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Biomedical subjects

G M Shaw

Publications and source records attributed to G M Shaw.

At least 145 records · Page 8Linked to original sources
PubMed1994

Unsuspected primary human immunodeficiency virus type 1 infection in seronegative emergency department patients.

To estimate the number of recently infected patients in the window period before human immunodeficiency virus type 1 (HIV-1) seroconversion among patients seeking medical care, randomly selected adults presenting to an inner city emergency department were tested for HIV-1 antibody and p24 antigen. Of 2300 patients enrolled, 180 (7.8%; 95% confidence interval [CI]: 6.7%-8.9%) were Western blot (WB)-positive for HIV-1 antibodies. Of 2120 antibody-negative or WB-indeterminate patients, none of whom were identified on clinical grounds as having primary HIV-1 infection, 6 (0.28%; CI, 0.07%-0.51%) were p24 antigen-positive with serologies consistent with primary HIV-1 infection. Of these 6, 3 were seronegative even with third-generation antibody ELISA. HIV-1 infection in these 6 patients was further confirmed by polymerase chain reaction amplification of virion-associated RNA in serum demonstrating 10(4)-10(5) virions/mL. With 40,000 new HIV-1 infections in the United States annually, approximately 750 persons with undiagnosed primary HIV-1 infections may seek primary health care in any given week in the United States. Testing for viral antibodies alone will fail to detect a large proportion of these persons. Thus, early identification by p24 antigen testing may be important to diagnose and treat symptomatic illness, implement public health and counseling measures, and arrange appropriate medical follow-up.

Adult↗
PubMed1994

Genetic diversity of human immunodeficiency virus type 2: evidence for distinct sequence subtypes with differences in virus biology.

The virulence properties of human immunodeficiency virus type 2 (HIV-2) are known to vary significantly and to range from relative attenuation in certain individuals to high-level pathogenicity in others. These differences in clinical manifestations may, at least in part, be determined by genetic differences among infecting virus strains. Evaluation of the full spectrum of HIV-2 genetic diversity is thus a necessary first step towards understanding its molecular epidemiology, natural history of infection, and biological diversity. In this study, we have used nested PCR techniques to amplify viral sequences from the DNA of uncultured peripheral blood mononuclear cells from 12 patients with HIV-2 seroreactivity. Sequence analysis of four nonoverlapping genomic regions allowed a comprehensive analysis of HIV-2 phylogeny. The results revealed (i) the existence of five distinct and roughly equidistant evolutionary lineages of HIV-2 which, by analogy with HIV-1, have been termed sequence subtypes A to E; (ii) evidence for a mosaic HIV-2 genome, indicating that coinfection with genetically divergent strains and recombination can occur in HIV-2-infected individuals; and (iii) evidence supporting the conclusion that some of the HIV-2 subtypes may have arisen from independent introductions of genetically diverse sooty mangabey viruses into the human population. Importantly, only a subset of HIV-2 strains replicated in culture: all subtype A viruses grew to high titers, but attempts to isolate representatives of subtypes C, D, and E, as well as the majority of subtype B viruses, remained unsuccessful. Infection with all five viral subtypes was detectable by commercially available serological (Western immunoblot) assays, despite intersubtype sequence differences of up to 25% in the gag, pol, and env regions. These results indicate that the genetic and biological diversity of HIV-2 is far greater than previously appreciated and suggest that there may be subtype-specific differences in virus biology. Systematic natural history studies are needed to determine whether this heterogeneity has clinical relevance and whether the various HIV-2 subtypes differ in their in vivo pathogenicity.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Infection of a yellow baboon with simian immunodeficiency virus from African green monkeys: evidence for cross-species transmission in the wild.

Many African primates are known to be naturally infected with simian immunodeficiency viruses (SIVs), but only a fraction of these viruses has been molecularly characterized. One primate species for which only serological evidence of SIV infection has been reported is the yellow baboon (Papio hamadryas cynocephalus). Two wild-living baboons with strong SIVAGM seroreactivity were previously identified in a Tanzanian national park where baboons and African green monkeys shared the same habitat (T. Kodama, D. P. Silva, M. D. Daniel, J. E. Phillips-Conroy, C. J. Jolly, J. Rogers, and R. C. Desrosiers, AIDS Res. Hum. Retroviruses 5:337-343, 1989). To determine the genetic identity of the viruses infecting these animals, we used PCR to examine SIV sequences directly in uncultured leukocyte DNA. Targeting two different, nonoverlapping genomic regions, we amplified and sequenced a 673-bp gag gene fragment and a 908-bp env gene fragment from one of the two baboons. Phylo-genetic analyses revealed that this baboon was infected with an SIVAGM strain of the vervet subtype. These results provide the first direct evidence for simian-to-simian cross-species transmission of SIV in the wild.

Amino Acid Sequence↗
PubMed1994

Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection.

Human immunodeficiency virus type 1 (HIV-1) Env-, Gag-, Pol-, Nef-, and Tat-specific cytotoxic T-lymphocyte (CTL) activities were quantitated temporally in five patients with symptomatic primary HIV-1 infection. A dominant CD8(+)-mediated, major histocompatibility complex class I-restricted CTL response to the HIV-1 envelope glycoprotein, gp160, was noted in four of the five patients studied. The level of HIV-1-specific CTL activity in the five patients paralleled the efficiency of control of primary viremia. Patients who mounted strong gp160-specific CTL responses showed rapid reduction of acute plasma viremia and antigenemia, while in contrast, primary viremia and antigenemia were poorly controlled in patients in whom virus-specific CTL activity was low or undetectable. These results suggest that HIV-1-specific CTL activity is a major component of the host immune response associated with the control of virus replication following primary HIV-1 infection and have important implications for the design of antiviral vaccines.

Amino Acid Sequence↗
PubMed1993

Kinetics of human immunodeficiency virus type 1 (HIV-1) DNA and RNA synthesis during primary HIV-1 infection.

HIV-1 replication and viral burden in peripheral blood mononuclear cells (PBMC) have been reported to be high in primary infection but generally very low during the prolonged period of clinical latency. It is uncertain precisely when this transition occurs during the HIV-1 infection and what the relationship is between the changes in HIV-1 replication versus the clearance of infected cells in the overall control of viral replication. In the present study, the kinetics of viral burden (i.e., frequency of HIV-1-infected cells) and replication during primary and early-chronic infection were analyzed in PBMC of four acutely infected individuals. High frequencies of HIV-1-infected cells and high levels of virus replication were observed in PBMC after primary HIV-1 infection. Down-regulation of virus replication in PBMC was observed in all four patients coincident with the emergence of HIV-1-specific immune responses. Other parameters of virus replication, such as circulating plasma p24 antigen and plasma viremia showed similar kinetics. In contrast, a significant decline in viral burden in PBMC was observed in only one of four patients. These results indicate that the down-regulation in the levels of virus replication associated with the clinical transition from acute to chronic infection does not necessarily reflect a reduction in viral burden, thus suggesting the involvement of additional factors. Identification of these factors will be important in elucidating the host mechanisms involved in the early control of HIV-1 infection and disease.

Base Sequence↗
PubMed1993

High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR.

Quantitative competitive polymerase chain reaction (QC-PCR) methods were used to quantify virion-associated human immunodeficiency virus type-1 (HIV-1) RNA in plasma from 66 patients with Centers for Disease Control stage I to IVC1 infection. HIV-1 RNA, ranging from 100 to nearly 22,000,000 copies per milliliter of plasma (corresponding to 50 to 11,000,000 virions per milliliter), was readily quantified in all subjects, was significantly associated with disease stage and CD4+ T cell counts, and decreased by as much as 235-fold with resolution of primary infection or institution of antiretroviral therapy. Plasma virus levels determined by QC-PCR correlated with, but exceeded by an average of 60,000-fold, virus titers measured by endpoint dilution culture. Quantitation of HIV-1 in plasma by QC-PCR may be useful in assessing the efficacy of antiretroviral agents, especially in early stage disease when conventional viral markers are often negative.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Surveillance for and comparison of birth defect prevalences in two geographic areas--United States, 1983-88.

PROBLEM/CONDITION: CDC and a number of states have developed surveillance systems to monitor the birth prevalence of major defects. REPORTING PERIOD COVERED: This report covers birth defects surveillance in Metropolitan Atlanta, Georgia and selected jurisdictions in California for the years 1983-1988. DESCRIPTION OF SYSTEM: The California Birth Defects Monitoring Program and the Metropolitan Atlanta Congenital Defects Program are two population based surveillance systems that employ similar data collection methods. The prevalence estimates for 44 diagnostic categories are based on data from 1983 to 1988 for 639,837 births in California and 152,970 births in metropolitan Atlanta. The prevalences in the two areas are compared adjusting for race, sex and maternal age using Poisson regression. RESULTS: Regional differences in the prevalence of aortic stenosis, fetal alcohol syndrome, hip dislocation/dysplasia, microcephalus, obstruction of the kidney/ureter, and scoliosis/lordosis may be attributable to general diagnostic variability. However, differences in the prevalences of arm/hand limb reduction, encephalocele, spina bifida, or trisomy 21 (Down Syndrome) are probably not attributable to differences in ascertainment because these defects are relatively easy to diagnose. INTERPRETATION: Regional differences in prenatal diagnosis and pregnancy termination may affect prevalences of trisomy 21 and spina bifida. However, the reason for differences in arm/hand limb reduction is unknown, but may be related to variability in environmental exposure, heterogeneity in gene pool, or random variation. ACTIONS TAKEN: Because of the similarities of these data bases, several collaborative studies are being implemented. In particular, the differences in the birth prevalence of spina bifida and Down Syndrome will focus attention on the impact of prenatal diagnosis.

California↗
PubMed1993

The acute retroviral syndrome and the pathogenesis of HIV-1 infection.

The acute retroviral syndrome associated with primary HIV-1 infection is characterized by clinical signs of immune activation, multi-system dysfunction, and high levels of cell-associated and plasma viremia, p24 antigenemia, and proviral burden. Clinical abnormalities associated with acute HIV-1 infection and measures of viral burden and replication generally decline in concert with seroconversion. Despite clearance of virus, patients experiencing severe forms of the acute retroviral syndrome appear to have a poorer prognosis than patients with asymptomatic primary infection. This accelerated natural history may be due to the virulence of strains causing symptomatic infection, sequelae of initial high-titer viremia and consequent high viral burden, or immune depletion through immunopathologic mechanisms accelerated by strong antigenic stimulus in primary infection. Early intervention with anti-retroviral and immune modulatory agents has the potential to alter the natural history of patients with this syndrome.

Acute Disease↗
PubMed1993

Intracellular transport and virion incorporation of vpx requires interaction with other virus type-specific components.

Viral protein X (vpx) is a virion-associated HIV-2/SIV accessory protein that enhances viral infectivity and replication in natural target cells. To investigate whether other viral components affect its biosynthesis, subcellular localization, and virion incorporation, we expressed HIV-2 vpx in a mammalian cell system and examined its transport and packaging requirements using an in trans complementation assay. The complete vpx coding region of HIV-2ST was placed under the control of a high-efficiency promoter system (SR alpha) which contained both an SV40 promoter/enhancer region and R/U5 elements of the HTLV-1 LTR. Following transfection of Cos-1 cells, this construct (pSR alpha-vpx) facilitated high level expression of vpx, as demonstrated by Western blot analysis of transfected cell lysates. Moreover, indirect immunofluorescence analysis revealed an intense vpx staining pattern distributed evenly throughout the cytoplasm of transfected cells. This distribution differed markedly from cells expressing wild-type HIV-2 in which vpx localized to the inner surface of the plasma membrane. To determine whether other HIV components were required for this surface localization, we expressed vpx in the context of replication competent HIV-1 and HIV-2 proviruses. Following cotransfection with a vpx-deficient HIV-2 provirus (pXM7), eukaryotically expressed vpx targeted to the plasma membrane and colocalized with HIV-2 p27 gag in a pattern indistinguishable from wild-type HIV-2. Moreover, progeny virions from cotransfected Cos-1 cells contained wild-type amounts of vpx protein, demonstrating that vpx could be efficiently packaged in trans. Under the same experimental conditions, cotransfection of vpx with wild-type HIV-1 (pHXB2) and with vpr-deficient HIV-1 (pR2) failed to result in detectable cell surface targeting or virion incorporation of vpx despite its high level cellular expression. These results demonstrate that efficient intracellular transport and packaging of vpx require interaction with other type-specific virus components.

Amino Acid Sequence↗
PubMed1993

A molecular clone of HIV-1 tropic and cytopathic for human and chimpanzee lymphocytes.

Previous studies of HIV-1 replication in chimpanzee lymphocytes have been limited to a small number of virus isolates which generally replicated poorly and without cytopathic effect. Here, we describe an HIV-1 provirus (SG3), cloned as a single proviral unit, which replicates more efficiently in chimpanzee than in human lymphocytes, resulting in syncytium formation and cell death. This provirus also replicates efficiently and with extraordinary cytopathic effect in immortalized human T-cell lines. The SG3 genome was completely sequenced and found to contain all genes typical of HIV-1 with the exception of vpu. Phylogenetically, SG3 is representative of North American/European strains of HIV-1 and shows no greater similarity to SIVCPZ in its envelope sequence than do other HIV-1 strains. Pilot studies indicate that SG3 can infect and replicate in chimpanzees and SCID-hu mice in vivo following intravenous or intrathymic inoculation. The SG3 proviral clone, because of its replication efficiency in human and chimpanzee cells and its complete molecular description, represents a new virologic reagent for the coordinated molecular analysis of HIV-1 replication and pathogenesis in relevant animal model systems.

Acquired Immunodeficiency Syndrome↗
PubMed1993

Determination of plasma viral load in HIV-1 infection by quantitative competitive polymerase chain reaction.

OBJECTIVES: To better characterize viral load profiles through the course of HIV-1 disease and in response to treatment, and to further evaluate quantitative competitive polymerase chain reaction for measurement of viral load, we extended our comparative evaluation of this and other viral load measurements to a total of 118 patients, representing all stages of HIV-1 disease. DESIGN: For cross-sectional analysis across the spectrum of HIV-1 disease, plasma viral load was evaluated in 112 HIV-1-infected patients by quantitative competitive polymerase chain reaction analysis, plasma p24 antigen assay, plasma immune complex-dissociated p24 antigen assay and an endpoint dilution viral culture. Longitudinal specimens from six additional patients were analyzed, extending from the time of presentation with symptomatic acute HIV-1 infection through up to more than 2 years of follow-up. Longitudinal specimens were also studied for three patients over the period of initiation of zidovudine treatment, for 6 weeks of treatment and following temporary withdrawal of the treatment. METHODS: All measurement techniques were assessed in replicate aliquots of plasma. RESULTS: Quantitative competitive polymerase chain reaction was the most sensitive measure of viral load, and was best correlated with CD4+ T-cell counts. In longitudinally studied patients, this technique also allowed measurement of plasma virus levels throughout the period of follow-up, even when culture and p24 assays became negative following resolution of acute HIV-1 infection. The quantitative competitive polymerase chain reaction was also able to detect rapid and substantial changes in viral load associated with initiation and temporary withdrawal of antiviral treatment. CONCLUSIONS: The quantitative competitive polymerase chain reaction is promising as a sensitive and accurate method for measuring plasma viral load in HIV-1-infected patients, and is useful for following changes in viral load over the natural history of infection and following treatment intervention. The technique is particularly useful for patients with > 200 x 10(6) CD4+ T cells/l, in whom other viral markers are typically negative.

Biomarkers↗
PubMed1993

Trends in Down's syndrome prevalence in California, 1983-1988.

Trends in the prevalence of Down's syndrome in livebirths were examined in California from 1983 to 1988, a time period when prenatal screening and subsequent termination of Down's syndrome pregnancies among women under 35 years of age was increasing. In the population-based ascertainment areas of the California Birth Defects Monitoring Program (CBDMP), 1058 infants with Down's syndrome were identified, giving a crude prevalence of 1.03 (95% confidence interval [CI]: 0.97, 1.09). The risk ratio for 1988 compared with 1983, after adjusting for maternal age and other confounders, was 0.98 (95% CI: 0.78, 1.23), showing that there was no change in livebirth prevalence over this period. The data were also examined for mothers under 35 years of age to determine whether increasing use of prenatal screening leading to termination masked an increase in prevalence. A modest increase was seen.

Abortion, Therapeutic↗
PubMed1993

Human adverse reproductive outcomes and electromagnetic field exposures: review of epidemiologic studies.

Concerns have been raised regarding a relation between residential and occupational electromagnetic (EM) field exposures and adverse reproductive effects. This paper reviews the epidemiologic evidence for this possible relation, including some pertinent methodologic issues, notes relevant findings from the experimental literature, and discusses areas for future research. Evidence is lacking for a strong association between a woman's use of a video display terminal (VDT) during pregnancy and spontaneous abortion. The evidence for a strong association between a women's use of a VDT and other adverse reproductive endpoints is also lacking, with some suggestive findings for congenital malformations and too few data to reach a conclusion about other endpoints. With respect to low-level EM field exposures other than VDTs, the paucity of data prevents one from determining whether there are reproductive health risks associated with such exposures. Therefore, this is an area that needs further investigation. Given that altered growth may be an underlying biologic effect of EM field exposures, endpoints that might be pursued in future studies include congenital malformations not associated with chromosomal anomalies, intrauterine growth retardation, and chromosomally normal spontaneous abortions.

Adult↗
PubMed1992

Human infection by genetically diverse SIVSM-related HIV-2 in west Africa.

Our understanding of the biology and origins of human immunodeficiency virus type 2 (HIV-2) derives from studies of cultured isolates from urban populations experiencing epidemic infection and disease. To test the hypothesis that such isolates might represent only a subset of a larger, genetically more diverse group of viruses, we used nested polymerase chain reactions to characterize HIV-2 sequences in uncultured mononuclear blood cells of two healthy Liberian agricultural workers, from whom virus isolation was repeatedly unsuccessful, and from a culture-positive symptomatic urban dweller. Analysis of pol, env and long terminal repeat regions revealed the presence of three highly divergent HIV-2 strains, one of which (from one of the healthy subjects) was significantly more closely related to simian immunodeficiency viruses infecting sooty mangabeys and rhesus macaques (SIVSM/SIVMAC) than to any virus of human derivation. This subject also harboured multiply defective viral genotypes that resulted from hypermutation of G to A bases. Our results indicate that HIV-2, SIVSM and SIVMAC comprise a single, highly diverse group of lentiviruses which cannot be separated into distinct phylogenetic lineages according to species of origin.

Adult↗
PubMed1992

Transmission of human T-lymphotropic virus type I by blood components from a donor lacking anti-p24: a case report. The Transfusion Safety Study Group.

The present criteria for confirmation of human T-lymphotrophic virus types I and II (HTLV-I/II) infection in blood donors are based on seroreactivity to p24 (gag) and gp46 and/or gp61 (env) on Western blot (WB) and radioimmunoprecipitation assays (WB/RIPA). Any single band and other combinations are classified as indeterminate. This case report documents infection in a donor with a repeatedly indeterminate pattern. The blood donor was anti-HTLV-I/II positive on enzyme-linked immunoassay, and two sera taken 5 years apart were WB/RIPA-indeterminate (p19 and gp68 only). His donations in the interval were associated with transmission of HTLV-I to four of the six recipients available for study. Other recipients of blood from donors whose WB/RIPA results were indeterminate by present criteria should be examined to determine if additional patterns are at least occasionally associated with transmission. The likelihood that such donors are infected is important to those who are counseling them and making decisions concerning recipients of their bloody.

Adult↗
PubMed1992

Segregation of human T cell lymphotropic virus type I and II infections by antibody reactivity to unique viral epitopes.

A recombinant protein of the human T cell lymphotropic virus type I (HTLV-I) gp46 outer membrane envelope, MTA-4 (residues 129-203), reacted by Western blot with sera from HTLV-I-infected individuals from the United States and Jamaica but not with 24 (10%) of 242 Japanese sera. A related gp46 recombinant protein, MTA-1 (residues 162-209), reacted with all 58 sera from HTLV-I-infected US and Jamaican individuals and 238 of 242 sera from infected Japanese (combined sensitivity of 99%). Neither recombinant showed reactivity to sera from HTLV-II-infected individuals or uninfected controls. The reactivity of recombinant proteins containing the region of HTLV-II gp46 analogous to MTA-1 was also evaluated by Western blot: GH2-K15 (residues 157-205) and GH2-K55 (residues 162-205) reacted with 88 (98%) and 89 (99%), respectively, of 90 sera from HTLV-II-infected individuals but not with sera from HTLV-I-infected individuals or uninfected controls. These recombinant proteins should permit the development of assays to unambiguously confirm and differentiate HTLV-I and HTLV-II infections.

Amino Acid Sequence↗