Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy.
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BACKGROUND AND METHODS: Although potent antiretroviral therapy can control infection with human immunodeficiency virus type 1 (HIV-1), a long-lived reservoir of infectious virus persists in CD4+ T cells. We investigated this viral reservoir by measuring the levels of cell-associated viral DNA and messenger RNA (mRNA) that are essential for HIV-1 replication. Approximately every 6 months, we obtained samples of peripheral-blood mononuclear cells from five men with long-standing HIV-1 infection who had had undetectable levels of plasma HIV-1 RNA for 20 months or more during treatment with potent antiretroviral drugs. RESULTS: Before treatment, plasma levels of HIV-1 RNA correlated with the levels of cell-associated unintegrated HIV-1 DNA and unspliced viral mRNA. After treatment, plasma levels of HIV-1 RNA fell by more than 2.7 log to undetectable levels. The decrease in cell-associated integrated and unintegrated HIV-1 DNA and mRNA occurred in two phases. The first phase occurred during the initial 500 days of treatment and was characterized by substantial decreases in the levels of DNA and mRNA, but not to undetectable levels. The concentrations of cell-associated unintegrated viral DNA, integrated proviral DNA, and unspliced viral mRNA decreased by 1.25 to 1.46 log. The second phase occurred during the subsequent 300 days or more of treatment and was characterized by a plateau in the levels of HIV-1 DNA and unspliced mRNA. After an initial rapid decline, the ratio of unspliced to multiply spliced viral mRNA (a measure of active viral transcription) stabilized and remained greater than zero at each measurement. CONCLUSIONS: Despite treatment with potent antiretroviral drugs and the suppression of plasma HIV-1 RNA to undetectable levels for 20 months or more, HIV-1 transcription persists in peripheral-blood mononuclear cells. Unless the quasi-steady state levels of HIV DNA and mRNA eventually disappear with longer periods of therapy, these findings suggest that HIV-1 infection cannot be eradicated with current treatments. (+info)
Distribution of 14 high risk HPV types in cervical intraepithelial neoplasia detected by a non-radioactive general primer PCR mediated enzyme immunoassay.
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AIM: To evaluate the presence of high risk human papillomaviruses (HPV) in cervical smears showing intraepithelial neoplasia (CIN). METHODS: The presence of 14 high risk HPV was evaluated in 114 cervical smears with CIN of different degrees, by comparing a non-radioactive polymerase chain reaction (PCR) enzyme immunoassay (EIA) with conventional PCR followed by radioactive Southern blot hybridisation. General primer PCR amplicons detecting low risk and high risk HPV were typed for 14 different high risk HPV types (HPV 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68) by a non-radioactive PCR-EIA. Virus load of HPV 16 positive CIN was assessed using the semiquantitative PCR-EIA. RESULTS: Histological evaluation confirmed CIN I in 49 cases (mean age 29.0 years, range 17 to 52), CIN II in 31 cases (mean age 30.8 years, 18 to 54), and CIN III in 34 cases (mean age 31.1 years, 16 to 57). The non-radioactive PCR-EIA showed an overall agreement rate of 90% (kappa value 0.75) when compared with conventional general primer PCR followed by radioactive Southern blot hybridisation. High risk HPVs were detected in 47% of CIN I, 77% of CIN II, and 97% of CIN III (p < or = 0.02). HPV types 39, 51, 56, and 58 were found in CIN I exclusively (between 2% and 8%). HPV 16 and HPV 31 were detected in 12% and 2% of CIN I, 35% and 21% of CIN II, and 74% and 13% of CIN III, respectively (p < or = 0.03 and p < or = 0.04). The virus load estimated by the semiquantitative PCR-EIA of HPV 16 was similar in CIN I, CIN II, and CIN III. CONCLUSIONS: The PCR-EIA has high clinical sensitivity for detecting CIN II/III (90%). There was a significantly higher prevalence rate of HPV 16 and 31 in CIN III than in CIN I and II. (+info)
A novel animal model for hemangiomas: inhibition of hemangioma development by the angiogenesis inhibitor TNP-470.
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Hemangiomas represent the most frequent tumors of infancy. However, the pathogenesis of these tumors is still largely unknown, and current treatment of juvenile hemangiomas remains unsatisfactory. Here we present a novel animal model to study proliferating hemangiomas and to evaluate the effect of angiostatic compounds on their growth. Intraperitoneal (i.p.) infection of 4-day-old rats with murine polyomavirus resulted in the development of multiple cutaneous, intramuscular (i.m.), and cerebral hemangiomas with 100% frequency. Histological examination of the brain revealed the formation of immature lesions as soon as 4 days postinfection (p.i.). The subsequent exponential growth of the hemangiomas, both in number and size, was associated with severe hemorrhage and anemia. The cerebral, cutaneous, and i.m. lesions consisted of blood-filled cysts, histologically similar to human cavernous hemangiomas and stained positive for proliferating cell nuclear antigen, urokinase-type plasminogen activator, and vascular endothelial growth factor. Mature cerebral hemangiomas also expressed von Willebrand factor. Cerebral lesions caused death of the untreated animals within 19.2 +/- 1.1 days p.i. Remarkably fewer and smaller hemangiomas developed in animals that had been treated s.c. with the angiogenesis inhibitor TNP-470. Accordingly, TNP-470 (50 mg/kg), administered twice a week from 3 days p.i., significantly delayed tumor-associated mortality [mean day of death, 28.2 +/- 3.3 (P < 0.001)]. Even if therapy was initiated when cerebral hemangiomas were already macroscopically visible (i.e., 9 days p.i.), a significant delay in hemangioma-associated mortality was observed. Also, the IFN-inducer polyinosinic-polycytidylic acid caused a delay of 9 days (P < 0.005) in tumor-associated mortality when administered i.p. at 5 mg/kg, twice a week, starting at day 3 p.i. The model described here may be useful for investigating (a) the angiogenic mechanism(s) underlying hemangioma progression; and (b) the effect of anti-angiogenic compounds on vascular tumor growth. (+info)
HPV testing in the evaluation of the minimally abnormal Papanicolaou smear.
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Minor cytologic abnormalities of the cervix, such as atypical squamous cells of undetermined significance (ASCUS), are vastly more common than high-grade squamous intraepithelial lesions or invasive cancer. Current guidelines for the management of ASCUS include repeating the Papanicolaou (Pap) smear at specific intervals, referring all patients for colposcopy or using an adjunctive test such as hybrid capture human papillomavirus (HPV) testing or cervicography. The usefulness of the Pap smear is limited by its considerable false-negative rate and its dependence on clinician and laboratory performance. Colposcopy is a highly sensitive procedure, but many patients with ASCUS have normal colposcopic findings. The hybrid capture test not only measures quantitative HPV load but also detects both oncogenic and nononcogenic HPV types, thereby increasing the probability that serious cervical disease is not missed. Hybrid capture sampling is simple to perform, and positive results are strongly associated with cervical dysplasia. HPV testing in women with ASCUS can be used as an adjunctive test to identify those with HPV-associated disease; it can also serve as a quality assurance measure. Together, repeat Pap smears and HPV testing should identify most patients with underlying cervical dysplasia. Combined testing may also minimize the number of unnecessary colposcopic examinations in women who have no disease. (+info)
Immunologic and virologic status after 14 to 18 years of infection with an attenuated strain of HIV-1. A report from the Sydney Blood Bank Cohort.
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BACKGROUND AND METHODS: The Sydney Blood Bank Cohort consists of a blood donor and eight transfusion recipients who were infected before 1985 with a strain of human immunodeficiency virus type 1 (HIV-1) with a deletion in the region in which the nef gene and the long terminal repeat overlap. Two recipients have died since 1994, at 77 and 83 years of age, of causes unrelated to HIV infection; one other recipient, who had systemic lupus erythematosus, died in 1987 at 22 years of age of causes possibly related to HIV. We present longitudinal immunologic and virologic data on the six surviving members and one deceased member of this cohort through September 30, 1998. RESULTS: The five surviving recipients remain asymptomatic 14 to 18 years after HIV-1 infection without any antiretroviral therapy; however, the donor commenced therapy in February 1999. In three recipients plasma concentrations of HIV-1 RNA are undetectable (<200 copies per milliliter), and in two of these three the CD4 lymphocyte counts have declined by 9 and 30 cells per cubic millimeter per year (P=0.3 and P=0.5, respectively). The donor and two other recipients have median plasma concentrations of HIV-1 RNA of 645 to 2850 copies per milliliter; the concentration has increased in the donor (P<0.001). The CD4 lymphocyte counts in these three cohort members have declined by 16 to 73 cells per cubic millimeter per year (P<0.001). In the recipient who died after 12 years of infection, the median plasma concentration of HIV-1 RNA was 1400 copies per milliliter, with a decline in CD4 lymphocyte counts of 17 cells per cubic millimeter per year (P=0.2). CONCLUSIONS: After prolonged infection with this attenuated strain of HIV-1, there is evidence of immunologic damage in three of the four subjects with detectable plasma HIV-1 RNA. The CD4 lymphocyte counts appear to be stable in the three subjects in whom plasma HIV-1 RNA remains undetectable. (+info)
Efficacy of low-dose subcutaneous interleukin-2 to treat advanced human immunodeficiency virus type 1 in persons with The immunologic efficacy of low-dose recombinant interleukin-2 (rIL-2) administered subcutaneously (sc) once a day in combination with highly active antiretroviral therapy (HAART) was assessed in a pilot study in patients with advanced human immunodeficiency virus (HIV) disease. Twenty-five persons with 24 weeks were randomly assigned to receive sc rIL-2 (3 x 10(6) IU once a day) with their previous antiretroviral regimen (n=13) or to continue with the same treatment (n=12). The level of CD4 T cells was significantly higher in the IL-2 group at week 24 (105+/-65/microL; P<.05) but not in the control group (30+/-78/microL). Memory T cells initially contributed to the CD4 T cell increase at week 4 (P<.05). Naive T cell increases (99+/-58/microL) in the IL-2 group became statistically significant at week 24 compared with the control group (28+/-27/microL; P<.05). Subcutaneous rIL-2 once a day in combination with HAART was well tolerated and improved immunologic surface markers in patients with advanced HIV infection. (+info)
CD8+ anti-human immunodeficiency virus suppressor activity (CASA) in response to antiretroviral therapy: loss of CASA is associated with loss of viremia.
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CD8+ anti-human immunodeficiency virus (HIV) suppressor activity (CASA) defines the noncytolytic suppression of HIV mediated by secreted soluble factors. Changes in CASA in patients receiving combination antiretroviral therapy have not been described. Thirty-two HIV-infected patients receiving mono- or dual therapy for 52 weeks followed by highly active antiretroviral therapy (HAART) for a further 52 weeks were analyzed. T cell number and functional subsets, cutaneous delayed-type hypersensitivity, and plasma HIV RNA were assessed in 17 patients for CASA. Prior to therapy, CASA correlated inversely with HIV RNA (P<.001). Dual therapy yielded greater and more sustained changes in CASA than monotherapy, but HAART decreased CASA to levels observed in HIV-uninfected individuals. The magnitude of HIV RNA suppression correlated significantly with a decrease in activated CD8+ T lymphocytes (CD38+HLA-DR+), increases in naive CD4+ T lymphocytes (CD45RA+62L+), and increases in the delayed-type hypersensitivity score. However, changes in CASA did not correlate with changes in any T lymphocyte subset. CASA increases with improving immune function but appears more dependent on ongoing HIV replication. (+info)
Human immunodeficiency virus load in breast milk, mastitis, and mother-to-child transmission of human immunodeficiency virus type 1.
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Human immunodeficiency virus (HIV) type 1 load in breast milk and mastitis were examined as risk factors for vertical transmission of HIV-1. Six weeks after delivery, HIV-1 load and sodium (an indicator of mastitis) were measured in breast milk from 334 HIV-1-infected women in Malawi. Median breast milk HIV-1 load was 700 copies/mL among women with HIV-1-infected infants versus undetectable (<200 copies/mL) among those with uninfected infants, respectively (P<. 0001). Elevated breast milk sodium levels consistent with mastitis occurred in 16.4% of HIV-1-infected women and were associated with increased vertical transmission of HIV-1 (P<.0001). Median breast milk HIV-1 load was 920 copies/mL among women with versus undetectable among those without elevated breast milk sodium levels, respectively (P<.0001). Mastitis and breast milk HIV-1 load may increase the risk of vertical transmission of HIV-1 through breast-feeding. (+info)