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PubMed1988

Binding and uptake of Col 1(I), a peptide capable of inhibiting collagen synthesis in fibroblasts.

Col 1(I), a collagenase-resistant segment of the amino-terminal propeptide of pro alpha 1(I) chains, is known to inhibit collagen synthesis in cultured skin fibroblasts and also in a cell-free protein synthesizing system by reducing the translation of procollagen mRNA. These findings prompted us to explore the fate of exogenous Col 1(I) in the cellular processing of human skin fibroblasts using colloidal gold labeled protein (Col 1(I)-Au). Distribution of Col 1(I)-Au on the cell surface was studied by the platinum-carbon replication technique. Three different types of binding pattern could be observed: 1) Binding sites in the form of a fibrillar network, 2) those in the form of clusters, and 3) solitary bound gold conjugates. The latter two cases were determined to be specific. The intracellular routing of Col 1(I)-Au was studied by thin sections. Specifically bound gold conjugates were found in coated pits and after the initiation of the internalization process in coated vesicles and endosomes. Acid phosphatase cytochemistry revealed that only a small amount of Col 1(I)-Au is delivered to lysosomes. The bulk of gold conjugates is present even after prolonged incubation at 37 degrees C in acid phosphatase-negative compartments of the cell. Our data suggest a mechanism in which Col 1(I) initially is bound to the cell surface and subsequently internalized via the coated pit-coated vesicle pathway.

Acid Phosphatase↗
PubMed1998

[AIDS: new developments. VI. HIV reservoirs during intensive antiretroviral treatment].

Treatment of human immunodeficiency virus (HIV) infected persons with potent antiretroviral combination therapy results in a strong decline of the viral load in the blood. Whether this effect is reached in all tissues and different infected cell types is an important question. There are several potential virus reservoirs. Lymphoid tissue constitutes the largest virus compartment. With potent, often protease inhibitor containing combinations the HIV-RNA decline in lymphoid tissue runs parallel to that in the blood. The central nervous tissue is a potentially important reservoir, because of the limited penetration of several antiretrovirals, especially protease inhibitors. A few short studies with different combinations showed a decline of the amount of virus in the cerebrospinal fluid. The risk of local resistance developing is not known. There are only few studies of the effects of potent anti-HIV therapy on semen but prostate and testis tissue do not appear inaccessible to treatment. The reservoir of latently infected cells that cannot be reached by the immune system or by the viral replication inhibiting therapy, can possibly be reached with immune stimulating agents. This will cause HIV replication and cell death, while the anti-HIV therapy will prevent further replication of the produced virions. This approach is still experimental, however.

Acquired Immunodeficiency Syndrome↗
PubMed1990

Human immunodeficiency virus type 1 infection of U937 cells promotes cell differentiation and a new pathway of viral assembly.

The differentiation of U937 monoblastoid cells after human immunodeficiency virus type 1 (HIV-1) infection was studied using the following approaches: reverse transcriptase activity measurement, immunofluorescence labeling, and electron microscopy. For comparison, uninfected U937 cells were induced to differentiate from monocyte to macrophage by phorbol 12-myristate 13-acetate (PMA) or retinoic acid (RA) treatment. Both infected and drug-treated cells showed important and similar ultrastructural cell modifications, with a phenotype that decreased in monocyte specificity and increased in that of macrophages. When U937 cells were induced to differentiate upon HIV-1 infection, a very different pathway of viral production was observed. Production and accumulation of the virus in a vacuolar compartment of intracytoplasmic origin and escape to the antiviral lysosomal activity could explain virus persistence. This makes the cell system a good model with which to study the relationship between HIV-1 production and cell differentiation.

Antigens, CD↗
PubMed1997

Epstein-Barr virus BMRF-2 and BDLF-3 expression in hairy leukoplakia.

Hairy leukoplakia (HL) is a lesion found on the side of the tongue of immunocompromised individuals, including those with human immunodeficiency virus (HIV) infection. The lesion has unique histopathologic features and is characterised by high-level Epstein-Barr virus (EBV) replication, multiple EBV strains, and extensive inter- and intra-strain recombination. Expression of EBV genes spanning the entire viral life cycle from latency-associated genes to late, replicative genes has been detected in the lesion. HL thus provides a unique opportunity to study EBV expression in oral epithelium, and to study expression of novel EBV genes. We therefore constructed a cDNA library from an HL biopsy and detected expression of two genes not previously described in vivo: BMRF-2 and BDLF-3. Sequence analysis of the cDNAs revealed few amino acid changes from the B95-8 sequence. Expression of both genes was localized to the lower prickle cell layer of the tongue epithelium. BMRF-2 protein expression was primarily detected in the cell nuclei of the upper prickle cell layer. BDLF-3 protein expression was observed in the peri-nuclear space and Golgi compartment. The function of these proteins is currently under investigation.

AIDS-Related Opportunistic Infections↗
PubMed2002

Benznidazole treatment following acute Trypanosoma cruzi infection triggers CD8+ T-cell expansion and promotes resistance to reinfection.

Many studies have shed light on the mechanisms underlying both immunoprotection and immune dysregulation arising after Trypanosoma cruzi infection. However, little is known about the impact of benznidazole (N-benzyl-2-nitroimidazole acetamide), the drug available for clinical treatment of the infection, on the immune system in the infected host. In the present study we investigated the effect of benznidazole therapy on the lymphoid compartment during the course of experimental T. cruzi infection. Although amelioration of a variety of clinical and parasitological signs was observed in treated mice, amelioration of splenocyte expansion was not detected. Interestingly, this sustained splenomegaly observed in benznidazole-treated mice showed a preferential expansion of CD8(+) T lymphocytes. Moreover, although benznidazole treatment blocked the expansion of recently activated CD4(+) and CD8(+) T cells seen in infected hosts, benznidazole treatment led to a selective expansion of effector and memory CD8(+) T lymphocytes in association with a lower rate of apoptosis. In addition, the surviving treated animals were protected from reinfection. Together, these data suggest that, in addition to its well-known direct role in blocking parasite replication in vivo, benznidazole appears to directly affect immune regulation in T. cruzi-infected hosts.

Animals↗
PubMed1996

Local suppression of IFN-gamma in hepatic granulomas correlates with tissue-specific replication of Leishmania chagasi.

BALB/c mice are susceptible to infection with the visceralizing species of Leishmania, Leishmania chagasi. The parasite load initially rises in the liver and spontaneously subsides, whereas parasite multiplication begins later and remains lower in the spleen. To investigate whether this organ-specific multiplication of L. chagasi correlates with localized immune responses, we compared cytokine production by splenic vs hepatic immune cells. Livers from infected mice contained granulomas harboring intracellular L. chagasi amastigotes, whereas few amastigotes were present in the spleen. FACS analysis granuloma cells showed granuloma lymphocytes expressed a memory/effector phenotype. Granuloma cells cultured in vitro produced IL-10 and IL-6 but no detectable IFN-gamma, IL-4 or IL-5. In contrast, splenocytes from the same animals secreted IFN-gamma, IL-4, IL-6, and IL-10. T cells were depleted from granuloma cells by immune lysis, and the results indicated that IL-10 and IL-6 were derived at least in part from a non-T cell compartment. Paradoxically, FACS-purified Thy-1+ granuloma lymphocytes were able to produce IFN-gamma in the absence of other granuloma cells, suggesting IFN-gamma production might usually be inhibited by a granuloma-associated non-T cell element. Coculture of splenocytes with either granuloma cells or supernatants from granuloma cultures inhibited the usual splenocyte production of IFN-gamma and IL-4 but not IL-10. Thus, there may be a unique granuloma-associated suppressive factor accounting for the absence of IFN-gamma in hepatic granuloma cultures. It may be the absence of IFN-gamma in the liver and presence in the spleen that allows or inhibits parasite survival, respectively, in these different locations.

Animals↗
PubMed2004

The subcellular distribution of multigene family 110 proteins of African swine fever virus is determined by differences in C-terminal KDEL endoplasmic reticulum retention motifs.

African swine fever virus (ASFV) is a large double-stranded DNA virus that replicates in discrete areas in the cytosol of infected cells called viral factories. Recent studies have shown that assembling virions acquire their internal envelopes through enwrapment by membranes derived from the endoplasmic reticulum (ER). However, the mechanisms that underlie the formation of viral factories and progenitor viral membranes are as yet unclear. Analysis of the published genome of the virus revealed a conserved multigene family that encodes proteins with hydrophobic signal sequences, indicating possible translocation into the ER lumen. Strikingly, two of these genes, XP124L and Y118L, encoded proteins with KDEL-like ER retention motifs. Analysis of XP124L and Y118L gene product by biochemical and immunofluorescence techniques showed that the proteins were localized to pre-Golgi compartments and that the KEDL motif at the C terminus of pXP124L was functional. XP124L expression, in the absence of other ASFV genes, had a dramatic effect on the contents of the ER that was dependent precisely on the C-terminal sequence KEDL. The normal subcellular distribution of a number of proteins resident to this important, cellular organelle was drastically altered in cells expressing wild-type XP124L gene product. PXP124L formed unusual perinuclear structures that contained resident ER proteins, as well as proteins of the ER-Golgi intermediate compartment. The data presented here hint at a role for MGF110 gene product in preparing the ER for its role in viral morphogenesis; this and other potential functions are discussed.

African Swine Fever Virus↗
PubMed1989

Use of yeast nuclear DNA sequences to define the mitochondrial RNA polymerase promoter in vitro.

We have extended an earlier observation that the TATA box for the nuclear GAL10 gene serves as a promoter for the mitochondrial RNA polymerase in in vitro transcription reactions (C. S. Winkley, M. J. Keller, and J. A. Jaehning, J. Biol. Chem. 260:14214-14223, 1985). In this work, we demonstrate that other nuclear genes also have upstream sequences that function in vitro as mitochondrial RNA polymerase promoters. These genes include the GAL7 and MEL1 genes, which are regulated in concert with the GAL10 gene, the sigma repetitive element, and the 2 microns plasmid origin of replication. We used in vitro transcription reactions to test a large number of nuclear DNA sequences that contain critical mitochondrial promoter sequences as defined by Biswas et al. (T. K. Biswas, J. C. Edwards, M. Rabinowitz, and G. S. Getz, J. Biol. Chem. 262:13690-13696, 1987). The results of these experiments allowed us to extend the definition of essential promoter elements. This extended sequence, -ACTATAAACGatcATAG-, was frequently found in the upstream regulatory regions of nuclear genes. On the basis of these observations, we hypothesized that either (i) a catalytic RNA polymerase related to the mitochondrial enzyme functions in the nucleus of the yeast cell or (ii) a DNA sequence recognition factor is shared by the two genetic compartments. By using cells deficient in the catalytic core of the mitochondrial RNA polymerase (rpo41-) and sensitive assays for transcripts initiating from the nuclear promoter sequences, we have conclusively ruled out a role for the catalytic RNA polymerase in synthesizing transcripts from all of the nuclear sequences analyzed. The possibility that a DNA sequence recognition factor functions in both the nucleus and the mitochondria remains to be tested.

Base Sequence↗
PubMed1990

Pasteurella multocida toxin: potent mitogen for cultured fibroblasts.

Native Pasteurella multocida toxin (PMT) is shown to be an extremely potent mitogen for Swiss 3T3 fibroblasts. Half-maximal stimulation of DNA synthesis was obtained at concentrations of 1 and 2 pM for recombinant PMT (rPMT) and PMT, respectively. The degree of rPMT-induced DNA synthesis was comparable to that elicited by 10% fetal bovine serum and, moreover, was observed in the complete absence of other factors. Cell proliferation was also enhanced by rPMT. The toxin was also a potent mitogen for BALB/c and NIH 3T3 cells, 3T6 cells, and tertiary mouse embryo or human fibroblasts. The mitogenic activity of rPMT was heat-labile. A polyclonal antiserum to PMT inhibited DNA synthesis when added early, but not late, during treatment of the Swiss 3T3 cells with rPMT. A similar time-dependent action of methylamine was also observed. Furthermore, transient exposure of the cells to rPMT at 37 degrees C, but not at 4 degrees C, resulted in a stimulation of DNA synthesis. Thus, toxin action may require cell entry and processing via an acidic compartment. The toxin, at mitogenic concentrations, caused a large increase in the production of inositol phosphates. In contrast, rPMT did not increase the intracellular concentration of cyclic AMP in Swiss 3T3 cells. The basis of rPMT action may afford a unique insight into molecular signaling events involved in the control of cell proliferation.

Animals↗
PubMed1995

Bayesian design criteria: computation, comparison, and application to a pharmacokinetic and a pharmacodynamic model.

In this paper 3 criteria to design experiments for Bayesian estimation of the parameters of nonlinear models with respect to their parameters, when a prior distribution is available, are presented: the determinant of the Bayesian information matrix, the determinant of the pre-posterior covariance matrix, and the expected information provided by an experiment. A procedure to simplify the computation of these criteria is proposed in the case of continuous prior distributions and is compared with the criterion obtained from a linearization of the model about the mean of the prior distribution for the parameters. This procedure is applied to two models commonly encountered in the area of pharmacokinetics and pharmacodynamics: the one-compartment open model with bolus intravenous single-dose injection and the Emax model. They both involve two parameters. Additive as well as multiplicative gaussian measurement errors are considered with normal prior distributions. Various combinations of the variances of the prior distribution and of the measurement error are studied. Our attention is restricted to designs with limited numbers of measurements (1 or 2 measurements). This situation often occurs in practice when Bayesian estimation is performed. The optimal Bayesian designs that result vary with the variances of the parameter distribution and with the measurement error. The two-point optimal designs sometimes differ from the D-optimal designs for the mean of the prior distribution and may consist of replicating measurements. For the studied cases, the determinant of the Bayesian information matrix and its linearized form lead to the same optimal designs. In some cases, the pre-posterior covariance matrix can be far from its lower bound, namely, the inverse of the Bayesian information matrix, especially for the Emax model and a multiplicative measurement error. The expected information provided by the experiment and the determinant of the pre-posterior covariance matrix generally lead to the same designs except for the Emax model and the multiplicative measurement error. Results show that these criteria can be easily computed and that they could be incorporated in modules for designing experiments.

Bayes Theorem↗
PubMed1991

Borna disease virus replicates in astrocytes, Schwann cells and ependymal cells in persistently infected rats: location of viral genomic and messenger RNAs by in situ hybridization.

Borna disease (BD) is an immune-mediated neurological disease caused by infection of the nervous system with a negative strand RNA virus, Borna disease virus (BDV). The host range for BDV is broad and extends from birds to primates. A BDV-like agent may cause disease in humans. Until recently, BDV-infected neural cells could only be identified immunocytochemically using serum from BDV-infected animals. The advent of BDV cDNA clones allowed definition of the relationship between viral nucleic acids and viral proteins in vivo. In situ hybridization with strand-specific RNA probes from a BDV cDNA clone, pAF4, identified BDV genomic RNA and BDV mRNAs in neurons, astrocytes, Schwann cells and ependymal cells in an anatomic distribution consistent with that of BDV proteins. Genomic RNA was contained primarily within the nucleus, whereas mRNAs were found in both the nuclear and cytoplasmic compartments. Viral RNAs were demonstrated in neurons expressing BDV proteins and in glial cells by combined techniques of immunocytochemistry and in situ hybridization.

Animals↗
PubMed2001

Impairment of Gag-specific CD8(+) T-cell function in mucosal and systemic compartments of simian immunodeficiency virus mac251- and simian-human immunodeficiency virus KU2-infected macaques.

The identification of several simian immunodeficiency virus mac251 (SIV(mac251)) cytotoxic T-lymphocyte epitopes recognized by CD8(+) T cells of infected rhesus macaques carrying the Mamu-A*01 molecule and the use of peptide-major histocompatibility complex tetrameric complexes enable the study of the frequency, breadth, functionality, and distribution of virus-specific CD8(+) T cells in the body. To begin to address these issues, we have performed a pilot study to measure the virus-specific CD8(+) and CD4(+) T-cell response in the blood, lymph nodes, spleen, and gastrointestinal lymphoid tissues of eight Mamu-A*01-positive macaques, six of those infected with SIV(mac251) and two infected with the pathogenic simian-human immunodeficiency virus KU2. We focused on the analysis of the response to peptide p11C, C-M (Gag 181), since it was predominant in most tissues of all macaques. Five macaques restricted viral replication effectively, whereas the remaining three failed to control viremia and experienced a progressive loss of CD4(+) T cells. The frequency of the Gag 181 (p11C, C-->M) immunodominant response varied among different tissues of the same animal and in the same tissues from different animals. We found that the functionality of this virus-specific CD8(+) T-cell population could not be assumed based on the ability to specifically bind to the Gag 181 tetramer, particularly in the mucosal tissues of some of the macaques infected by SIV(mac251) that were progressing to disease. Overall, the functionality of CD8(+) tetramer-binding T cells in tissues assessed by either measurement of cytolytic activity or the ability of these cells to produce gamma interferon or tumor necrosis factor alpha was low and was even lower in the mucosal tissue than in blood or spleen of some SIV(mac251)-infected animals that failed to control viremia. The data obtained in this pilot study lead to the hypothesis that disease progression may be associated with loss of virus-specific CD8(+) T-cell function.

Animals↗
PubMed1985

Similar changes in cardiac morphology and DNA synthesis induced by doxorubicin and 4'-epi-doxorubicin.

Doxorubicin is an antineoplastic agent whose clinical administration is limited by dose-dependent irreversible cardiomyopathy. Doxorubicin inhibits the rate of DNA synthesis in cultured rat myocardial cells after 1 h incubation with 16 microM, as is demonstrated by a decreased incorporation of [methyl-3H]thymidine. An analogue of doxorubicin, 4'-epi-doxorubicin, also inhibits the rate of DNA synthesis within 1 h after treatment with 16 microM, to the same extent as doxorubicin-treatment of myocardial cells. Furthermore, similarity between doxorubicin and 4'-epi-doxorubicin in their effect on the myocardial thymidylate pool was also demonstrated by a significantly decreased incorporation of total [methyl-3H]thymidine. The effect of doxorubicin on the rate of DNA synthesis in cultured rat skeletal muscle cells treated for 1 h with 16 microM was quantitatively the same as in myocardial cells. Light microscopy of doxorubicin- and 4'-epi-doxorubicin-treated myocardial cells and doxorubicin-treated skeletal muscle cells showed distinct nucleolar fragmentation and revealed no differences between the two drugs in their effect on either myocardial or skeletal muscle cells. Electron microscopy of myocardial cells following doxorubicin treatment showed increased nuclear pleomorphism and invaginations, along with a striking and distinctive clumping of nuclear chromatin. Furthermore, an apparent high density of the mitochondria due to an increased matrix volume and a concomitant decrease in the intermembrane compartment were observed. The results of this study indicate that doxorubicin-induced inhibition of cardiac DNA synthesis in cultured myocardial cells is nonpredictive of cardiotoxicity. The mechanism is at least bimodal, and the apparent minor toxicity of 4'-epi-doxorubicin compared with that of doxorubicin in clinical trials cannot be distinguished by a difference in the inhibition of DNA synthesis in the rat heart.

Animals↗
PubMed2004

Nuclear bodies and compartments: functional roles and cellular signalling in health and disease.

There is much interest in recent years in the possible role of different nuclear compartments and subnuclear domains in the regulation of gene expression, signalling, and cellular functions. The nucleus contains inositol phosphates, actin and actin-binding proteins and myosin isoforms, multiple protein kinases and phosphatases targeting Cdk-1 and Cdk-2, MAPK/SAPK, and Src-related kinases and their substrates, suggesting the implication of several signalling pathways in the intranuclear organization and function of nuclear bodies (NBs). NBs include the well-characterized Cajal bodies (CBs; or coiled bodies), the nucleolus, perinucleolar and perichromatin regions, additional NBs best illustrated by the promyelocytic leukemia nuclear bodies [PML-NBs, also named PML oncogenic dots (PODs), ND10, Kr-bodies] and similar intranuclear foci containing multi-molecular complexes with major role in DNA replication, surveillance, and repair, as well as messenger RNA and ribosomal RNA synthesis and assembly. Chromatin modifying proteins, such as the CBP acetyltransferase and type I histone deacetylase, accumulate at PML-NBs. PML-NBs and Cajal bodies are very dynamic and mobile within the nuclear space and are regulated by cellular stress (heat shock, apoptosis, senescence, heavy metal exposure, viral infection, and DNA damage responses). NBs strongly interact, using signalling mechanisms for the directional and ordered traffic of essential molecular components. NBs organize the delivery and storage of essential RNAs and proteins that play a role in transcription, pre-mRNA biosynthesis and splicing, and the sequestration and/or degradation of regulatory proteins, such as heterogenous nuclear ribonuclear proteins (hnRNPs), p53, Rb1, CBP, STAT3, and others. The objective of this review is to summarize some aspects of these nuclear structures/bodies/domains, including their proposed roles in cellular signalling and in human diseases, mainly neurodegenerative disorders and cancer.

Animals↗
PubMed1999

Homing of negatively charged albumins to the lymphatic system: general implications for drug targeting to peripheral tissues and viral reservoirs.

The present study shows the lymphatic distribution of the negatively charged anti-HIV-1 agents succinylated or aconytilated human serum albumins (HSAs) in rats. Quantitation of blood and lymphatic concentrations of these proteins was performed through fluorescence detection of the fluorescein isothiocyanate (FITC)-labeled proteins. At several time points after i.v. injection, samples were taken from the cannulated thoracic duct and the carotid artery. Distribution of the negatively charged albumins (NCAs) to lymph was much more rapid than that of albumin itself and was dependent on the total net negative charge added to the protein: the half-life times of lymphatic equilibration were 15, 30, and 120 min for FITC-labeled aconytilated HSA, FITC-labeled succinylated HSA, and FITC-labeled HSA, respectively. Lymph to blood concentration ratios of the studied compounds obtained at steady state approached unity. In addition, the fluorescence in both body fluids was shown to represent unchanged labeled proteins. It was therefore inferred that the NCAs efficiently passed the endothelial barrier from blood to the interstitial compartment. Subsequently, we studied whether a specialized process was involved in the endothelial passage of the NCAs to the lymph. The following observations supported such a mechanism: a) preinjection of the scavenger receptor blockers polyinosinic- and formaldehyde-treated HSA reduced the transport from blood to the lymphatic compartment of FITC-labeled aconytilated HSA by more than 90%; b) the rate of lymphatic distribution was largely reduced when the body temperature of the rat was lowered to 28 degrees; and c) pre-administration of chloroquine resulted in a significant reduction in the lymphatic distribution of the NCAs. These data collectively indicate that a scavenger receptor-mediated process is involved in the transendothelial transport of NCAs. In situ localization in lymph nodes of the rat showed that FITC-labeled aconytilated and succinylated HSA are mainly present in the germinal center and parafollicular zones. The efficient distribution of these anionized proteins to the lymphatic system is of particular interest for HIV therapy, taking into account that replication of HIV mainly takes place in the lymphoid system. The observation that macromolecules, through charge modification, can extravasate through a receptor-mediated transcytotic process is potentially of major importance for the delivery of drugs with macromolecular carriers to cells not directly in contact with the blood.

Albumins↗
PubMed2003

Origin of sex revisited.

Why did sex ever arise in the first place? Why it does not disappear in view of the greater efficiency of asexuals? These are clearly two different questions, and we suggest here that the solution for the origin of sex does not necessarily come from theoretical considerations based on currently existing genetic systems. Thus, while we agree with a number of authors in that the emergence of sex (understood as the exchange of genetic material between genomes) is deeply rooted in the origin of life and happened during the very early stages in the transition from individual genes ('replicators') to bacteria-like cells ('reproducers'), we challenge the idea that recombinational repair was the major selective force for the emergence of sex. Taking the stochastic corrector model as a starting point, we provide arguments that question the putative costs of redundancy in primitive protocells. In addition, if genes that cause intragenomic conflict (i.e., parasites) are taken into account, it is certainly wrong to suggest that cellular fusion would be beneficial at the population level (although this strong claim needs some qualifications). However, when a continuous input of deleterious mutations that impair the fitness of the protocell as a whole is considered in the model (in the realistic range in which stable mutant distributions of quasi-species within compartments are established), there are circumstances when sex could be beneficial as a side effect of the dynamic equilibrium between cellular fusion-mutation-selection. The scenario we have explored numerically is fully consistent with the idea that the universal ancestor was not a discrete entity but an ensemble of proto-organisms that exchanged much genetic information.

Biological Evolution↗
PubMed2003

Simian immunodeficiency virus infection in neonatal macaques.

Children with human immunodeficiency virus infection often have higher viral loads and progress to AIDS more rapidly than adults. Since the intestinal tract is a major site of early viral replication and CD4(+) T-cell depletion in adults, we examined the effects of simian immunodeficiency virus (SIV) on both peripheral and intestinal lymphocytes from 13 neonatal macaques infected with SIVmac239. Normal neonates had more CD4(+) T cells and fewer CD8(+) T cells in all tissues than adults. Surprisingly, neonates had substantial percentages of CD4(+) T cells with an activated, memory phenotype (effector CD4(+) T cells) in the lamina propria of the intestine compared to peripheral lymphoid tissues, even when examined on the day of birth. Moreover, profound and selective depletion of jejunum lamina propria CD4(+) T cells occurred in neonatal macaques within 21 days of infection, which was preceded by large numbers of SIV-infected cells in this compartment. Furthermore, neonates with less CD4(+) T-cell depletion in tissues tended to have higher viral loads. The persistence of intestinal lamina propria CD4(+) T cells in some neonates with high viral loads suggests that increased turnover and/or resistance to CD4(+) T-cell loss may contribute to the higher viral loads and increased severity of disease in neonatal hosts.

Animals↗
PubMed1991

Macrophage-active colony-stimulating factors enhance human immunodeficiency virus type 1 infection in bone marrow stem cells.

To define the relationship between human immunodeficiency virus type 1 (HIV-1) infection in hematopoietic stem cells and virus production by their progeny, we performed kinetic studies infecting bone marrow (BM) stem cells and culturing them in the presence of hematopoietic growth factors. CD34-positive (CD34+), CD4-negative (CD4-) BM cells were isolated and infected in vitro with the monocytotropic HIV-1JR-FL strain or the laboratory-maintained HTLV-IIIB strain at a high multiplicity of infection. The cells were susceptible to productive infection only with HIV-1JR-FL, and virus production as measured by p24 protein release was markedly increased (more than fivefold) in the presence of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-3 (IL-3). Macrophage CSF (M-CSF) was less stimulatory and granulocyte CSF (G-CSF) had no effect on virus production. Virus production coincided with proliferation of mononuclear phagocytes but was not related to granulocytic proliferation in G-CSF-treated BM cultures. Although peak virus production from GM-CSF-treated macrophages occurred 2 to 3 weeks after infection, peak virus production in infected stem cells was observed 5 to 6 weeks after. Enhancement in virus production had a more rapid onset when CD34+/CD4- cells were cultured in the presence of both GM-CSF and IL-3 for 7 or 14 days. Under these conditions there was a 10-fold enhancement in virus production after 7 days of preincubation and a 50-fold enhancement after 14 days. These data indicate that while the stem cell compartment may be susceptible to infection with a monocytotropic HIV-1 strain, productive and sustained infection is realized only after macrophage differentiation. The lack of effect of G-CSF on virus production is likely because of the limited effect of this hematopoietin on mononuclear phagocyte generation and function.

Antigens, CD↗