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D S Burke

Publications and source records attributed to D S Burke.

At least 19 recordsLinked to original sources
PubMed1998

Size and duration of zidovudine benefit in 1003 HIV-infected patients: U.S. Army, Navy, and Air Force natural history data. Military Medical Consortium for Applied Retroviral Research.

OBJECTIVES: The study's objectives were to determine the size and duration of benefits of early versus delayed versus late treatment with zidovudine (ZDV) on disease progression and mortality in HIV-infected patients, and whether patients rapidly progressing before ZDV treatment had a different outcome from those not rapidly progressing before ZDV. DESIGN: The design was an inception cohort of 1003 HIV-infected patients. One hundred and seventy-four of the 1003 patients were treated before CD4 counts fell to <400 x 10(9)/L, ("early treatment"); 183 of 1003 patients were treated after CD4 counts fell to <400 x 10(9)/L but before clinical disease developed ("delayed treatment"); and 646 of the 1003 patients had either been treated after clinical disease developed or had not been treated at all by the end of follow-up ("late treatment"). Outcomes were progression to clinical HIV disease and mortality. RESULTS: The relative risk (RR) of progression for early versus delayed treatment was 0.58 (p < .03), and durability of ZDV benefits on progression was estimated at no more than 2.0 years; however, this estimate had wide confidence intervals. The RR of progression for delayed versus late treatment was 0.54 p < .0001, and durability of ZDV benefits was estimated at 1.74 years; this estimate had narrow confidence intervals. Survival was better for the early versus delayed treatment (RR = 0.55), but this difference was not statistically significant. In the subgroup of patients with more rapid CD4 decline prior to ZDV therapy, significant benefits on progression were observed for early versus delayed ZDV therapy (RR = 0.42, p = .02) and delayed versus late ZDV therapy (RR = 0.51; p = .0004). Duration of benefit was estimated to be 4.5 years (early versus delayed) and 1.7 years (delayed versus late). For patients with less rapid pre-ZDV decline in CD4 levels, a significant progression benefit was observed for delayed versus late therapy (RR = 0.50; p = .02). Duration of benefit in this subgroup was estimated to be 1.8 years. No significant benefit was found for early versus delayed treatment (RR = 1.12) in the less rapid pre-ZDV CD4 cell decline subgroup. CONCLUSIONS: Early treatment compared with delayed treatment was associated with a sizable reduction in HIV progression, but the duration of benefits was estimated to last only about 2 years. Delayed treatment compared with late treatment with ZDV was associated with substantial reduction of progression, but this reduction was also clearly limited in duration. Benefits on progression and mortality for the early treatment group were heavily dependent on the pre-ZDV CD4 slope. In the subgroup of patients with the most rapid pre-ZDV CD4 cell declines, the duration of benefit was much longer, possibly as long as 4 years.

Adult↗
PubMed1998

Putting more genetics into genetic algorithms.

The majority of current genetic algorithms (GAs), while inspired by natural evolutionary systems, are seldom viewed as biologically plausible models. This is not a criticism of GAs, but rather a reflection of choices made regarding the level of abstraction at which biological mechanisms are modeled, and a reflection of the more engineering-oriented goals of the evolutionary computation community. Understanding better and reducing this gap between GAs and genetics has been a central issue in an interdisciplinary project whose goal is to build GA-based computational models of viral evolution. The result is a system called Virtual Virus (VIV). VIV incorporates a number of more biologically plausible mechanisms, including a more flexible genotype-to-phenotype mapping. In VIV the genes are independent of position, and genomes can vary in length and may contain noncoding regions, as well as duplicative or competing genes. Initial computational studies with VIV have already revealed several emergent phenomena of both biological and computational interest. In the absence of any penalty based on genome length, VIV develops individuals with long genomes and also performs more poorly (from a problem-solving viewpoint) than when a length penalty is used. With a fixed linear length penalty, genome length tends to increase dramatically in the early phases of evolution and then decrease to a level based on the mutation rate. The plateau genome length (i.e., the average length of individuals in the final population) generally increases in response to an increase in the base mutation rate. When VIV converges, there tend to be many copies of good alternative genes within the individuals. We observed many instances of switching between active and inactive genes during the entire evolutionary process. These observations support the conclusion that noncoding regions serve as scratch space in which VIV can explore alternative gene values. These results represent a positive step in understanding how GAs might exploit more of the power and flexibility of biological evolution while simultaneously providing better tools for understanding evolving biological systems.

Algorithms↗
PubMed1997

Genetic, antigenic and serologic characterization of human immunodeficiency virus type 1 from Indonesia.

To examine the genetic and antigenic characteristics of HIV-1 in Indonesia, samples from 19 HIV-positive volunteers were studied. By a combination of PCR typing and DNA sequence analysis, 12 of the 19 volunteers were determined to be infected with HIV-1 clade B and seven with clade E. Six of the seven Indonesian clade E isolates were from volunteers associated with the Indonesian Military during a peacekeeping mission in Cambodia. Infectivity reduction neutralization assays showed that the Indonesian E viruses were effectively neutralized by Thailand clade E HIV-1 antisera but not by U.S. clade B antisera. The Indonesian clade B virus tested was neutralized by U.S. clade B antisera and not by the Thailand E antisera. Using a previously described serologic typing ELISA based on clade B and E V3 peptides, genetic clade was accurately determined in eight of eight sera tested. This is the first report of the genetic and antigenic analysis of HIV-1 isolates from Indonesia. The data indicate that at least two genetic and antigenic HIV-1 clades (clade E and B) circulate in Indonesia.

Amino Acid Sequence↗
PubMed1997

Expansion of restricted cellular immune responses to HIV-1 envelope by vaccination: IL-7 and IL-12 differentially augment cellular proliferative responses to HIV-1.

The failure of immune effector mechanisms to control HIV-1 infection has important consequences for the human host. In a randomized cohort of HIV-infected patients, there was striking in vitro restriction of the proliferative response to HIV-1 envelope protein (Env), gp160; only 34% of patients recognized Env. Therapeutic vaccination with recombinant gp160 or gp120 (rgp160, rgp120) reversed the restriction in vitro, with Env recognition rising to 81%. Peripheral blood mononuclear cells (PBMC) from HIV-infected vaccine recipients, placebo recipients, and seronegative volunteers were cultured with exogenous IL-7 or IL-12 and either tetanus toxoid (TT) or gp160. IL-7 significantly augmented proliferative responses to TT and gp160, whereas IL-12 only affected proliferation to gp160. IL-7, but not IL-12, increased the number of HIV-infected placebo recipients who recognized rgp160. IL-12 had its greatest effect in the induction of rgp160-specific responses from seronegative individuals. The data suggest that these two cytokines have differential activity in the relief of restricted cellular immunity to Env; the predominant effect of IL-7 is in individuals who have been primed by exposure to antigen, while the effect of IL-12 is most evident in seronegative, unprimed individuals. Modification of restricted proliferative responses to Env by vaccination or cytokines in vitro suggests that strategies incorporating IL-7 or IL-12 as adjuvants may selectively boost cellular reactivity to HIV-1.

AIDS Vaccines↗
PubMed1997

Serum levels of virus burden in early-stage human immunodeficiency virus type 1 disease in women.

The fundamental clinical, viral, and immunologic features of early-stage human immunodeficiency virus type 1 (HIV-1) disease were examined in a seroprevalent cohort of 28 men and 14 women assessed longitudinally at three equally dispersed time points over a mean of 43 months. There were no gender differences in the relative risk of developing AIDS-defining end points or death. The median serum RNA levels assessed at the three study time points were 3.3-, 4.9-, and 1.5-fold lower, respectively, in women than in men. This suggests that while serum virus load may be as powerful a correlate of disease status in women as it is in men, the absolute values of the virus levels may be different in the 2 populations. These observations may have implications for the interpretation of levels of virus burden in women for the assessment of disease progression, transmission, and treatment.

Acquired Immunodeficiency Syndrome↗
PubMed1997

Human immunodeficiency virus type 1 strains of subtypes B and E replicate in cutaneous dendritic cell-T-cell mixtures without displaying subtype-specific tropism.

A report that genetic subtype E human immunodeficiency virus type 1 (HIV-1) strains display a preferential tropism for Langerhans cells (epidermal dendritic cells [DCs]) compared to genetic subtype B strains suggested a possible explanation for the rapid heterosexual spread of subtype E strains in Thailand (L. E. Soto-Ramirez et al., Science 271:1291-1293, 1996). In an independent system, we applied subtype E and B isolates to skin leukocytes, since skin is a relevant model for the histologically comparable surfaces of the vagina and ectocervix. Isolates of both HIV-1 subtypes infected DC-T-cell mixtures, and no subtype-specific pattern of infection was observed. Purified DCs did not support the replication of strains of either subtype B or E. Our findings do not support the conclusion that subtype E strains have a preferential tropism for DCs, suggesting that other explanations for the rapid heterosexual spread of subtype E strains in Asia should be considered.

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↗
PubMed1996

Human immunodeficiency virus type 1 neutralizing antibody serotyping using serum pools and an infectivity reduction assay.

Classification of human immunodeficiency virus type 1 (HIV-1) by neutralization serotype may be important for the design of active and passive immunization strategies. Neutralizing antibody serotyping is hindered by the lack of standard reagents and assay format, and by the weak activity of many individual sera. To facilitate cross-clade neutralization analysis, we used an infectivity reduction assay (IRA) and selected clade-specific serum (or plasma) pools from subjects infected with clade B and E HIV-1, respectively. Several serum pools were utilized; some were selected for strong neutralizing activity against intraclade viruses and others were derived from conveniently available samples. Against a panel of 51 clade B and E viruses, serum pools displayed strong neutralization of most intraclade viruses and significantly diminished cross-clade neutralization. Results were confirmed against a blinded panel of 20 viruses. The data indicate that the phylogenetic classification of virus subtypes B and E corresponds to two distinct neutralization serotypes. This approach to neutralizing antibody serotyping may be useful in defining the antigenic relationship among viruses from other clades.

Enzyme-Linked Immunosorbent Assay↗
PubMed1996

Full-length sequence of an ethiopian human immunodeficiency virus type 1 (HIV-1) isolate of genetic subtype C.

Genetic subtype C of the human immunodeficiency virus type-1 (HIV-1) has established foci of infection in India and in at least eight African countries, and is expected to contribute significantly to the global pandemic. Here we report the first almost full-length sequence of a subtype C HIV-1 from Ethiopia. Clone C2220, 9031 nt in length, was derived by long PCR amplification of proviral DNA from virus cultured on primary peripheral blood mononuclear cells, and contains all but 74 nt of the unique sequence information of the HIV-1 genome. This clone resembles HIV-1 isolates of subtypes A, B, and D in its genome organization with one notable exception: the core promoter contains not two, but three potential binding sites for the transcription factor NF-kB. The extra NF-kB site was found in all other Ethiopian strains analyzed, as well as in subtype C viruses from Zambia, suggesting it is typical for the C-subtype of HIV-1. The phylogenetic relationship of C2220 to other HIV-1 isolates is also presented. Subtype C viruses circulating in Ethiopia exhibit the low interisolate diversity typical of other, newly established HIV-1 epidemics, and C2220 is both representative of Ethiopian subtype C viruses and a suitable prototype for the development of vaccines against HIV-1 subtype C.

Amino Acid Sequence↗
PubMed1996

Transcriptional effects of superinfection in HIV chronically infected T cells: studies in dually infected clones.

We had previously shown that chronically infected ACH-2 cells (HIVLAI) could be superinfected with HIVRF, that the frequency of superinfection increased with time, and that the transcription of the superinfecting virus exceeded that of the host HIVLAI provirus. In contrast, ACH-2 cells superinfected with a nef-substituted neomycin-resistant (proNEO) provirus were not detectable by DNA polymerase chain reaction (PCR) until geneticin (G418) was added, suggesting that the ability to propagate progressively in culture may be HIV strain specific. Clonal populations of ACH-2 superinfected with proNEO did not demonstrate preferential transcription of the superinfecting virus. However, clones of ACH-2 superinfected with HIVRF (ACH2/RF) showed a preponderance of HIVRF transcripts similar to that seen in bulk populations. Induction of the superinfecting virus by phorbol ester (PMA) occurred more rapidly than the hose provirus and did not equalize transcriptional activity. PCR-derived long terminal repeat (LTR) fragments and Tat cDNAs from A3.01 cells acutely infected with HIVRF or from ACH-2 cells were sequenced and tested for transactivation. The HIVLAI LTR was two to three times more Tat-responsive than the HIVRF LTR. TatRF was two to three times more transcriptionally active on either LTR than TatLAI. Demethylation with 5-azacytidine did not significantly affect HIV expression from the HIVLAI host provirus of superinfected ACH2/RF cell clones. These data suggest that the mechanism of preferential transcription in HIVRF superinfected ACH2/RF may be attributed to the Tat/TAR axis and the effect of the specific locus of host proviral integration.

Amino Acid Sequence↗
PubMed1996

Antiviral effect and ex vivo CD4+ T cell proliferation in HIV-positive patients as a result of CD28 costimulation.

Because stimulation of CD4+ lymphocytes leads to activation of human immunodeficiency virus-type 1 (HIV-1) replication, viral spread, and cell death, adoptive CD4+ T cell therapy has not been possible. When antigen and CD28 receptors on cultured T cells were stimulated by monoclonal antibodies (mAbs) to CD3 and CD28 that had been immobilized, there was an increase in the number of polyclonal CD4+ T cells from HIV-infected donors. Activated cells predominantly secreted cytokines associated with T helper cell type 1 function. The HIV-1 viral load declined in the absence of antiretroviral agents. Moreover, CD28 stimulation of CD4+ T cells from uninfected donors rendered these cells highly resistant to HIV-1 infection. Immobilization of CD28 mAb was crucial to the development of HIV resistance, as cells stimulated with soluble CD28 mAb were highly susceptible to HIV infection. The CD28-mediated antiviral effect occurred early in the viral life cycle, before HIV-1 DNA integration. These data may facilitate immune reconstitution and gene therapy approaches in persons with HIV infection.

Antibodies, Monoclonal↗
PubMed1996

Correlates of HIV-1 seropositivity among young men in Thailand.

Geographic and demographic correlates of risk for HIV-1 seropositivity were studied in 120,216 young men selected by lottery for service in the Royal Thai Army (RTA). The study population consisted of men selected between November 1991 and May 1993. Venous blood was collected at induction, and a brief demographic questionnaire was administered. HIV-1 seropositivity was established by Western blot confirmation of duplicate reactive ELISAs. Geographic variable provided the strongest correlate of risk, clearly distinguishing residents of the upper north, Bangkok, and the central region from the northeast. Overall 12.2% of men from the upper north were HIV-positive. Men who had lived in rural areas were at less risk in most regions of the country, but had equal risk in the upper north. Unmarried men and those with less education were at higher risk throughout the country. These data provide valuable information on the prevalence of HIV infection in one segment of the general population. Continued surveillance of this group will facilitate evaluation of Thailand's response to the epidemic.

Adult↗
PubMed1996

Immunization with envelope subunit vaccine products elicits neutralizing antibodies against laboratory-adapted but not primary isolates of human immunodeficiency virus type 1. The National Institute of Allergy and Infectious Diseases AIDS Vaccine Evaluation Group.

Phase I studies of volunteers not infected with human immunodeficiency virus type 1 (HIV-1) have shown that immunization with envelope subunit vaccine products elicits antibodies that neutralize laboratory-adapted (prototype) HIV-1 strains in vitro. Prototype strains are adapted to grow in continuous (neoplastic) cell lines and are more susceptible to neutralization than are primary isolates cultured in human peripheral blood mononuclear cells. In this study, 50 sera from nine phase I vaccine trials and 16 from HIV-1-infected persons were evaluated for neutralizing antibody activity against 3 laboratory-adapted and 5 primary HIV-1 isolates. Of 50 sera, 49 neutralized at least 1 of the prototype strains; however, none displayed neutralizing activity against primary isolates of HIV-1. Serum from most HIV-1-infected persons neutralized both laboratory-adapted and primary HIV-1 isolates. These data demonstrate a qualitative, or large quantitative, difference in the neutralizing antibody response induced by envelope subunit vaccination and natural HIV-1 infection.

AIDS Vaccines↗
PubMed1996

Patterns of virus burden and T cell phenotype are established early and are correlated with the rate of disease progression in human immunodeficiency virus type 1-infected persons.

Human immunodeficiency virus (HIV)-1 DNA and RNA levels and T lymphocyte cell surface markers were measured in blood serum and cell fractions from asymptomatic infected patients to find novel virologic and immunologic features in early disease predictive of subsequent clinical disease course. Thirty-two patients with rapid disease progression (rapid CD4+ cell loss and progression to clinical AIDS) were compared with 25 patients with stable infections (constant or rising CD4+ cell counts, no clinical disease manifestations). All HIV-1 burdens measured by polymerase chain reaction were consistently higher in specimens from rapid progressors than slow progressors. For each patient, virus burden remained relatively constant throughout the study period (mean, 42-44 months). Flow cytometry also disclosed stable lymphocyte immunophenotype patterns that correlated strongly with subsequent rapid progression to clinical disease. Thus, in early HIV-1 infection, a constellation of high virus burden and in vivo costimulatory antigen and lymphocyte activation abnormalities is predictive of rapid disease course.

Adult↗
PubMed1996

V3 seroreactivity and sequence variation: tracking the emergence of V3 genotypic variation in HIV-1-infected patients.

OBJECTIVE: To investigate the relationship between V3-specific immune responses and viral quasispecies evolution in 10 HIV-1-seropositive patients enrolled in a phase I trial of recombinant gp160. METHODS: Serologic responses to the HIVLAI V3 loop and autologous V3 loop DNA sequences were sequentially determined over a 3-4-year interval. RESULTS: Six patients either seroconverted or had a > or = 42-fold boost in titer to the V3 reagent associated with an average of 3.2 amino-acid changes in their autologous V3 loops. Four patients with < or = 11-fold change in titer to the V3 loop showed an average of 0.75 amino-acid changes. Attempts to measure autologous V3 loop responses in four patients using a peptide enzyme-linked immunosorbent assay technique did not show a distinct binding preference for autologous versus heterologous V3 loop peptides. Thus, we interpret seroreactivity to the heterologous HIVLAI V3 loop to reflect the broadness of the V3 immune response rather than a direct measure of epitope-specific immune pressure. CONCLUSIONS: These data suggest that the broadness of serologic responses to viral epitopes are reflected in the rate of evolution of their cognate coding sequences and support the view that the immune response to HIV-1 results in the continuous selection of new viral variants during the course of disease.

AIDS Vaccines↗
PubMed1996

Diversity of the envelope glycoprotein among human immunodeficiency virus type 1 isolates of clade E from Asia and Africa.

Human immunodeficiency virus type 1 isolates of clade E, known to be largely responsible for the fulminating epidemic in Southeast Asia, have been derived exclusively from Asia and Africa. Here we provide full or partial sequences of the envelope glycoprotein gene from 13 additional clade E isolates from Asia representing patients in both early and late stages of disease. More extensive comparison of isolates within clade E by geographic locale, stage of disease, and year of isolation is now possible. The genetic diversity of clade E isolates from Asia, particularly among those derived from early-stage patients, is restricted compared with African isolates (mean interisolate distances in gp120, 5.4 and 20.2%, respectively). However, patients hospitalized with AIDS-related illnesses in Thailand harbored clade E isolates exhibiting broader interisolate diversity and with highly heterogeneous third hypervariable loop sequences. An additional pair of cysteine residues, predicting a novel disulfide bridge and present in 80% of clade E isolates from Asia, was uniformly absent from six African isolates. Clade E isolates in Thailand from early-stage subjects continue to be genetically similar to potential vaccine prototype strains, providing a favorable environment for the evaluation of genotype E candidate vaccines. However, evidence of increasing interisolate diversity is appearing among late-stage patients in Asia. This diversification of the clade E virus, if sustained, may impact preventive vaccine development strategies.

Africa↗
PubMed1996

Full-length sequence and mosaic structure of a human immunodeficiency virus type 1 isolate from Thailand.

Human immunodeficiency virus type 1 isolates of envelope genotype E are contributing substantially to the global pandemic. These strains appear to be mosaics, with the gag gene from clade A and the envelope from clade E; the parental clade E strain has not been found. Here we report the first full genomic sequence of one such mosaic virus, isolate CM240 from Thailand. Multiple breakpoints between the two parental genotypes have been found in a CM240 virus. The entire gag-pol region and most, if not all, of the accessory genes vif, vpr, tat, rev, and vpu appear to derive from clade A. The genotype switches to E shortly after the signal peptide of the envelope and back to clade A near the middle of gp41; thus, the portion of the envelope that lies on the cytoplasmic side of the membrane appears to be principally derived not from clade E, as previously thought, but from clade A. Another small segment not belonging to any recognized clade and presumably also contributed by the parental E strain has been found in the long terminal repeat. It may be significant that the implied virion structure resembles a pseudotype virus with the matrix and core from one clade and the outer envelope from another. In the long terminal repeat, differences were observed between CM240 and other clades in the number of NF-kappa B binding sites, the sequence of the TATA box, and the putative secondary structure of the transactivation response region stem-loop. The mosaic structure of a CM240 virion is suggestive of phenotypic differences which might have contributed to the emergence of this variant.

Adult↗