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[Contribution of immunoblot to the diagnosis and monitoring of toxoplasmosis in acquired immunodeficiency syndrome].

This study evaluates the potential value of immunoblot for serological survey of toxoplasmosis infection in HIV infected patients. This technique was applied to the detection of IgG, IgM, IgA and IgE antibodies to Toxoplasma gondii in serum and cerebrospinal fluid. We compared the patterns obtained from sera of immunocompetent and HIV+ subjects in different situations: absence of toxoplasmosis, primo-infection, chronic infection and reactivation of toxoplasmosis. IgA antibodies were demonstrated in sera of all HIV+ patients with chronic infection: so, these antibodies have any diagnosis value in this group. IgE were only detected by immunoblot when clinical symptoms of toxoplasmosis occurred in cases of HIV+ patients with reactivation of the parasitosis; previously, these subjects presented a serological rise of IgG specific antibodies. In ten cases of neurotoxoplasmosis immunoblot allowed detection of IgA and IgE antibodies in serum and CSF and demonstrated their intrathecal synthesis in three cases. In conclusion immunoblot is a powerful technique for detection of IgA and IgE to Toxoplasma gondii. Demonstration of IgE antibodies seem to be a good criterion to evaluate the evolutivity of the parasitosis in HIV patients.

AIDS-Related Opportunistic Infections↗

[A case of anal Burkitt's lymphoma].

Burkitt non hodgkin lymphoma affects children and young adults. It is endemic in tropical Africa and it has especially facial and abdominal localisations. We report a case of anal localisation in a 22 years-old man, human immunodeficiency virus (HIV), negative aiming to show clinical, therapeutical and evolutive particularities of this exceptional localisation. Only two cases were reported but in HIV positive patients. Perianal abscess was first evoked, but per-operatory findings and histology rectify the diagnosis. Without chemotherapy, the "natural" evolution was rapidly fatal. Despite the efficacy of nowadays protocols, showing 80% of recovery, this observation illustrates the difficulty of malignant affection's management in developing countries caused by diagnostic delay and high cost of chemotherapy.

Adult↗

Constrained evolution of human immunodeficiency virus type 1 protease during sequential therapy with two distinct protease inhibitors.

Human immunodeficiency virus type 1 (HIV-1) variants that have developed protease (PR) inhibitor resistance most often display cross-resistance to several molecules within this class of antiretroviral agents. The clinical benefit of the switch to a second PR inhibitor in the presence of such resistant viruses may be questionable. We have examined the evolution of HIV-1 PR genotypes and phenotypes in individuals having failed sequential treatment with two distinct PR inhibitors: saquinavir (SQV) followed by indinavir (IDV). In viruses where typical SQV resistance mutations were detected before the change to IDV, the corresponding mutations were maintained under IDV, while few additional mutations emerged. In viruses where no SQV resistance mutations were detected before the switch to IDV, typical SQV resistance profiles emerged following the introduction of IDV. We conclude that following suboptimal exposure to a first PR inhibitor, the introduction of a second molecule of this class can lead to rapid selection of cross-resistant virus variants that may not be detectable by current genotyping methods at the time of the inhibitor switch. Viruses committed to resistance to the first inhibitor appear to bear the "imprint" of this initial selection and can further adapt to the selective pressure exerted by the second inhibitor following a pathway that preserves most of the initially selected mutations.

Acquired Immunodeficiency Syndrome↗

The theory of genotypic selection: predicting the direction of evolution as a consequence of G:U base pairing and the existence of non-pathogenic strains of HIV-1.

One aspect of the Theory of Genotypic Selection states that G:U base pairs are selected for function and structure. RNA secondary structures stabilised by G:U base pairs are suggested to be involved in the evolution of attenuated strains of polio virus. Asymmetric mutations (C-->U and A-->G) and convergent evolutionary solutions are explained as a direct consequence of G:U base pairing. The possibility of a naturally occurring attenuated strain of HIV-1 is predicted.

Base Composition↗

Comparative study of adaptive molecular evolution in different human immunodeficiency virus groups and subtypes.

Molecular adaptation, as characterized by the detection of positive selection, was quantified in a number of genes from different human immunodeficiency virus type 1 (HIV-1) group M subtypes, group O, and an HIV-2 subtype using the codon-based maximum-likelihood method of Yang and coworkers (Z. H. Yang, R. Nielsen, N. Goldman, and A. M. K. Pedersen, Genetics 155:431-449, 2000). The env gene was investigated further since it exhibited the strongest signal for positive selection compared to those of the other two major HIV genes (gag and pol). In order to investigate the pattern of adaptive evolution across env, the location and strength of positive selection in different HIV-1 sequence alignments was compared. The number of sites having a significant probability of being positively selected varied among these different alignment data sets, ranging from 25 in HIV-1 group M subtype A to 40 in HIV-1 group O. Strikingly, there was a significant tendency for positively selected sites to be located at the same position in different HIV-1 alignments, ranging from 10 to 16 shared sites for the group M intersubtype comparisons and from 6 to 8 for the group O to M comparisons, suggesting that all HIV-1 variants are subject to similar selective forces. As the host immune response is believed to be the dominant driving force of adaptive evolution in HIV, this result would suggest that the same sites are contributing to viral persistence in diverse HIV infections. Thus, the positions of the positively selected sites were investigated in reference to the inferred locations of different epitope types (antibody, T helper, and cytotoxic T lymphocytes) and the positions of N and O glycosylation sites. We found a significant tendency for positively selected sites to fall outside T-helper epitopes and for positively selected sites to be strongly associated with N glycosylation sites.

Adaptation, Physiological↗

N-linked glycosylation of CXCR4 masks coreceptor function for CCR5-dependent human immunodeficiency virus type 1 isolates.

The chemokine receptors CXCR4 and CCR5 are the principal coreceptors for infection of X4 and R5 human immunodeficiency virus type 1 (HIV-1) isolates, respectively. Here we report on the unexpected observation that the removal of the N-linked glycosylation sites in CXCR4 potentially allows the protein to serve as a universal coreceptor for both X4 and R5 laboratory-adapted and primary HIV-1 strains. We hypothesize that this alteration unmasks existing common extracellular structures reflecting a conserved three-dimensional similarity of important elements of CXCR4 and CCR5 that are involved in HIV envelope glycoprotein (Env) interaction. These results may have far-reaching implications for the differential recognition of cell type-dependent glycosylated CXCR4 by HIV-1 isolates and their evolution in vivo. They also suggest a possible explanation for the various observations of restricted virus entry in some cell types and further our understanding of the framework of elements that represent the Env-coreceptor contact sites.

Amino Acid Sequence↗

[Neurological manifestations in HIV-infected child].

The authors describe the main epidemiological, pathogenetic and clinical features of HIV-related encephalopathy in 50 pediatric patients (36 females, 24 males), born to HIV-seropositive mothers or infected by contaminated blood, observed in the Institute of Infectious Diseases of Pavia, between January 1984 and December 1994. All the patients (age 1 day-7 years) received a comprehensive evaluation, including subsequent neurodevelopmental assessments, by a multidisciplinary équipe of pediatric infectivologists and neuro-psychiatrists: the follow-up ranges from 6 months to 8.5 years. To evaluate the role of potentially covariates in HIV-vertically infected children, some maternal, gestational and perinatal factors were investigated. The neurodevelopmental assessment was carried out by a standardized protocol: tests were always conducted and evaluated by the same examiner. Seventeen pediatric patients with HIV-related neurologic impairment were observed (34%): 16 cases of encephalopathy (static-stable = 4, plateau = 6, subacute-progressive = 5, uncertain origin = 1) and 1 case of neurotoxoplasmosis. Findings of the current study demonstrate the high frequency of neurological impairment in HIV-infected infant/child, a worse evolution in this kind of patients and the effectiveness of an antiretroviral therapy only if administrated in the early phases of the disease. It was also emphasized the pathogenetic role of some covariates poorly evaluated in previously reported studies.

AIDS Dementia Complex↗

Analysis of the env V3 sequences obtained from patients with HIV type 1 infection treated with the immune modulant agent tucaresol.

Tucaresol, a Schiff base-forming compound that is shown to enhance cytotoxic T cell responses and the production of type 1 cytokines, represents a potentially useful adjuvant factor for treating HIV-1 infection. We studied the effect of tucaresol on V3 sequences within the HIV-1 env region derived from patients with different virologic and immunologic features who were enrolled in a phase I/II randomized clinical trial. The sequence analysis of the env V3 region of the viruses at baseline has confirmed a genotypic pattern similar to a macrophagotropic virus model; we analyzed the follow-up sequences at week 16 of the protocol and did not observe any difference in the tropism determinants within the third variable fragment of the env region. The administration of tucaresol did not accelerate env V3 evolution thus preventing modifications of HIV-1 tropism over time.

Amino Acid Sequence↗

Similar serological response to conventional therapy for syphilis among HIV-positive and HIV-negative women.

OBJECTIVES: To compare characteristics of syphilis serological reactivity in HIV positive (+) and HIV negative (-) female sex workers, as well as the serological response to therapy after treatment with intramuscular benzathine penicillin, 2.4 million U weekly, for three consecutive weeks. METHODS: Rapid plasma reagin (RPR) and Treponema pallidum haemagglutination assay (TPHA) results of 72 HIV-positive and 121 HIV-negative women reactive in both tests were assessed. The response to therapy was prospectively monitored with quantitative RPR serology in 47 HIV-positive and 73 HIV-negative patients. Cumulative probabilities of becoming nonreactive by RPR were compared at six months, one and two years after therapy. RESULTS: At enrolment, the geometric mean titres of RPR and TPHA were lower in HIV-positive patients (RPR, 1:2.6) than in HIV-negative patients (RPR, 1:3.8; p < 0.01). The evolution over time of RPR titres was similar among HIV-positive patients as compared to HIV-negative patients. Among patients with an initial RPR titre of < 1:8, 53% of HIV-positive and 44% of HIV-negative patients became RPR negative two years after therapy. Among patients with an RPR titre of 1:8 or greater at enrolment, 83% of HIV-positive and 90% of HIV-negative patients had reached at least a fourfold decline of RPR titres two years after therapy. CONCLUSIONS: Syphilis serology findings (both RPR and TPHA) may be altered in the presence of HIV infection, but the serological response to therapy was similar in HIV-positive and HIV-negative patients.

Adult↗

[Treatment of chronic hepatitis C virus infection].

At present the treatment of chronic hepatitis C virus infection is based on the combination of pegylated interferon (PEG-INF) and rivabirin (RBV) and basically attempts to eradicate the viral infection (sustained viral response). The pattern depends above all on the viral genotype, hence, patients with genotype 1, 4 and 5 require 48 weeks of treatment and high doses of RBV, while those with genotype 2 and 3 require 24 weeks of treatment and low doses of RBV. All patients with chronic C infection are possible candidates for antiviral therapy. However, given that the response to treatment is variable, that the treatment has secondary effects and supposes a high economic cost, it is recommendable in patients with hypertransaminasemia and moderate-severe chronic hepatitis in the histological study, as long as there are no counter-indications. This does not exclude other groups of patients who should be evaluated individually. In those patients with compensated hepatic cirrhosis, treatment can stabilise the disease and reduce the risk of complications appearing, although the rate of response is lower and some adverse effects are more frequent. In patients who have received previous antiviral treatment with standard interferon, alone or in association with RBV, without response to this or with response but later relapse, the decision on treatment must be individual. In patients with coinfection by human immunodeficiency virus (HIV), special attention must be paid to the degree of evolution of the disease due to HCV and to HIV, as well as the possible hepatoxicity of the antiretroviral treatment and the risk of secondary effects.

Decision Trees↗

Virus evolution within patients increases pathogenicity.

Viruses like the human immunodeficiency virus (HIV), the hepatitis B virus (HBV), the hepatitis C virus (HCV) and many others undergo numerous rounds of inaccurate reproduction within an infected host. The resulting viral quasispecies is heterogeneous and sensitive to any selection pressure. Here we extend earlier work by showing that for a wide class of models describing the interaction between the virus population and the immune system, virus evolution has a well-defined direction toward increased pathogenicity. In particular, we study virus-induced impairment of the immune response and certain cross-reactive stimulation of specific immune responses. For eight different mathematical models, we show that virus evolution reduces the equilibrium abundance of uninfected cells and increases the rate at which uninfected cells are infected. Thus, in general, virus evolution makes things worse. An idea for combating HIV infection, however, is constructing a virus mutant that could outcompete the existing infection without being pathogenic itself.

Antigens, Viral↗

[Osteopathies that weaken HIV-infected patients].

OSTEOPOROSIS AND OSTEOPENIA: The use of multiple antiretroviral therapies has transformed the prognosis of HIV infection. However, the potential disadvantages of these treatments have rapidly appeared: lipodystrophy, cardiovascular complications and, more recently bone affections with osteonecrosis, followed by other weakening osteopathies (osteoporosis and osteopenia). Osteoporosis is a reduction in bone mineral density (BMD) leading to a high risk of fracture. It is measured by dual energy x-ray absorptiometry and is defined by a T-score<-2.5 standard deviations from the mean value of a young adult. Osteopenia corresponds to low bone density with, avec -1>T-score>-2.5. REGARDING THE AVAILABILITY OF RETROVIRAL AGENTS: During HIV infections, an osteopathy (most often osteopenia) is observed in a quarter to more than half of patients who have never received antiretroviral agents, and in up to three quarters in those in whom treatment in ongoing. The transversal nature of the majority of the studies, the heterogeneity of the treatments, the inclusion of both male and female patients in some studies, and the differences in the results observed do not permit one to draw any conclusions as to the possible responsibility of antiretroviral agents. An association between an osteopathy and a lipodystrophy is inconstant. Lastly, the substitution of a class of a antiretroviral agents by another does not lead to any significant modification in BMD. THE MECHANISM OF OCCURRENCE OF AN OSTEOPATHY: Has not been clearly established. The modifications in serum concentrations of biochemical markers of bone formation and resorption observed in HIV-infected patients and their evolution under antiretroviral treatment, suggest a viral origin, mediated by pro-inflammatory cytokines. The rare in vitro studies, or on animal models, are contradictory, with the results of clinical trials regarding the inherent role of antiretroviral drugs. However, it is probable that the classical risk factors for osteoporosis are often implied.

Anti-Retroviral Agents↗

[AIDS and tuberculosis: the immunopathogenic processes].

HIV infection is characterized by CD4+ lymphocyte depletion manifested through the loss of the immune response capacity. The resulting immunodeficit is expressed by the blocking of immune surveillance mechanisms and, thus, by the establishment of favourable conditions to the development of opportunistic infections and/or malignant processes. In tuberculosis, the immunodeficiency associated with HIV infection makes possible the evolution of a latent infection to a clinically manifest disease. Latent tuberculosis is characterized by the intracellular persistence of some metabolically inactive Tb bacillus forms which are incapable of multiplication. The conversion of these inactive into metabolically active forms capable of multiplication is usually neutralized by immunosurveillance mechanisms. The blocking of such mechanisms in case of CD4+ cell depletion will allow the multiplication of metabolically active Tb bacillus forms, and the development of a clinically manifest tuberculosis. CD4+ lymphocyte depletion is the result of facilitating antibodies and certain cytokines, and of some autoimmune processes which also affect the non-infected CD4+ cells. Therefore, it is necessary that Tb chemoprophylaxis in HIV infected subjects should also be addressed to the processes initiating the immune deficit, which include autoimmune mechanisms as well as those facilitating HIV infection.

AIDS-Related Complex↗

Neuropathologic aspects of lentiviral infections.

Studies of lentiviral infections of various animals and man have shown that all may invade the CNS and induce pathological lesions. This is well established in infections with VV, CAEV, SIV, HIV-1, and FIV. Although VV and CAEV do not cause an overt immunodeficiency, they share several features pertinent for the establishment of neuropathologic lesions with those that induce immunodeficiency. This holds especially true for the initial steps and early CNS lesions. 1) Infection of the CNS is from the blood stream. Although a definite proof of how the different viruses cross the blood-brain barrier remains to be brought forward there are indications that it may occur through migration of infected monocytes and/or lymphocytes into the brain. Furthermore free virus may enter the CNS, either directly or through infection of endothelial cells. 2) The lesion pattern at least in initial stages is similar; that is, it consists of meningitis, perivascular infiltrations especially of the deep white matter, and inflammation of the choroid plexus. In visna a local amplification of the inflammatory response is frequently observed in choroid plexus often with formation of active lymphoid follicles. Multinucleated giant cells are prominent in HIV-1 and SIV infections, but rare in VV, and practically nonexistent in infections with FIV and CAEV, possibly a reflection of differences in virus replication. Myelin breakdown is a feature of various lentiviral infections but its mechanisms and morphological expression may vary. Sharply demarcated plaques of primary demyelination seem to be unique for VV infection and vacuolar myelopathy for infection with HIV-1. 3) The main target cells in the brain are cells of the monocyte/macrophage/microglial lineage. In visna infected monocytes are found but evidence for infection of the enigmatic resident microglial cells is still lacking. Infection, especially productive, of neuroectodermal cells is rare, but may, however be important for viral persistence. Infection of endothelial cells occurs in the various lentiviral infections and may play a part in viral entry into the CNS and contribute to tissue damage. 4) The discrepancy between the frequency of productively infected cells and cell types infected and extent and character of pathological lesions, indicates that a mechanism other than the direct effect of the virus contributes to the evolution of CNS lesions. In HIV-1 infection evidence, mainly obtained by in vitro studies, indicates that lesions are mediated by cytokines and other toxic factors secreted by inflammatory or glial cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Acquired Immunodeficiency Syndrome↗

[Economic burden and clinical course of HIV infection and AIDS today: how the variation of natural history, available treatments, and strictly related costs play a role in needs of health care].

In order to provide an updated balance of the evolution of the natural history of HIV infection, the major clinical end-points of disease morbidity and mortality were compared with the progressively increasing use of highly active antiretroviral therapy (HAART), in a cohort of patients followed by our tertiary care centre in an eight-year period including both the pre-HAART and the HAART era. Although direct expenditures for antiretroviral agents reached even 99.8% of overall costs related to drugs and blood derivatives at our entire unit in the year 2000, a clear shift towards outpatient assistance of HIV infection was realized during recent years, leading to an increased and greatly varied spectrum of infectious diseases hospitalized at our inpatient and Day-Hospital units. Due to the significant reduction of inpatient expenditures, even the elevated costs of management of HIV disease based on HAART and periodic virological and immunological monitoring are expected to remain cost-effective, at least during the next few years.

Acquired Immunodeficiency Syndrome↗

Learning multiple evolutionary pathways from cross-sectional data.

We introduce a mixture model of trees to describe evolutionary processes that are characterized by the ordered accumulation of permanent genetic changes. The basic building block of the model is a directed weighted tree that generates a probability distribution on the set of all patterns of genetic events. We present an EM-like algorithm for learning a mixture model of K trees and show how to determine K with a maximum likelihood approach. As a case study, we consider the accumulation of mutations in the HIV-1 reverse transcriptase that are associated with drug resistance. The fitted model is statistically validated as a density estimator, and the stability of the model topology is analyzed. We obtain a generative probabilistic model for the development of drug resistance in HIV that agrees with biological knowledge. Further applications and extensions of the model are discussed.

Algorithms↗

Resistance to antiretroviral agents in individuals with HIV-1 non-B subtypes.

Naturally occurring polymorphisms at positions involved in resistance to antiretroviral agents are frequently seen in HIV-1 non-B subtypes. Although they do not seem to affect significantly the susceptibility to antiretroviral drugs in vitro, they may facilitate the selection of different pathways and/or a more rapid emergence of drug resistance and treatment failure under not fully suppressive treatment regimens.

Anti-HIV Agents↗

Rapid evolution of cardiac tamponade due to bacterial pericarditis in two patients with HIV-1 infection.

We describe two HIV-seropositive patients with acute pneumococcal empyema and pericarditis. Cardiac tamponade evolved rapidly in each patient and was reversed with prompt surgical intervention. In each case, immunologic abnormalities were detected which could have facilitated local spread of infection and progression to tamponade. Pericarditis, an otherwise rare manifestation of pneumococcal infection in the antibiotic era, should be anticipated in HIV-seropositive patients with pneumococcal empyema.

Acquired Immunodeficiency Syndrome↗