response. Clones differ in functional avidity for HIV epitopes. Importantly, in contrast to previous models, in this model we obtained coexistence of multiple clones at steady-state viral set-point, as seen in HIV infection. We found that, for certain parameter conditions, multiple steady states are possible: with few initial CD4 helper cells and high virus inoculum, no immune response is established and target-cell-limited infection follows, with associated high viral load; when CD4 clones are initially large and virus inoculum is low, infection can be controlled by several clones. The conditions for the dependence of viral set-point on initial inoculum and CD4 T-helper clone availability are investigated in terms of the effector mechanism of the clones involved.
HIV Infections↗
Mathematical models of human CD4+ T-cell population kinetics.
We review how mathematical models help the interpretation of data measuring CD4+ T-cell kinetics by two recently-developed techniques. Mathematical models are developed for the average content of T-cell receptor excision circles (TRECs) and the average telomeric restriction fragment (TRF) in T-cells in the peripheral blood. Changes in the TRECs were supposed to indicate changes in thymic production. The rate at which naive and memory CD4+ T-cells erode their telomeres was supposed to reflect their respective division rates. Analysing the mathematical models, we show that rapid changes in the TRECs per naive T-cell are most likely due to changes in the division rates, and that the rates of telomere erosion fail to reflect naive and memory division rates. The model is applied to explain data showing that rheumatoid arthritis (RA) patients have abnormal TRECs and telomeres.
Arthritis, Rheumatoid↗
Selection by AZT and rapid replacement in the absence of drugs of HIV type 1 resistant to multiple nucleoside analogs.
We studied the intrahost evolution and dynamics of a multidrug-resistant HIV-1, which contains an insertion of two amino acids (aa) and several aa changes within the reverse transcriptase (RT) gene. From an individual receiving intermittent therapy, sequences of 231 full-length molecular clones of HIV-1 RT were obtained from serum-derived viruses at 12 consecutive time points over a period of 6 years, 17 to 20 clones per time point. In the 3.5-year period prior to the first course of therapy, only wild-type (wt) viruses were found. As soon as 6 months after the start of zidovudine (AZT) monotherapy, all viruses contained an insertion of two aa between positions 68 and 69 of the RT and aa changes at positions 67 and 215, a combination conferring resistance to multiple nucleoside analogs. After termination of therapy, the insertion mutants were rapidly and completely replaced by the wt viruses. In turn, the insertion mutants replaced the wt viruses after initiation of therapy with 3TC, d4T, and saquinavir. After termination of triple therapy, the wt viruses completely replaced the mutants within 1 month, which is markedly faster than has been observed earlier for the replacement of AZT-resistant viruses. Fast replacements of the mutant virus populations after termination of therapy indicate gross competitive disadvantage of the insertion mutant in the absence of therapy, which we estimated by using several models. The insertion mutants attained high virus loads, demonstrating that virus load cannot be used as a direct measure of virus fitness.
Amino Acid Sequence↗
The dominant source of CD4+ and CD8+ T-cell activation in HIV infection is antigenic stimulation.
To distinguish between antigenic stimulation and CD4+ T-cell homeostasis as the cause of T-cell hyperactivation in HIV infection, we studied T-cell activation in 47 patients before and during highly active antiretroviral therapy (HAART). We show that expression of human leukocyte antigen (HLA)-DR, CD38, and Ki67 on T cells decreased during HAART but remained elevated over normal values until week 48 of therapy. We confirm previous reports that T-cell activation correlates positively with plasma HIV RNA levels (suggesting antigenic stimulation), and negatively with CD4 count (suggesting CD4+ T-cell homeostasis). However, these correlations may be spurious, because misleading, due to the well-established negative correlation between CD4 count and plasma HIV RNA levels. To resolve this conflict, we computed partial correlation coefficients. Correcting for CD4 counts, we show that plasma HIV RNA levels contributed to T-cell hyperactivation. Correcting for plasma HIV RNA levels, we show that CD4+ T-cell depletion contributed to T-cell activation. Correcting for both, activation of CD4+ and CD8+ T cells remained positively correlated. Because this suggests that CD4+ and CD8+ T-cell activation is caused by a common additional factor, we conclude that antigenic stimulation by HIV or other (opportunistic) infections is the most parsimonious explanation for T-cell activation in HIV infection. Persistence of HIV antigens may explain why T-cell activation fails to revert to levels found in healthy individuals after 48 weeks of therapy.
ADP-ribosyl Cyclase↗
Bohring syndrome.
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Abnormalities, Multiple↗
T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART).
In human immunodeficiency virus (HIV)-1 infection, highly increased T-cell turnover was proposed to cause exhaustion of lymphocyte production and consequently development of AIDS. Here, we investigated cell proliferation, as measured by expression of the Ki-67 nuclear antigen, in peripheral blood CD4(+) and CD8(+) lymphocyte subpopulations before and during highly active antiretroviral therapy (HAART). In untreated HIV-1 infection, both the percentage and number of Ki-67(+) CD4(+) and CD8(+) lymphocytes were significantly increased, compared with values obtained from healthy individuals. A more than 10-fold increase in the percentage of dividing naive CD4(+) T cells in the blood was found when the number of these cells were below 100 per microL. HAART induced an immediate decline in Ki-67 antigen expression, despite often very low CD4(+) T-cell numbers, arguing against increased proliferation being a homeostatic response. After approximately 24 weeks of HAART treatment, a transient increase in the number of proliferating cells was seen, but only in the CD4(+) CD27(+) memory pool. In the CD8(+) T-cell compartment, the number of dividing cells was elevated 20- to 25-fold. This increase was most notable in the CD27(+) CD 45RO(+) and CD27(-) CD45RO(+) memory CD8(+) T-cell pool, corresponding with the degree of expansion of these subsets. Reduction of plasma HIV-RNA load by HAART was accompanied by a decrease in numbers and percentages of dividing cells in all CD8(+) T-cell subsets. Taken together, our results indicate that peripheral T-cell proliferation is a consequence of generalized immune activation. (Blood. 2000;95:249-255)
Anti-HIV Agents↗
Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection.
Recent thymic emigrants can be identified by T cell receptor excision circles (TRECs) formed during T-cell receptor rearrangement. Decreasing numbers of TRECs have been observed with aging and in human immunodeficiency virus (HIV)-1 infected individuals, suggesting thymic impairment. Here, we show that in healthy individuals, declining thymic output will affect the TREC content only when accompanied by naive T-cell division. The rapid decline in TRECs observed during HIV-1 infection and the increase following HAART are better explained not by thymic impairment, but by changes in peripheral T-cell division rates. Our data indicate that TREC content in healthy individuals is only indirectly related to thymic output, and in HIV-1 infection is mainly affected by immune activation.
Anti-HIV Agents↗
Competition for antigenic sites during T cell proliferation: a mathematical interpretation of in vitro data.
By fitting different mathematical T cell proliferation functions to in vitro T cell proliferation data, we studied T cell competition for stimulatory signals. In our lymphocyte proliferation assays both the antigen (Ag) availability and the concentration of T cells were varied. We show that proliferation functions involving T cell competition describe the data significantly better than classical proliferation functions without competition, thus providing direct evidence for T cell competition in vitro. Our mathematical approach allowed us to study the nature of T cell competition by comparing different proliferation functions involving (i) direct inhibitory T-T interactions, (ii) Ag-specific resource competition, or (iii) resource competition for nonspecific factors such as growth factors, and access to the surface of Ag-presenting cells (APCs). We show that resource competition is an essential ingredient of T cell proliferation. To discriminate between Ag-specific and nonspecific resource competition, the Ag availability was varied in two manners. In a first approach we varied the concentration of APCs, displaying equal ligand densities; in a second approach we varied the Ag density on the surface of the APCs, while keeping the APC concentration constant. We found that both resource competition functions described the data equally well when the Ag availability was increased by adding APCs. When the APC concentration was kept constant, the nonspecific resource competition function yielded the best description of the data. Our interpretation is that T cells were competing for "antigenic sites" on the APCs.
Algorithms↗
T cell dynamics in HIV-1 infection.
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Animals↗
[Need for centralization of pediatric intensive care].
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Child↗
Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation.
The origin of CD4+ T cells reappearing in the blood following antiretroviral therapy in human immunodeficiency virus type-1 (HIV-1) infection is still controversial. Here we show, using mathematical modeling, that redistribution of T cells to the blood can explain the striking correlation between the initial CD4+ and CD8+ memory T-cell repopulation and the observation that 3 weeks after the start of treatment memory CD4+ T-cell numbers reach a plateau. The increase in CD4+ T cells following therapy most likely is a composite of initial redistribution, accompanied by a continuous slow repopulation with newly produced naive T cells.
Anti-HIV Agents↗
Limited CD4+ T-cell renewal in early HIV-1 infection: effect of highly active antiretroviral therapy.
We show that the fraction of proliferating CD4+ lymphocytes is similar in HIV-infected subjects in the early stage of disease and in HIV-negative subjects, whereas the fraction of proliferating CD8+ lymphocytes is increased 6.8-fold in HIV-infected subjects. After initiation of antiviral therapy, there is a late increase in proliferating CD4+ T cells associated with the restoration of CD4+ T-cell counts. These results provide strong support for the idea of limited CD4+ T-cell renewal in the early stage of HIV infection and indicate that after effective suppression of virus replication, the mechanisms of CD4+ T-cell production are still functional in early HIV infection.
Adult↗
Neonatal tolerance revisited by mathematical modelling.
The classical view of a neonatal tolerance window has recently been challenged by several studies showing that neonates can evoke normal immune responses. For example, neonatal immunity against the male antigen H-Y can be induced in female recipients by inoculation of male donor spleen cells enriched for professional antigen-presenting cells (APCs). In the same set-up, adult female recipients become tolerant by giving large doses of spleen cells. Using a probabilistic model, we here show how the number of T cells and endogenous APCs in the recipient, and the dose and quality of donor APCs can explain all observed phenomena. We thus reconcile the classical neonatal tolerance window with the recent data on neonatal immunity and adult tolerance.
Animals↗
Overshoot of HIV-1 viraemia after early discontinuation of antiretroviral treatment.
OBJECTIVE: To determine whether, as predicted by predator-prey dynamics, early withdrawal of antiretroviral therapy, i.e. when the number of CD4+ lymphocytes is still elevated, results in an overshoot of HIV-1 viraemia due to infection of increased numbers of available target cells at that time. DESIGN AND METHODS: Five HIV-1-infected individuals were identified who discontinued antiretroviral therapy for various reasons after 8-19 days, and from whom stored serum samples obtained before, during, and shortly after treatment were available for measurement of HIV-1 RNA load. A mathematical model was designed to assess whether increased target cell availability could quantitatively explain the clinical observations. RESULTS: After therapy withdrawal, increases in the HIV-1 RNA load to levels exceeding pretreatment values by log10 0.6-1.5 copies/ml were observed after 2-17 days in all four of the individuals who had treatment-induced increases in CD4+ cell counts at the time of therapy withdrawal. Increases in viraemia were maximal within a few days, and subsequently seemed to wane until the pretreatment equilibrium between virus and its target cells was attained. Mathematical modelling confirms that these transient increases in viraemia can be explained by increased availability of target cells at the time of therapy withdrawal. CONCLUSIONS: Transient rises in HIV-1 viraemia do occur following early therapy withdrawal. These rises especially warrant consideration in short-term antiretroviral regimens for prevention of mother-to-child transmission, as are being studied in developing countries, since they could result in an increased transmission risk during the post-partum period through breast-feeding. This possibility needs to be investigated urgently.
Anti-HIV Agents↗
Host-parasite dynamics and outgrowth of virus containing a single K70R amino acid change in reverse transcriptase are responsible for the loss of human immunodeficiency virus type 1 RNA load suppression by zidovudine.
The association between human immunodeficiency virus type I (HIV-1) RNA load changes and the emergence of resistant virus variants was investigated in 24 HIV-1-infected asymptomatic persons during 2 years of treatment with zidovudine by sequentially measuring serum HIV-1 RNA load and the relative amounts of HIV-1 RNA containing mutations at reverse transcriptase (RT) codons 70 (K-->R), 41 (M-->L), and 215 (T-->Y/F). A mean maximum decline in RNA load occurred during the first month, followed by a resurgence between 1 and 3 months, which appeared independent of drug-resistance. Mathematical modeling suggests that this resurgence is caused by host-parasite dynamics, and thus reflects infection of the transiently increased numbers of CD4+ lymphocytes. Between 3 and 6 months of treatment, the RNA load returned to baseline values, which was associated with the emergence of virus containing a single lysine to arginine amino acid change at RT codon 70, only conferring an 8-fold reduction in susceptibility. Despite the relative loss of RNA load suppression, selection toward mutations at RT codons 215 and 41 continued. Identical patterns were observed in the mathematical model. While host-parasite dynamics and outgrowth of low-level resistant virus thus appear responsible for the loss of HIV-1 RNA load suppression, zidovudine continues to select for alternative mutations, conferring increasing levels of resistance.
Base Sequence↗
Extending the quasi-steady state approximation by changing variables.
The parameter domain for which the quasi-steady state assumption is valid can be considerably extended merely by a simple change of variable. This is demonstrated for a variety of biologically significant examples taken from enzyme kinetics, immunology and ecology.
Animals↗
Diversity and virulence thresholds in AIDS.
We propose a model for the interaction between human immunodeficiency virus and the immune system. Two differential equations describe the interactions between one strain of virus and one clone of T lymphocytes. We use the model to generalize earlier results pertaining to the AIDS diversity threshold [Nowak, M. A., Anderson, R. M., McLean, A. R., Wolfs, T. F. W., Goudsmit, J. and May, R. M. (1991) Science 254, 963-969]. Our model has (i) a stable steady state corresponding to the "controlled" persistence of the virus and (ii) a region corresponding to AIDS. The separatrix between the two regimes is formed by the stable manifold of a saddle point. We define a dimensionless "virulence" parameter which combines the infectivity and antigenicity of a virus strain. We derive analytically two parameter conditions involving virulence. The first corresponds to a saddle-node bifurcation which causes AIDS due to the loss of the stable equilibrium. The second corresponds to a global bifurcation which causes AIDS due to a change in the basins of attraction. Incorporating diversity into the model, we derive a diversity threshold corresponding to the saddle-node bifurcation. In this threshold condition diversity and virulence have an equivalent effect. By studying the effect of diversity on the critical virulence that is required for a new mutant to cause AIDS, we again establish that diversity and virulence are equivalent parameters. Because in our model increasing diversity decreases the critical virulence, the strain that eventually causes AIDS need not be a virulent one.
Acquired Immunodeficiency Syndrome↗