摘要:

SummaryIt is thought that monocyte-macrophages and probably dendritic cells play a central role in HIV-1 primary infection, as well as in its evolution, given that they are among the first cells infected and later function as important reservoirs for the virus. These cells may participate in the selection of certain viral strains instead of others. Levels of CCR5 coreceptor expression on the surface of monocytes and macrophages determine their susceptibility to infection by HIV-1 strains using this coreceptor and may explain, in part, the differences in the infectivity of these cells through the maturation process. However, selection for certain strains is not only determined by the level of coreceptor expression, but by the biochemical properties of the different coreceptors and their relationship with other surface molecules and the chemokine and cytokine networks, which also influence the selective viral infection and replication in these cells. Any current or newly designed therapies need to be evaluated, including careful analysis of the levels of HIV-1 infection of the cells of the monocyte-macrophage lineage, because these cells are both significant viral reservoirs and a center of virus production at all stages of the disease.

ISSN:1525-4135    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

SummaryProtease inhibitors used in combination with reverse transcriptase inhibitors have demonstrated potent anti-HIV-1 activity in vitro as well as in vivo. We evaluated interactions among five protease inhibitors: indinavir (IDV), ritonavir (RTV), saquinavir (SQV), amprenavir (APV), and nelfinavir (NFV), when used in combinations of two and three drugs in vitro against several HIV-1 isolates, including those susceptible and resistant to various nucleoside and nonnucleoside reverse transcriptase inhibitors. Interactions ranged from synergy to slight antagonism depending on the viral isolates and the experimental conditions employed. Further clinical evaluation of protease inhibitor combinations is warranted.

ISSN:1525-4135    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

SummaryPlasma HIV-1 RNA and CD4+T-cell counts after HIV-1 seroconversion are important independent markers that predict the clinical course of HIV-1 infection. The prognostic significance of these parameters during primary HIV-1 infection, however, remains largely unknown. In a cohort of 53 male study subjects (age, 33 ± 7 years), who consecutively presented with primary HIV-1 infection, we analyzed the relationship between early plasma HIV-1 RNA, CD4+and CD8+T-cell counts, &bgr;2-microglobulin, and p24-antigen levels determined in the first 3 months and subsequent plasma HIV-1 RNA levels and CD4+T-cell counts 6 to 12 months after onset of primary symptoms. Peak, nadir, and median HIV-1 RNA levels in the first 30 days were already significantly associated with HIV-1 RNA levels at 6 to 12 months (p= .02,p< .0001, andp= .01, respectively). Similarly, early nadir and median CD4+T-lymphocyte counts in the first 30 days showed a significant relationship with CD4+T-cell counts at 6 to 12 months (p= .009 andp= .0008, respectively). Study subjects with an early decline of CD4+counts to <500 cells/&mgr;l had an eightfold higher risk that CD4+counts were <500 cells/&mgr;l at 1 year. Of all evaluated virologic parameters, only nadir HIV-1 RNA at 76 days predicted CD4+counts at 6 to 12 months (p= .006). Early HIV-1 RNA levels and CD4+counts are already associated with the time course of those parameters 6 to 12 months after onset of symptoms. Nadir viral load was the strongest predictor of HIV-1 RNA levels as well as of CD4+counts at 6 to 12 months. An early decline of CD4+T lymphocytes may be a useful clinical prognostic marker for rapid disease progression.

ISSN:1525-4135    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

SummaryIt has been speculated that infection with HIV-1 may lead to a significant increase in turnover, and subsequent exhaustion, of immune repopulation. Given that telomeric DNA is lost on mitotic replication, telomere lengths can be used as an indirect gauge of this rate. We have analyzed the mean telomere restriction fragment lengths in peripheral blood mononuclear cells (PBMC) from 31 patients with established, though mainly untreated, HIV infection and found them to be no different than those among healthy controls. Our results are in line with several findings in CD4+cell fractions but contradict a previous report suggesting that telomere shortening contributes to immune failure. Interestingly, after approximately 2 years of subsequent aggressive antiretroviral treatment we found a telomere reduction corresponding to a loss of about 250 base pairs per year; this is roughly tenfold above that predicted from healthy individuals. This could partly result from nucleoside analogue inhibition of the natural telomere replacement enzyme, telomerase—a reverse transcriptase inducible in certain hematopoietic cells. However, this may also indicate accelerated cell replacement on initiation of optimal therapeutic regimes or result from changes in the composition of the PBMC pool. These results suggest careful monitoring of telomere lengths during long-term HAART.

ISSN:1525-4135    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

SummaryTolerability, activity, and pharmacokinetic parameters of a combination therapy with efavirenz (EFV), nelfinavir (NFV), and stavudine (d4T) were evaluated in this study. Forty-seven HIV-1–infected study subjects, naive to NFV and nonnucleoside reverse transcriptase inhibitors (NNRTIs), who had experienced virologic failure while being treated with combination antiretroviral therapies including protease inhibitors (PIs), were enrolled. At baseline, HIV-1 viral load in plasma was 4.8 log10, CD4+count was 204 cells/&mgr;l (both mean values); patients had received a mean of 3.1 different treatments (range, 2–5 treatments). Study medications were generally well tolerated; 7 of 47 patients (14.8%) were dropped from the study because of related drug toxicity. At week 24, mean plasma viral load (pVL) was reduced by 1.9 log10, with mean CD4+count increased to 324 cells/&mgr;l (±59% from baseline); pVL was below the limit of detection (500 copies/ml) in 46.1% of patients. An extended follow-up study was performed at 12 months. Results showed a reduction of 1.7 log10in pVL from basal values that was consistent with values observed at months 3 and 6. A history of previous use of PIs represented a negative prognostic marker. Sequencing analysis, performed in a subset of patients, showed the presence of multiple point mutations associated with PI resistance. Pharmacokinetic analysis demonstrated a marked interindividual variability in NFV plasma concentrations, producing in 4 of 18 patients (22%) trough concentrations lower than minimum effective concentration. In pretreated patients, further studies are needed to characterize the pharmacokinetic factors that affect response to therapy and the association of these results with the 95% inhibitory concentration (IC95) determined by phenotyping.

ISSN:1525-4135    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

ObjectiveTo assess rates of prescriptions of protease inhibitors (PI) and determinants of not being prescribed PIs in a cohort of HIV-infected people eligible (according to published guidelines) for highly active antiretroviral therapy (HAART).DesignCross-sectional survey.MethodsA total of 684 patients with CD4+counts <500 cells/&mgr;l were enrolled from seven Italian HIV treatment centers from October 1997 to April 1998. A questionnaire on health-related quality of life (MOS-HIV) and patient ratings of the quality of care was administered. Sociodemographic variables, HIV disease-related factors, and prescribed antiretroviral therapy were also recorded.Results61% of those enrolled were prescribed PI (median, 7.5 months). In addition, 75% of patients had previously received antiretroviral therapy. Fewer than 1% were prescribed nonnucleoside reverse transcriptase inhibitors (NNRTIs). Using multivariable logistic regression considering those with CD4+counts <500 cells/&mgr;l, patients reporting the least information received (odds ratio [OR], 1.78; 95% confidence interval [CI], 1.23–2.58), injecting drug users (IDUs; OR, 1.73; 95% CI, 1.18–2.54), people with CD4+counts >200 cells/&mgr;l (OR, 1.76; 95% CI, 1.19–2.61), and patients with early stage disease (OR, 2.24; 95% CI, 1.73–2.90) were less likely to have be prescribed PIs.ConclusionsOf patients eligible for HAART, only 61% were prescribed PIs. People who wanted more information, IDUs, and patients in earlier disease stages are significantly less likely to be prescribed PIs. Access to HAART remains a critical issue in the management of HIV disease.

ISSN:1525-4135    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

SummaryV3 loop peptide sequences from several HIV-1 strains were covalently linked to purified protein derivative (PPD) ofMycobacterium tuberculosis. A mixture of PPD conjugates of V3 loop peptides from six different strains of HIV-1 induced a stronger antibody response than a single V3 peptide-conjugate administered to guinea pigs and humans. Sera from animals immunized with a PPD–six peptide–PPD conjugate neutralized multiple primary-isolate strains of HIV-1. Potent immune responses were noted only when animals were primed with bacillus Calmette-Guérin (BCG), PPD was covalently bound to the peptides, and PPD was used as the carrier protein. Based on these animal studies, an immunogen consisting of PPD-conjugated V3 loop peptides from five HIV-1 strains was tested in 7 HIV-1 seropositive PPD skin test–positive study subjects. Vaccinees exhibited over time a uniform increase in neutralizing antibodies for both laboratory adapted and primary isolates of HIV-1, including strains from multiple clades. In 3 patients with baseline viral loads between 8000 and 12,000 RNA copies/ml, the viral load declined in 2 patients to <400 copies/ml and in 1 patient to 1200 copies/ml without concurrent administration of highly active antiretroviral therapy (HAART).

ISSN:1525-4135    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

SummaryIn the United States, the nucleoside analogue drug 3´-azido-3´-deoxythymidine (AZT; also called zidovudine or ZDV) is given to most pregnant women who produce a positive test result for HIV-1. To investigate transplacental distribution and genotoxicity of AZT, near-term pregnant rhesus (Macaca mulatta) monkeys and their fetuses were studied. Four pregnant monkeys were continuously infused with 8 mg AZT/kg body weight for the 4 hours just prior to hysterotomy at term. This short-term AZT exposure resulted in AZT incorporation into DNA of fetal liver, lung, heart, skeletal muscle, brain, testis, and placenta, which varied between 29 and 1944 molecules of AZT/106nucleotides. In contrast, values for AZT and combined metabolites, determined by radioactivity, varied between 0.94 and 5.20 &mgr;g AZT equivalents/g tissue. A fifth animal, (H076), was infused with 17.3 mg AZT/kg body weight for ∼3 hours, followed by 1 hour without drug before hysterotomy. Similar to the 4 other monkeys, variable levels of AZT (16–147 molecules of AZT/106nucleotides) were incorporated into organ DNA of H076, whereas organ tissues contained less-variable levels of AZT and metabolites (0.86–2.05 &mgr;g AZT equivalents/g tissue). For H076, at hysterotomy 1 hour after discontinuation of drug, values for AZT and the 3´-azido-3´-deoxythymidine-&bgr;-D-glucuronide (AZTG) in fetal blood and amniotic fluid were twofold and threefold higher than those in maternal blood. Most AZT pharmacokinetic parameters in the fifth monkey were similar to those previously reported for the first 4 monkeys and those observed in a similar study of pregnant women. These data show that a short-term AZT infusion in pregnant rhesus monkeys, which have similar AZT pharmacokinetics to those present in a pregnant human, results in incorporation of drug into the DNA of placenta and most fetal organs. Data imply that the human fetus may also be subject to incorporation of AZT into DNA even after short-term AZT infusion to the mother just before delivery.

ISSN:1525-4135    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

SummaryTimely estimates of HIV incidence are needed to monitor the epidemic and target primary prevention but have been difficult to obtain. We applied a sensitive/less-sensitive (S/LS) enzyme immunoassay (EIA) testing strategy to stored HIV-positive sera (N= 452) to identify early infections, estimate incidence, and characterize correlates of recent seroconversion among persons seeking anonymous HIV testing in San Francisco from 1996 to 1998 (N= 21,292). Sera positive on a sensitive EIA but negative on a less-sensitive EIA were classified as early HIV infections; sera positive on both EIA were classified as long standing. Seventy-nine sera were from people with early HIV infection. Estimated HIV incidence was 1.1% per year (95% confidence interval [CI], 0.68%–1.6%) overall and 1.9% per year (95% CI, 1.2%–3.0%) among men who have sex with men (MSM). Early HIV infection among MSM was associated with injection drug use, unprotected receptive anal sex, and multiple sex partners in the previous year. No temporal trend in HIV incidence was noted over the study period. The S/LS strategy provides a practical public health tool to identify early HIV infection and estimate HIV incidence in a variety of study designs and settings.

ISSN:1525-4135    

出版商:OVID    

年代:1999

数据来源: OVID

摘要:

SummaryNo recent population-based data on HIV testing in people with high-risk sexual behavior are available. We sought predictors of testing using data from the 1997 Los Angeles County Health Survey, a random-digit telephone survey of 8004 county households. An estimated 2.3 million (35.5%) adults were tested for HIV in the past 2 years and approximately 370,000 (5.6%) engaged in high-risk sexual behavior (defined as having ≥2 partners in the past 12 months and not always using condoms). Among high-risk persons, an estimated 46% of heterosexual men, 56% of heterosexual women, and 72% of men who had sex with men (MSM) were tested for HIV. In a multivariable model of high-risk people, both heterosexual men (odds ratio [OR], 0.31; 95% confidence interval [CI], 0.16–0.61) and women (OR, 0.41; 95% CI, 0.19–0.87) had significantly lower proportions of testing than MSM. Although African Americans and Hispanics had significantly higher testing proportions than whites overall among all county residents, those reporting high-risk sexual behavior did not test at higher proportions. We conclude that the proportion of adults with high-risk sexual behavior tested for HIV is higher than almost a decade ago. However, testing among this group remains suboptimal. Future public health campaigns should intensify efforts to encourage HIV testing among this population.

ISSN:1525-4135    

出版商:OVID    

年代:1999

数据来源: OVID