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At least 685 records · Page 38Linked to original sources
PubMed2003

Inferring evolutionary rates using serially sampled sequences from several populations.

The estimation of evolutionary rates from serially sampled sequences has recently been the focus of several studies. In this paper, we extend these analyzes to allow the estimation of a joint rate of substitution, omega, from several evolving populations from which serial samples are drawn. In the case of viruses evolving in different hosts, therapy may halt replication and therefore the accumulation of substitutions in the population. In such cases, it may be that only a proportion, p, of subjects are nonresponders who have viral populations that continue to evolve. We develop two likelihood-based procedures to jointly estimate p and omega, and empirical Bayes' tests of whether an individual should be classified as a responder or nonresponder. An example data set comprising HIV-1 partial envelope sequences from six patients on highly active antiretroviral therapy is analyzed.

Algorithms↗
PubMed2006

Rate of viral evolution and risk of losing future drug options in heavily pretreated, HIV-infected patients who continue to receive a stable, partially suppressive treatment regimen.

BACKGROUND: Many treatment-experienced, HIV-infected patients who have limited therapeutic options for complete viral suppression continue to receive a partially suppressive treatment regimen pending the availability of at least 2 new antiretroviral drugs. The major risk of this approach is ongoing viral evolution and the loss of future drug options. METHODS: Antiretroviral-treated subjects with incomplete viral suppression were sampled from a clinic-based cohort. Inclusion criteria were receipt of a stable treatment regimen for > or = 120 days, a plasma HIV RNA load of > 500 copies/mL, and > or = 1 resistance mutation. Phenotypic and genotypic resistance testing was performed every 4 months. RESULTS: The 106 patients who were eligible for the study had a median of 3 observations during a median of 11.3 months. An estimated 23% and 18% developed at least 1 new nucleoside analogue and 1 new protease inhibitor mutation at 1 year, respectively. An estimated 30% lost the phenotypic equivalent of 1 susceptible drug at 1 year. A lower number of total mutations at baseline was a significant predictor of developing a new nucleoside analogue mutation (P=.01). At 1 year, the probability that an existing mutation would become undetectable using population-based sequencing was 32%. There was a higher rate of change at nonresistance codons than at codons known to be associated with drug resistance. CONCLUSIONS: Heavily pretreated patients with HIV infection who remain on a partially suppressive regimen have a measurable risk of losing future drug options, particularly those patients who have few baseline mutations. Resistance mutations vary over time, which suggests that the results of any single resistance test may not be representative of all mutations selected by a given treatment regimen.

Anti-HIV Agents↗
PubMed2001

Can correlated mutations in protein domain families be used for protein design?

Evidence from diverse studies, such as protein design experiments and analysis of the emergence of drug resistance in human immunodeficiency virus 1 (HIV-1), indicates that protein function can be diminished or altered by mutations at positions distant from the classic 'functional' site. Furthermore, results from correlation analysis of the ligand-binding domain of nuclear receptors suggest that mutation events at positions distributed throughout a protein domain may be involved in functional diversification during the evolution of homologous domain families. This review explores potential applications for a protein design procedure based on correlated substitutions.

Computational Biology↗
PubMed2003

Evolution of CD8+ T cell immunity and viral escape following acute HIV-1 infection.

Induction of HIV-1-specific CD8(+) T cells during acute infection is associated with a decline in viremia. The role CD8(+) effectors play in subsequently establishing viral set point remains unclear. To address this, we focused on two acutely infected patients with the same initial Tat-specific CD8(+) response, analyzing their CD8(+) T cell responses longitudinally in conjunction with viral load and sequence evolution. In one patient initiating treatment during acute infection, the frequencies of Tat-specific CD8(+) T cells gradually diminished but persisted, and the Tat epitope sequence was unaltered. By contrast, in the second patient who declined treatment, the Tat-specific CD8(+) T cells disappeared below detection, in conjunction with Gag-specific CD4(+) T cell loss, as plasma viremia reached a set point. This coincided with the emergence of an escape variant within the Tat epitope and an additional Vpr epitope. New CD8(+) T cell responses emerged but with no further associated decline in viremia. These findings indicate that, in the absence of treatment, the initial CD8(+) T cell responses have the greatest impact on reducing viremia, and that later, continuously evolving responses are less efficient in further reducing viral load. The results also suggest that T cell help may contribute to the antiviral efficiency of the acute CD8(+) T cell response.

Acute Disease↗
PubMed1991

Naturally occurring mutations within HIV-1 V3 genomic RNA lead to antigenic variation dependent on a single amino acid substitution.

In a study on the evolution of genomic diversity of HIV-1, genomic RNA was isolated from serum of two individuals. Starting at the time of primary infection we collected six samples of serum from each patient over a period of 5 years. Ninety-four cDNA clones (50 of patient 1 and 44 of patient 495) of part of the envelope coding region including the principal neutralization domain (PND) were sequenced. Around the time of antibody seroconversion, genomic RNA levels reached a peak and the population of sequences was highly homogeneous. In the course of the infection, the number of amino acid substitutions accumulated, which led to a higher genomic diversity within successive samples and a drift in the consensus sequence, progressively differing from the first found consensus sequence. Fixation of a substitution at glycoprotein 120 amino acid 308 was observed in both patients between two time points (patient 1, H----P; patient 495, P----H). With the use of 16-meric synthetic peptides, differing only at the 308 position (H308 versus P308), antibody binding specificity was found to be dependent on this difference. In patient 495, the nonconservative (P308----H) substitution reduced the binding affinity with the patient's antibodies. Furthermore, antibody competition assays showed that the observed substitution at position 308 elicited a new antibody population, indicating antigenic variation. After the decline of V3-specific antibodies, the simultaneous increase in genomic RNA levels and progression to AIDS in patient 495, a new variant with major changes in the PND emerged, again forming a homogeneous population of sequences.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Sinusitis in HIV-infected patients.

The purpose of this study is to retrospectively review the clinical, radiographic and laboratory characteristics, the therapy and evolution of sinusitis in HIV-infected patients hospitalized between January 1, 1985 and July 31, 1994. We have observed 65 cases of sinusitis in 58 HIV-infected patients (77.6% classified as group C). Forty-five of 65 cases (69.2%) showed radiographic evidence of acute sinusitis; the remaining 20 cases (30.8%) showed chronic sinusitis. In 61 cases (93.8%) there were symptoms related to sinusitis. In 61 sinusitis cases antibiotics were administered. Although the majority of patients responded at least partially to antibiotic therapy, a complete resolution of clinical and radiographic signs was observed in only 47.4% of acute sinusitis cases. No resolution was observed in chronic sinusitis after treatment stop. Sinusitis appears to occur quite frequently in HIV-infected patients, is often related to non-specific symptoms, may be recurrent and is commonly refractory to treatment.

Adult↗
PubMed2004

Immunological and virological study of enfuvirtide-treated HIV-positive patients.

OBJECTIVE: To evaluate the predictive value and evolution of immunological and virological parameters related to HIV entry and pathogenesis in patients receiving enfuvirtide (ENF) plus an optimized regimen. METHODS: A phase III clinical trial substudy of ENF in 22 patients measured virus coreceptor use and sensitivity to ENF, levels of chemokines, cytokines and chemokine receptors, CD38 and HLA-DR expression as markers of T cell activation and ex vivo cell death at baseline and at week 32. RESULTS: Treatment including ENF reduced HIV viral load (P < 0.001) and increased the CD4 cell count in patients that responded (RP) to treatment (n = 14). Significant (P < 0.05) increases were noted in the RP group in CXCR4 and CCR5 expression in CD4 cells without major differences in chemokine and interleukin-7 levels. A decrease in CD38 expression in the absence of HLA-DR changes was observed in CD4 cells. Apoptosis of peripheral blood mononuclear cells was significantly reduced in the RP group. Coreceptor use or ENF sensitivity of virus isolated at baseline was not associated with virus resistance or response to treatment, which appeared to be related to the activation state (HLA-DR expression) of CD4 cells at baseline. CONCLUSION: The outcome of ENF-containing treatment could not be associated with HIV coreceptor use at baseline. CD4 cell activation and viral drug resistance were the only markers of treatment response. Changes induced by ENF-containing regimen were seen in HIV coreceptor expression, including an increase in CCR5+CD4+ cells, a decrease in CD38 T cells and a concomitant reduction of T cell apoptosis.

ADP-ribosyl Cyclase↗
PubMed2005

The HIV coreceptor switch: a population dynamical perspective.

Over the course of infection, the coreceptor usage of the HIV virus changes from a preference for CCR5 to a preference for CXCR4 in approximately 50% of infected individuals. The change in coreceptor usage is the result of the complex interaction of the viral population with various cell populations of the immune system. Although many of the molecular processes involved in viral attachment and entry have been resolved, the population dynamical mechanisms leading to the emergence of CXCR4-using HIV variants in some infected individuals are not yet understood. Here, we review various hypotheses that have been proposed to explain the change of HIV coreceptor usage in the course of infection, and conclude that any corroboration or rejection of these hypotheses requires a quantitative analysis of the interaction between the virus and immune cells.

Disease Progression↗
PubMed2006

Comment on "Evidence for positive epistasis in HIV-1".

Bonhoeffer et al. (Reports, 26 November 2004, p. 1547) presented evidence for positive epistasis in a clinical data set of HIV-1 mutants and corresponding fitness values. We demonstrate that biases in the original and simulated data sets may lead to erroneous evidence for epistasis. More rigorous statistical tests must be used to account for such biases before one can infer epistasis.

Anti-HIV Agents↗
PubMed1989

Azidothymidine.

Azidothymidine is active against HIV and effective in patients with AIDS or ARC, as it clearly prolongs life. However the rapid development and marketing of this drug has left some crucial questions under discussion. Trials all over the world are currently under way to confirm the effectiveness and toxicity of AZT when administered for a prolonged period, to appreciate its potential benefits in patients in other HIV-related conditions and to determine whether it can prevent evolution towards ARC or AIDS in HIV asymptomatic carriers.

Acquired Immunodeficiency Syndrome↗
PubMed2004

Immunogen sequence: the fourth tier of AIDS vaccine design.

While worldwide efforts to develop an effective HIV-1 vaccine are underway, the virus continues to spread, particularly in developing countries where the delivery of antiviral therapies presents formidable challenges. Vaccine research has largely focused on three general aspects: vectors, adjuvants, and immunization schedules. Our group favor the use of computational methods to design potential immunogens that capture the genetic and biological features of circulating viruses. These methods allow researchers to predict, in silico, the presence of potential glycosylation sites, humoral immune responses, and epitope coverage. This review shall compare three computational approaches for immunogen design: the consensus sequence, which has at each site the modal nucleotide or amino acid residue across a sequence alignment; the most recent common ancestor, the sequence estimated at the basal node of the clades seen in the HIV-1 phylogeny; and the center of tree method, which minimizes the evolutionary distance to all sequences in the data set.

AIDS Vaccines↗
PubMed1994

The paradox of HIV/AIDS as expanding consciousness.

A heuristic approach employing Newman's method for pattern identification was used to examine the theory of health as expanding consciousness in persons with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). Themes derived from the interview of nine gay men portrayed a pattern of alienation during childhood, followed by a breaking away from family, and progressing to cycles of aloneness and searching. Recognition of HIV/AIDS in their lives brought them to a turning point of more meaningful connectedness. This pattern is viewed as expanding consciousness and possibly a phenomenon of cultural evolution.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Evolution and probable transmission of intersubtype recombinant human immunodeficiency virus type 1 in a Zambian couple.

The extraordinary genetic diversity of human immunodeficiency virus type 1 (HIV-1) results from the introduction of mutations by an error-prone reverse transcriptase and from recombination of the two RNA genomes packaged in the virion during the synthesis of proviral DNA. The occurrence of multiple, genetically distant HIV-1 subtypes and their geographic intermixing set up conditions for dramatic, rather than gradual, changes in genotype whenever genomes from different subtypes are copackaged in virions. Here we describe, for the first time, the sequential generation of multiple different, but related, intersubtype HIV-1 recombinants within an infected individual. Full-length gag and env genes were recovered directly from peripheral blood mononuclear cells or from primary virus cultures, using serial blood samples from a Zambian woman and a sample from her spouse. DNA sequencing and phylogenetic analysis established that two different A/C recombinant forms of HIV-1 predominated at two time points in the woman. A related but distinct recombinant HIV-1 was recovered from her spouse. Intersubtype recombination apparently played a central role in the evolution of HIV-1 in this couple and may contribute substantially to the rapid emergence of HIV-1 variants whenever mixed-subtype HIV-1 infections occur.

Base Sequence↗
PubMed1991

Polymerase chain reaction (PCR) in various stages of HIV infection. Relationship to disease progression.

In order to establish whether the Polymerase Chain Reaction (PCR) may constitute a new marker of evolution towards AIDS in symptomless HIV infected subjects, we used PCR with three primer pairs (in the gag, pol and LTR regions) in 223 seropositive individuals at different stages of HIV infection. Among 176 symptomless seropositive individuals, 174 (98.8%) were positive with at least one primer pair. The subjects negative with at least one primer pair had a CD4 lymphocyte count significantly higher (p less than 0.01), and serum immunoglobulin G, immunoglobulin A, neopterin and beta-2-microglobulin concentrations significantly lower (p less than 0.01) than the individuals positive with the three primer pairs. Among 73 seropositive individuals followed over a two year period, 59 presented the same PCR pattern over this time period, while PCR showed different results in 14. Forty-seven AIDS patients were positive with the three primer pairs. The number of PCR negative with at least one primer pair was significantly fewer (p less than 0.001) in symptomatic individuals than in symptomless individuals. We conclude that the percentage of positive PCR results in HIV infected individuals is linked to the clinical stage of infection and to the disease progression.

Acquired Immunodeficiency Syndrome↗
PubMed1996

[Rhodococcus equi pneumonia in patients with HIV infection: report of 2 cases and review of the literature].

BACKGROUND: Pneumonia by Rhodococcus equi is infrequent and is associated with patients with important immunosuppression. To date 66 cases of pneumonia by Rhodococcus equi in patients with HIV infection have been published. The diagnosis, problems in determining diagnosis and treatment are discussed. MATERIALS AND METHODS: Two new cases of pneumonia by Rhodococus equi in C3 stage patients with HIV infection are reported. Diagnosis was achieved by study of bronchoalveolar lavage samples with the Apy-Coryne method and gas chromatography. RESULTS: The two patients presented pneumonia, one of which was necrotizing pneumonia with localization in the upper left lung and in the lower right lung, respectively. The clinical manifestations were characterized by respiratory involvement of a subacute course with pleural involvement in both cases and hemoptisis in one. Prolonged, combined antibiotic treatment was administered with good response in both cases. One patient died at one year of diagnosis from consumptive syndrome while the other remains asymptomatic. CONCLUSIONS: Infection by Rhodococcus equi should be suspected in HIV patients with slow evolution pneumonia, especially in the pneumonia is necrotizing. Combined i.v. antibiotic treatment is recommended and followed from 3 to 5 months with an association including clarithromycin.

Actinomycetales Infections↗
PubMedDate not supplied

Orofacial manifestations of histoplasmosis in HIV-positive patients: a case report.

Amongst the main opportunistic diseases that affect the HIV-positive patient, histoplasmosis is found. This systemic mycosis caused by the fungus Histoplasma capsulatum has the capacity to disseminate from the lung to the skin and oral mucosa. Oral lesions of histoplasmosis can be found with ulcerated or nodular aspect, being always very painful and infiltrating the mucosa. When they are present in the mouth, they strongly indicate the presence of some kind of immunosuppression. This study shows the disease's evolution in an HIV-positive patient, who presented several ulcerated lesions in the oral cavity and facial skin. The symptomatology and clinical aspects of the lesions were not specific for the disease, and due to this, the diagnosis was obtained by cytological smear and oral biopsy. The results of the exams defined the disseminated picture of the infection. The treatment plan involved the use of amphotericin B for the lesions' remission, and, following this, itraconazole was administered in the maintenance phase.

AIDS-Related Opportunistic Infections↗
PubMed2006

Human immunodeficiency virus type 1 coreceptor switching: V1/V2 gain-of-fitness mutations compensate for V3 loss-of-fitness mutations.

Human immunodeficiency virus type 1 (HIV-1) entry into target cells is mediated by the virus envelope binding to CD4 and the conformationally altered envelope subsequently binding to one of two chemokine receptors. HIV-1 envelope glycoprotein (gp120) has five variable loops, of which three (V1/V2 and V3) influence the binding of either CCR5 or CXCR4, the two primary coreceptors for virus entry. Minimal sequence changes in V3 are sufficient for changing coreceptor use from CCR5 to CXCR4 in some HIV-1 isolates, but more commonly additional mutations in V1/V2 are observed during coreceptor switching. We have modeled coreceptor switching by introducing most possible combinations of mutations in the variable loops that distinguish a previously identified group of CCR5- and CXCR4-using viruses. We found that V3 mutations entail high risk, ranging from major loss of entry fitness to lethality. Mutations in or near V1/V2 were able to compensate for the deleterious V3 mutations and may need to precede V3 mutations to permit virus survival. V1/V2 mutations in the absence of V3 mutations often increased the capacity of virus to utilize CCR5 but were unable to confer CXCR4 use. V3 mutations were thus necessary but not sufficient for coreceptor switching, and V1/V2 mutations were necessary for virus survival. HIV-1 envelope sequence evolution from CCR5 to CXCR4 use is constrained by relatively frequent lethal mutations, deep fitness valleys, and requirements to make the right amino acid substitution in the right place at the right time.

Amino Acid Sequence↗