Biomedical subjects
Publications and source records attributed to M A Nowak.
We establish a general relation between the diagonal correlator of eigenvectors and the spectral Green's function for non-Hermitian random-matrix models in the large-N limit. We apply this result to a number of non-Hermitian random-matrix models and show that the outcome is in good agreement with numerical results.
Human immunodeficiency virus (HIV) disease progression is characterized by a slow but steady decline in the number of CD4+ T cells. It results in the development of AIDS when the immune response collapses and the virus grows uncontrolled. Pathogenicity of HIV may be due to viral escape from cellular immune responses as well as virus-induced immune impairment. Here we discuss how the dynamic interactions between the virus population and the immune response may lead to the development of AIDS. In particular we argue that in vivo evolution of HIV may be the driving force successively weakening the immune system. This may lead to increased levels of viraemia as well as to the evolution of more virulent phenotypes which indicate progression to AIDS. These insights are important for understanding the disease process itself and for designing effective treatment regimes.
Little is known of the changes in human immunodeficiency virus type 1 (HIV-1)-specific effector cytotoxic T lymphocytes (CTL) after potent antiretroviral therapy. Using HLA/peptide tetrameric complexes, we show that after starting treatment, there are early rapid fluctuations in the HIV-1-specific CTL response which last 1 to 2 weeks. These fluctuations are followed by an exponential decay (median half-life, 45 days) of HIV-1-specific CTL which continues while viremia remains undetectable. These data have implications for the immunological control of drug-resistant virus.
Patients with human T-cell leukemia virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) typically have a high HTLV-1 proviral load in peripheral blood mononuclear cells and abundant, activated HTLV-1-specific cytotoxic T lymphocytes (CTLs). No effective treatment for HAM/TSP has been described so far. We report a 10-fold reduction in viral DNA for five patients with HAM/TSP during treatment with the reverse transcriptase inhibitor lamivudine. In one patient with recent-onset HAM/TSP, the reduction in viral DNA was associated with a fall in the frequency of CTLs specific to two peptides in the immunodominant viral antigen Tax. The half-life of peripheral blood mononuclear cell populations was estimated from changes in viral DNA copy number, CTL frequency, reduction in CD25 expression, and the loss of dicentric chromosomes following radiation-induced damage. Each of these four different techniques indicated a cellular half-life of approximately 3 days consistent with continuous lymphocyte replication and destruction. These results indicate that viral replication through reverse transcription significantly contributes to the maintenance of HTLV-1 viral DNA load. The relative contribution of proliferation versus replication may vary between infected people.
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Benign fibroepithelial polyps of the renal pelvis are rare. Although many ureteral fibroepithelial polyps have been reported, there are, to our knowledge, only 20+ reported cases in the renal pelvis. We report herein the clinical and pathologic features of fibroepithelial polyp of the renal pelvis and provide a detailed review of the literature.
We use mathematical models to determine possible mechanisms contributing to the evolution and rise of virulent CXCR4-tropic HIV in vivo. The models predict that the ability of the virus to specialize on a given target cell type depends on the exact fitness landscape of the viral mutants. Because this fitness landscape varies between people, this may explain why the evolution of fully CXCR4-tropic strains only occurs in about 50% of infected patients. Assuming that CXCR4-tropic HIV may evolve, we investigate the effect of different immune responses on the rise of such virulent strains. If we assume that CXCR4-tropic HIV is more cytopathic than CCR5-tropic virus, virulent CXCR4-tropic mutants remain suppressed at low levels both in the absence of an immune response, and in the presence of responses that act on the virus before integration into the host genome. On the other hand, this difference in cytopathogenicity is reduced by the presence of immune responses acting on infected cells, allowing CXCR4-tropic HIV to coexist with the CCR5-tropic virus. These results may help to interpret experimental data and are discussed with reference to the literature.
Richard Alexander has argued that moral systems derive from indirect reciprocity. We analyse a simple case of a model of indirect reciprocity based on image scoring. Discriminators provide help to those individuals who have provided help. Even if the help is never returned by the beneficiary, or by individuals who in turn have been helped by the beneficiary, discriminating altruism can be resistant against invasion by defectors. Indiscriminate altruists can invade by random drift, however, setting up a complex dynamical system. In certain situations, defectors can invade only if their invasion attempts are sufficiently rare. We also consider a model with incomplete information and obtain conditions for the stability of altruism which differ from Hamilton's rule by simply replacing relatedness with acquaintanceship.
Darwinian evolution has to provide an explanation for cooperative behaviour. Theories of cooperation are based on kin selection (dependent on genetic relatedness), group selection and reciprocal altruism. The idea of reciprocal altruism usually involves direct reciprocity: repeated encounters between the same individuals allow for the return of an altruistic act by the recipient. Here we present a new theoretical framework, which is based on indirect reciprocity and does not require the same two individuals ever to meet again. Individual selection can nevertheless favour cooperative strategies directed towards recipients that have helped others in the past. Cooperation pays because it confers the image of a valuable community member to the cooperating individual. We present computer simulations and analytic models that specify the conditions required for evolutionary stability of indirect reciprocity. We show that the probability of knowing the 'image' of the recipient must exceed the cost-to-benefit ratio of the altruistic act. We propose that the emergence of indirect reciprocity was a decisive step for the evolution of human societies.
Earlier models of virus evolution during single infections do not include target cell limitation. Here we extend the basic mathematical framework of these theories and study the effect of target cell limitation on the evolution of antigenic variation, increasing replication rates and increasing virus load. We find that target cell limitation provides a selection pressure against antigenic diversification, and can therefore provide a limit to diversity. Antigenic diversity increases virus load; at the maximum level of antigenic diversity, virus load, too, is at a maximum.
Although cytotoxic T lymphocytes (CTLs) are thought to be involved in the control of human immunodeficiency virus-type 1 (HIV-1) infection, it has not been possible to demonstrate a direct relation between CTL activity and plasma RNA viral load. Human leukocyte antigen-peptide tetrameric complexes offer a specific means to directly quantitate circulating CTLs ex vivo. With the use of the tetrameric complexes, a significant inverse correlation was observed between HIV-specific CTL frequency and plasma RNA viral load. In contrast, no significant association was detected between the clearance rate of productively infected cells and frequency of HIV-specific CTLs. These data are consistent with a significant role for HIV-specific CTLs in the control of HIV infection and suggest a considerable cytopathic effect of the virus in vivo.
OBJECTIVE: To calculate the expected prevalence of resistant HIV mutants before antiviral therapy. DESIGN: HIV replication generates virus mutants. The prevalence of these mutants is determined by mutation and selection/fitness. Some mutations will confer drug resistance and it is crucial for the success of antiviral drug therapy to determine whether these resistant viruses are present before the initiation of therapy. METHODS: A quasispecies equation was used to calculate the expected frequency of drug-resistant virus prior to therapy. RESULTS AND CONCLUSIONS: We show how the pretreatment frequency of resistant virus depends on the number of point mutations between wild-type and mutant virus, the selective disadvantage of the resistant mutant and the intermediate mutants, and the mutation rate.
We examine simple mathematical models to investigate the circumstances under which the dynamics of cytotoxic T-lymphocyte (CTL) activation and differentiation may result in the loss of virus specific CD8+ cells, a process known as CTL exhaustion. We distinguish between two general classes of viruses: (i) viruses infecting cells that are not involved in the immune response; and (ii) viruses infecting antigen presenting cells (APCs) and helper cells. The models specify host and viral properties that lead to CTL exhaustion and indicate that this phenomenon is only likely to be observed with viruses infecting APCs and helper cells. Moreover, it is found that for such viruses, a high rate of replication and a low degree of cytopathogenicity promote the exhaustion of the CTL response. In addition, a high initial virus load and a low CD4+ cell count promote the occurrence of CTL exhaustion. These conclusions are discussed with reference to empirical data on lymphocytic choriomeningitis virus and on human immunodeficiency virus.
T-20, a synthetic peptide corresponding to a region of the transmembrane subunit of the HIV-1 envelope protein, blocks cell fusion and viral entry at concentrations of less than 2 ng/ml in vitro. We administered intravenous T-20 (monotherapy) for 14 days to sixteen HIV-infected adults in four dose groups (3, 10, 30 and 100 mg twice daily). There were significant, dose-related declines in plasma HIV RNA in all subjects who received higher dose levels. All four subjects receiving 100 mg twice daily had a decline in plasma HIV RNA to less than 500 copies/ml, by bDNA assay. A sensitive RT-PCR assay (detection threshold 40 copies/ml) demonstrated that, although undetectable levels were not achieved in the 14-day dosing period, there was a 1.96 log10 median decline in plasma HIV RNA in these subjects. This study provides proof-of-concept that viral entry can be successfully blocked in vivo. Short-term administration of T-20 seems safe and provides potent inhibition of HIV replication comparable to anti-retroviral regimens approved at present.
The human immunodeficiency virus type 1 (HIV-1) encodes a protein, called Vpr, that prevents proliferation of infected cells by arresting them in G2 of the cell cycle. This Vpr-mediated cell-cycle arrest is also conserved among highly divergent simian immunodeficiency viruses, suggesting an important role in the virus life cycle. However, it has been unclear how this could be a selective advantage for the virus. Here we provide evidence that expression of the viral genome is optimal in the G2 phase of the cell cycle, and that Vpr increases virus production by delaying cells at the point of the cell cycle where the long terminal repeat (LTR) is most active. Although Vpr is selected against when virus is adapted to tissue culture, we show that selection for Vpr function in vivo occurs in both humans and chimpanzees infected with HIV-1. These results suggest a novel mechanism for maximizing virus production in the face of rapid killing of infected target cells.
OBJECTIVE: After identifying a metastatic glycogen-rich balloon cell malignant melanoma, originally thought to be a benign clear cell tumor of the lung, we investigated the extent of positive reactions, or "positivity," of malignant melanoma to periodic acid-Schiff (PAS) staining. METHODS: Frequency, intensity, and distribution of PAS positivity was studied in 61 excisional biopsy specimens from 58 patients with malignant melanoma. For comparison, 17 benign nevi from 10 patients were examined. RESULTS: Positivity for PAS was seen in all cases. All malignant melanomas and benign nevi were characterized by weak, diffuse, diastase-resistant PAS positivity. Additionally, focal or diffuse, strong diastase-sensitive PAS positivity was observed in 9 of 61 melanomas (15%); 7 were metastatic and 2 were primary invasive melanomas. Strong diastase-sensitive PAS positivity was seen in all lesions with 30% or more balloon cell features and only in advanced primary or metastatic lesions. The presence of glycogen was confirmed by transmission electron microscopy. CONCLUSIONS: Cutaneous malignant melanomas have weak, diastase-resistant PAS positivity. Strong diastase-sensitive PAS positivity, consistent with the presence of intracytoplasmic glycogen, is seen in many primary and metastatic melanomas with balloon cell features. Depending on the content of the balloon cells, these melanomas are best categorized as either glycogen-rich malignant melanomas or glycogen-rich balloon cell malignant melanomas. Because many tumors with clear cell features contain glycogen, such content often is an unreliable differential feature.
BACKGROUND: Extramammary Paget's disease most commonly occurs on the female external genitalia and rarely occurs in the perianal region and male external genitalia. We present the clinical and pathologic features of 5 cases of perianal Paget's disease and review the literature. METHODS: Clinical and pathologic data were recorded for 5 cases of perianal Paget's disease. Cases were studied retrospectively with special stains, including periodic acid-Schiff, mucicarmine, Alcian blue, carcinoembryonic antigen, S100 protein, pan-keratin, gross cystic disease fluid protein-15 (GCDFP-15), lysozyme, CD15 (Leu-M1), cytokeratin 7 (CK7), and cytokeratin 20 (CK20). RESULTS: Three (60%) of 5 patients had concurrent rectal adenocarcinomas. All cases reacted positively for pankeratin, although the intensity and distribution of staining varied. Both cases not associated with an underlying carcinoma showed strong GCDFP-15 and CK7 expression and an absence of CK20 expression. The 3 cases associated with an underlying malignancy demonstrated CK7 and CK20 expression and an absence of GCDFP-15 expression. All cases were negative for lysozyme and CD15 (Leu-M1). CONCLUSIONS: The 5 cases reported herein demonstrate that perianal Paget's disease is a heterogeneous entity. The high frequency of associated underlying malignancies and resultant poor clinical outcomes highlight the importance of an aggressive search for a second malignancy. In some cases, perianal Paget's disease merely represents a cutaneous manifestation of an underlying rectal adenocarcinoma and demonstrates a CK7+/CK20+/GCDFP-15-/lysozyme-/Leu-M1- immunophenotype and signet ring Paget's cells. Other cases represent primary adenocarcinomas of the skin, which are associated with a CK7+/CK20-/GCDFP-15+/lysozyme /Leu-M1- immunophenotype and an excellent prognosis if adequately resected. Immunohistochemical studies, particularly CK20 and GCDFP-15, are useful adjuncts in distinguishing primary and secondary perianal Paget's disease.
Although highly active antiretroviral therapy (HAART) in the form of triple combinations of drugs including protease inhibitors can reduce the plasma viral load of some HIV-1-infected individuals to undetectable levels, it is unclear what the effects of these regimens are on latently infected CD4+ T cells and what role these cells play in the persistence of HIV-1 infection in individuals receiving such treatment. The present study demonstrates that highly purified CD4+ T cells from 13 of 13 patients receiving HAART with an average treatment time of 10 months and with undetectable (<500 copies HIV RNA/ml) plasma viremia by a commonly used bDNA assay carried integrated proviral DNA and were capable of producing infectious virus upon cellular activation in vitro. Phenotypic analysis of HIV-1 produced by activation of latently infected CD4+ T cells revealed the presence in some patients of syncytium-inducing virus. In addition, the presence of unintegrated HIV-1 DNA in infected resting CD4+ T cells from patients receiving HAART, even those with undetectable plasma viremia, suggests persistent active virus replication in vivo.