摘要:

Summary:The effect of human immunodeficiency virus (HIV-1) infection on the programmed cell death of CD4+ lymphocytes was studied by using Jurkat cells stably expressing high levels of the Bcl-2 protein (Jurkat-Bcl2) or control cells (Jurkat-P). Both Jurkat-Bcl2 and Jurkat-P cells exhibited surface CD4 expression adequate to support HIV-1 infection. We observed no differences between HIV-1-infected Jurkat Bcl2 cells and control cells with respect to kinetics of virus replication, protein expression, and processing. Severe cytopathic effects, which were typical of acute HIV-1 infection and consisted of syncytium formation followed by single-cell lysis, were observed in both cell types. However, several lines of evidence, such as cell viability analysis by trypan blue dye exclusion, chromosomal DNA laddering, and morphologic analysis by acridine orange/ethidium bromide or Giemsa staining, indicated that HIV-1 did not induce a significant amount of programmed cell death in either cell type. These results suggest that apoptosis is at most a minor element in HIV-1-induced cytopathicity in Jurkat lymphocytes.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Summary: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 HIVLAIprovirus. In contrast, ACH-2 cells superinfected with anef-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 HIVRFtranscripts similar to that seen in bulk populations. Induction of the superinfecting virus by phorbol ester (PMA) occurred more rapidly than the host provirus and did not equalize transcriptional activity. PCR-derived long terminal repeat (LTR) fragments and Tat cDNAs from A3.01 cells acutely infected with HIVRFor from ACH-2 cells were sequenced and tested for transactivation. The HIVLAILTR was two to three times more Tat-responsive than the HIVRFLTR. TatRFwas two to three times more transcriptionally active on either LTR than TatLAI. Demethylation with 5-azacytidine did not significantly affect HIV expression from the HIVLAIhost provirus of superinfected ACH2/RF cell clones. These data suggest that the mechanism of preferential transcription in HIVRFsuperinfected ACH2/RF may be attributed to the Tat/TAR axis and the effect of the specific locus of host proviral integration.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Summary:The life cycle of human immunodeficiency virus type 1 (HIV-1) is critically dependent on the transregulatory proteins Tat and Rev. Tat increases the production of HIV-specific mRNAs by direct binding to the transactivation response (TAR) element located at the 5' end of all HIV transcripts. In contrast, Rev uses a comples RNA stem loop structure, the Rev response element (RRE), which is found in full-length and singly spliced HIV transcripts. Rev is required for the cytoplasmic expression of full-length mRNAs encoding Gag, Pol, and Env structural proteins. The complex intracellular interactions between Tat, Rev, host cell factors, and their respective RNA response elements should be susceptible to interdiction by genetic therapies designed to introduce and express novel genetic information. We show that the expression of antisense RREs inhibited the cytoplasmic expression of RRE containing HIV-1 transcripts. HIV-based retroviral vectors containing either the antisense (-) or sense (+) RREs inhibited HIV replication in transient transfections. The production of full-length HIV mRNA was also decreased significantly by the expression of RREs in either orientation. Interestingly, there was a paradoxic increase in HIV p24 gag production at low levels of inhibitor; this effect may have been the result of encapsidation of RRE-containing HIV-based retroviral vectors. The data suggest that the introduction and inducible expression of RRE-containing, HIV-based retroviral vectors may have therapeutic value in HIV infection.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Summary:Human immunodeficiency virus type 1 (HIV-1) in plasma reflects the replicating virus population at any point in time in vivo. Studies of the relationship of the complete HIV-1 genome to pathogenesis therefore need to focus on plasma virions. Since dual infections and recombination can occur in vivo, cloning an intact plasma virus genome as a single full-length molecule is desirable. For these reasons, we developed an efficient method to clone full-length HIV-1 genomes directly from plasma viral RNA. This method used reverse transcription and long polymerase chain reaction (PCR) amplification. Virion-associated RNA was isolated from plasma samples and then reverse-transcribed to make cDNA for PCR amplification. Two different strategies were employed to amplify the full-length genome: one amplified a 9-kb fragment, and the other amplified two overlapping 5-kb fragments. Although both strategies were successful, the second was preferable for amplifying HIV-1 genomes from samples with low viral titers. By directly ligating the PCR-derived fragments into a phagemid vector, we constructed clones that comprised full-length HIV-1 RNA genomes. Using this technique, we have constructed hundreds of clones containing full-length HIV-1 genomes derived from the plasma of HIV-1-infected individuals, some of whom had low HIV-1 titers. Different HIV-1 molecular species were cloned from a single clinical sample, as demonstrated by restriction site polymorphism. This method provides a tool for studying complete HIV-1 genomes in relation to pathogenic processes.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Summary:In a clinical trial involving asymptomatic, HIV-seropositive subjects treated with either the HIV-1 immunogen (an inactivated, gp120-depleted HIV-1 virus in incomplete Freund's adjuvant) or an adjuvant control, we examined the relationship between changes in the percentage of CD4 cells over time and early clinical markers of HIV disease progression. Subjects who had an early clinical event were more likely to have a greater decline in the percentage of CD4 cells than those subjects who did not have a clinical event (p = 0.054). The greatest decline in CD4 percentage occurred within 10 weeks prior to a clinical event (mean 11% decrease from baseline). Subjects from the quartile with the greatest decline in CD4 percentage had a fivefold greater risk of having a clinical event than subjects from the quartile with the second largest decline (p = 0.045). These results demonstrate a relationship between changes in the percentage of CD4 cells and early clinical events. Further validation of this association may be useful in clinical monitoring and in evaluating therapies to treat HIV infection.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Summary:We performed a pilot study that examined the clinical and pharmacokinetic interactions between zidovudine (ZDV) and a pyridinone derivative, L-697-661. The results indicate that the drugs were well tolerated, with no important pharmacokinetic interactions, when administered concomitantly for as long as 8 weeks. Although the number of study participants was small, we noted rapid emergence of resistance to L-697,661 among ZDV-naive study subjects who were administered L-697,661 as monotherapy but did not observe isolates of human immunodeficiency virus type 1 (HIV-1) resistant to L-697,661 among those who were administered concomitant ZDV. These results suggest a potential interaction between development of resistance to L-697,661 and ZDV. Although the clinical development of L-697,661 has been halted, our results support the need for further studies to test whether specific interactions among antiretroviral agents administered in combination and the molecular target can delay the emergence of isolates that exhibit resistance to all drugs in the regimen.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Summary:Estimates of the lifetime cost of illnesses are needed for temporal and international comparisons and for assessment of the efficiency of prevention strategies. The goal of the present study was to estimate the average present value, at both the time of diagnosis and the time of seroconversion, of the lifetime cost of health care for HIV infection. Australian data on the monthly cost of HIV-related health care for homosexual men were linked with published data on disease progression using survival analysis methods. Future costs were discounted at 5% per annum. For a patient diagnosed when his CD4+count fell below 500 × 106/L, the average present value in 1992-1993 of lifetime cost was ≈$93,000, of which 49% was for drugs and 32% was for hospital bed-days. For a man infected in 1992-1993 and diagnosed when his CD4+count falls below 500 × 106/L, the average present value of lifetime cost at the time of seroconversion is ≈$70,000. These estimates are lower than the lifetime cost of $119,000 reported recently in the United States. However, when the U.S. figure was adjusted to make discounting of future costs consistent between the two studies, lifetime costs were ≈17% lower in the United States. The lower American costs appear to be due to lower rates of hospitalization and drug prescribing, possibly because of reduced access to health services, but underestimation of costs due to study methodology might also explain the difference.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Summary:To determine whether patient and hospital characteristics were significantly associated with variations inPneumocystis carinii(PCP) care and outcomes, we analyzed the use of diagnostic tests, intensive care units (ICUs), anti-PCP medications for persons hospitalized with human immunodeficiency virus (HIV)-related PCP, and hospital discharge status. We conducted retrospective chart reviews of a cohort of 2,174 patients with PCP hospitalized in 1987-1990. Outcomes included process of care for PCP and in-hospital mortality rates. Persons with PCP who were more severely ill at admission were more likely to have early medical care, to receive care in an intensive care unit, and to die in hospital. After we adjusted for differences in this severity of illness, we noted that Medicaid patients, injection drug users (IDUs), and patients treated at VA or county hospitals were significantly less likely than others to have diagnostic bronchoscopies and that persons covered by Medicaid, with a previous diagnosis of acquired immunodeficiency syndrome (AIDS), who did not receive prior zidovudine (AZT) or who received care in a VA hospital had the highest chances of in-hospital death. Insurance and risk group characteristics, severity of illness, and hospital characteristics appear to be the most important determinants of the intensity and timing of medical care and outcomes among patients hospitalized with PCP.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Summary:We wished to determine the short-term safety and efficacy of a Chinese medicinal herb preparation in treating symptoms of human immunodeficiency virus (HIV) infection in a 12-week randomized, double-blind, placebo-controlled clinical trial in a University-affiliated acquired immunodeficiency syndrome (AIDS) clinic at a public general hospital. Thirty adults with symptomatic HIV infection, no previous AIDS-defining diagnosis, and CD4+counts of 0.200 - 0.499 × 109/L (200-499/mm3) received 28 tablets each day of either a standardized oral preparation of 31 Chinese herbs or a cellulose placebo. Primary outcome measures were changes in life satisfaction, perceived health, and number and severity of symptoms. Other outcomes included adherence, and changes in weight, CD4+count, depression, anxiety, physical and social function, and mental health. Two placebo- and no herb-treated subjects had mild adverse events (AE). Subjects on both arms reported taking 94% of prescribed tablets. No differences between treatment groups reached the p < 0.05 level. Life satisfaction improved in herb-treated [+0.86, 95% confidence interval (CI): +0.29, +1.43] but not in placebo-treated subjects (+0.20, 95% CI -0.35, +0.75). Number of symptoms was reduced in subjects receiving herbs (-2.2, 95% CI -4.1, -0.3) but not in those receiving placebo (-0.3, 95% CI -3.2, +2.7). There were trends toward greater improvements among herb-treated subjects on all symptom subscales except dermatologic. Believing that one was receiving herbs was strongly associated with reporting that the treatment had helped (p < 0.005), but not with changes in life satisfaction or symptoms. There were improvements in life satisfaction and symptoms among subjects receiving the herbal therapy. Whether Chinese herbs are effective in the management of symptomatic HIV infection can be adequately addressed only by larger trials of longer duration.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID

摘要:

Summary:Data from a cohort of 62 HIV-positive individuals with hemophilia or von Willebrands disease infected for a maximum period of 15 years were analyzed. The relation between CD4+and total lymphocyte counts and their rate of decline was analyzed with respect to age at seroconversion, time of seroconversion, and development of disease and subsequent death. As expected, the CD4+and total lymphocyte population decline correlated with increased probability of disease and death. The patients fell into two distinct categories with respect to this decline: those whose cell count declined steadily (single slope) and those whose cell count remained steady or decreased very slowly for a variable period and then declined sharply (double slope). Within this cohort, the presence of a double slope appears to indicate a poorer prognosis, as 9 of 18 of the patients who have died showed this pattern, whereas only 6 of 42 of the remaining patients have this pattern even though more than half of this group have CD4+lymphocyte counts <0.2 × 109/L. In addition, the ratio of CD4+lymphocyte count to total lymphocyte count decreased with increasing cumulative frequency of the cumulative incidence of disease and death and the overall probability of death in this cohort was lower than expected, being 30% 12 years after seroconversion.

ISSN:1077-9450    

出版商:OVID    

年代:1996

数据来源: OVID