摘要:

Summary:Neutralizing antibodies and specific cytotoxic T lymphocytes (CTL) may contribute to controlling viral spread, and ideally, to virus clearance in HIV infection. Both effector mechanisms depend on specific CD4 T-helper (Th) cells. Nevertheless, HIV hypervariability facilitates appearance of escape mutants for antibodies and for CTL responses. Here we also show that natural mutations (i.e., from sequences of different HIV strains) in an immunodominant Th epitope recognized by human CD4 clones specific for the envelope glycoprotein gp120 escape CD4 T-cell recognition. Furthermore, several natural analogue peptides exert an antagonistic function by inhibiting proliferative response of T cells specific to gp120 with a wild-type sequence. If similar events occur in vivo, they may represent an additional escape mechanism for HIV. In fact, antagonism for CD4 Th response may occur during superinfection with a different strain, or with the appearance of a variant carrying a mutated antagonistic sequence. In both cases, impaired Th cell function could lead to reduced immune control of HIV infection by interfering with CTL and antibody response.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Summary:Although direct feline immunodeficiency virus (FIV) proviral DNA inoculation has been shown to be infectious in cats, long-term studies to assess the pathogenic nature of DNA inoculation are lacking. We have recently reported that direct feline leukemia virus (FeLV) DNA inoculation resulted in infection and the development of FeLV-related disease end points with similar temporal expression and virulence to that of cats infected with whole virus. We show in this study that pFIV-PPR DNA inoculation resulted in infection of cats and the development of FIV-related immunologic and neurologic abnormalities. Infected cats demonstrated progressive loss of CD4+lymphocytes resulting in decreased CD4:CD8 ratios. Neurologic dysfunction was demonstrated by increased bilateral frontal lobe slow-wave activity. Prolongation of the visual evoked potential peak latency onset response pattern also supported a similar progression of abnormal cortical response. Furthermore, histopathologic examination revealed lesions attributed to FIV infection in lymph node, thymus, brain, and lung. Finally, nested polymerase chain reaction detected FIV provirus in brain, bone marrow, mesenteric lymph node, thymus, spleen, tonsil, and liver. These results confirm that FIV DNA inoculation is an efficient model for study of the pathogenic nature of molecular clones in vivo and offers the opportunity to measure temporal genomic stability of a homogeneous challenge material.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Summary:To assess the effects of early initiation of antiretroviral therapy on cell-free and cell-associated viral load in blood and lymphoid tissue, we performed a randomized, open-label, multicenter trial comparing a double (zidovudine + lamivudine) and triple (zidovudine + lamivudine + ritonavir) drug combination in treatment-naive, asymptomatic patients with CD4 counts >400 cells/&mgr;l. HIV-1 RNA was measured in plasma, peripheral blood mononuclear cells, and sequential tonsil or lymph node biopsies (27 patients); the study follow-up was 2 years. Among 42 randomized patients, the proportion with plasma HIV-1 RNA <50 copies/ml was 16% and 74% at week 24 (p< .001) in those randomized to double and triple therapy, respectively, necessitating frequent treatment intensification in the double arm. After a rapid decline within 4 weeks in both arms, cell-associated HIV-1 RNA decreased further only in those patients with sustained suppression of plasma viral load, but remained almost always detectable at low levels, indicating persisting transcription of viral RNA. CD4 counts increased by 200 to 250 cells/&mgr;l at week 96 in both arms without significant differences (intent-to-treat analyses). Thus, even if treatment is initiated early in asymptomatic patients with preserved CD4 counts, three drugs are necessary to achieve sustained decreases of HIV load in blood and lymphoid tissue.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Summary:Presence of mutations associated with resistance to zidovudine or lamivudine was determined in isolates of HIV-1 obtained after long-term follow-up of 64 infected individuals who received zidovudine, lamivudine, or both drugs as initial antiretroviral therapy. Zidovudine resistance mutations were less frequent in isolates from patients treated with combination lamivudine plus zidovudine compared with zidovudine alone, but these mutations accumulated over time. Phenotypic resistance to both drugs was found in isolates from 3 of 23 patients. In 3 other patients, lamivudine-resistant virus detected at week 12 was replaced by wild-type virus after longer follow-up, which correlated with a return to baseline levels of plasma HIV-1 RNA. These results show that dual resistance to zidovudine and lamivudine develops over time despite the delayed emergence of zidovudine-resistant mutations. These results also suggest a selective advantage in vivo for HIV-1 species that are wild-type at RT codon 184.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Summary:Although protease inhibitor (PI) therapy has improved the clinical status of patients with HIV infection, concerns have arisen that such treatment may have deleterious effects on glucose control, lipid metabolism, and body fat distribution. To determine whether initiation of PI therapy uniquely affects glucose and lipid metabolism, we analyzed paired data in HIV-infected patients before and after beginning antiretroviral therapy that included a PI (PI;N= 20) or lamivudine (3TC) but no PI (3TC;N= 9); and a control group on stable regimens that included neither of these agents (CONT;N= 12). Measurements included fasting glucose; insulin; triglycerides; total, high-density lipoprotein (HDL) and low-density lipoprotein (LDL) cholesterol; HIV RNA; CD4+lymphocytes; weight; and total and regional body composition. Neither weight nor total or regional fat content changed significantly in any group during the period of observation. Nonetheless, in patients beginning PI therapy, there were significant increases in glucose (+9 ± 3 mg/dl;p= .0136), insulin (+12.2 ± 4.9 U/ml;p= .023), triglycerides (+53 ± 17 mg/dl;p= .0069), and total and LDL cholesterol (+32 ± 11 and +18 ± 5 mg/dl;p= .0082 and .0026, respectively). None of these parameters changed significantly in the 3TC or CONT groups. The PI and 3TC groups experienced comparable increases in CD4+lymphocytes, suggesting that the observed metabolic effects may be associated with PIs uniquely, rather than improvement in clinical status. However, it is also possible that the metabolic effects of PIs are associated with more effective viral suppression, because a greater proportion of patients in the PI group achieved undetectable levels of virus. We conclude that changes in glucose and lipid metabolism are induced by PI therapy in the absence of significant changes in weight or fat distribution. Longer periods of follow-up will be required to determine the clinical significance of these changes. However, at the moment, the risks associated with these metabolic effects do not appear to outweigh improvements in survival seen with PI therapy.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Objective:The aim of the study was to compare accepted surrogate markers of HIV disease progression with markers of lymphocyte apoptosis in their ability to predict short-term disease progression.Methods:In all, 40 HIV-positive patients were studied prospectively and observed during follow-up for HIV-related adverse clinical events. Ex vivo apoptosis was measured with the markers CD95 expression, annexin V binding, and Apostain dye uptake by flow cytometry at baseline. Established markers of disease progression (CD4 count, HIV-RNA level, and CD8/38 count), CD8, B-cell, and natural killer (NK) cell counts were determined by standard procedures at baseline and after 6 months.Results:In HIV-infected patients, CD95 expression and annexin V binding showed significantly elevated apoptosis in peripheral blood lymphocytes and all lymphocyte subsets at baseline compared with HIV-negative, healthy controls. Apostain failed to differentiate between HIV-infected patients and healthy controls. HIV-related complications could be predicted by CD4 and CD8/38 counts, but not HIV viral load as assessed by relative operating characteristic (ROC) analysis (CD4,p= .003; CD8/38,p= .031). A similar or even better diagnostic accuracy was found for CD95 expression in total lymphocytes (p< .001), the CD4+(p= .003) and CD8+(p= .005) T-cell subsets and for annexin V binding in CD4+T cells (p= .005). When patients with CD4 counts <200 cells/&mgr;l were analyzed separately, only annexin V binding in CD4+T cells, but none of the other prognostic markers could predict complications (p= .001).Conclusion:Determination of annexin V binding on CD4+T cells may be a useful tool to monitor HIV-infected patients with low (<200 cells/&mgr;l) CD4 counts, as it can reliably assess the risk for imminent complications in such patients.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Summary:The effects of chemokine and chemokine receptor genetic polymorphisms such as stromal derived factor 1 (SDF1-3´A), CCR2-64I, and CCR5-&Dgr;32 associated with HIV-1 transmission and/or rate of disease progression in infected study subjects remain highly controversial and have been analyzed primarily only in adults. We have investigated whether these polymorphisms may provide similar beneficial effects in children exposed to HIV-1 perinatally. The prevalence of CCR2-64I allele was significantly increased (p= .03) and the CCR2-64I genotype distribution was not in Hardy-Weinberg equilibrium, among HIV-1–exposed uninfected infants. Moreover, in the HIV-1–infected group, a delay to AIDS progression was observed among carriers of CCR2-64I allele. This is the first report that suggests a protective role of CCR2-64I allele in mother-to-infant HIV-1 transmission and documents a delay in disease progression, after the child has been infected with HIV-1. However, SDF1-3´A and CCR5-&Dgr;32 alleles did not modify the rate of HIV-1 transmission or disease progression in HIV-1–infected children.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Objectives:To study the molecular epidemiology of HIV-1 strains found in Switzerland and to determine possible genetic linkages among strains sorted by risk group or geographic region.Design:A cross-sectional, clinic-based survey of HIV-1 molecular sequences and linked patient history from Swiss people.Methods:Specimens were collected from 215 HIV-1–infected people in HIV outpatient clinics of four tertiary referral centers (Lausanne, St. Gallen, Zurich, and Basel) between May and August 1996, mainly from homosexual men, injecting drug users (IDU), and heterosexually infected people. In addition, specimens collected between 1991 and 1995 in the HIV outpatient clinic at University of Geneva were included into this survey. These specimens were collected primarily for an ongoing, prospective cohort (Swiss HIV Cohort Study). Direct C2V3C3 sequences of theenvgene were determined from 158 samples of peripheral blood mononuclear cells. Genetic data were analyzed with the available patient history on each specimen.Results:As found in other previous studies in Europe, primarily subtype B viruses were identified, whereas seven (4%) of 158 were non-subtype B: one subtype D, four subtype A, and two subtype E. Five of seven non-B subtypes occurred in immigrants from African or Asian countries and all seven were found exclusively in individuals who had been infected by heterosexual contact. No significant clustering of strains within different study sites or risk groups was found. A silent mutation (LAI env 834) occurred significantly more often in IDU than in homosexual men (p< .001).Conclusions:Although the lack of significant clustering of strains by risk group or geographic region may result from early introduction of subtype B viruses in Switzerland, the strong association of a silent mutation with IDU suggests that, early in the epidemic, there was a unique founder virus among IDUs. The HIV epidemic in Switzerland is still predominantly caused by subtype B viruses.GenBank Accession Numbers:AF181288–AF181445.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Summary:To characterize the viruses responsible for the HIV-1 epidemic in Spain, we genetically characterized 79 samples obtained from Spanish patients with different risk practices (injecting drug users and male homosexuals) in two regions (Madrid and Navarra). Genetic characterization was carried out by nucleotide sequencing in the C2-V3-C3 region and by phylogenetic analysis. All samples were of subtype B except one that clustered with clade F. Because no segregation of samples was determined according to the risk group of patients nor to their geographic origin, the Spanish samples analyzed constitute a single group of viruses. These data, along with the starlike topology of the phylogenetic tree, support the existence of a single introduction of HIV-1 subtype B in Spain. The mean genetic distance among subtype B sequences was of 13.9% ± 0.06% (range, 5%–25%), suggesting an epidemic of long evolution. Analysis of sequences in relation to isolation dates revealed an increase in the heterogeneity of the nucleotide sequences with time. According to these data, a divergence rate of 0.49% ± 0.11% per year was calculated for the Spanish samples during the period analyzed.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID

摘要:

Objective:To estimate the incidence rate of tuberculosis in HIV-1–infected adults resident in a region with a high tuberculosis prevalence and to identify clinical and laboratory parameters associated with increased risk of developing tuberculosis.Methods:Adult patients going to the University of Cape Town HIV clinics between January 1986 and May 1996. The following variables were assessed for the risk of developing tuberculosis: ethnicity, employment and education status, World Health Organization (WHO) clinical stage, erythrocyte sedimentation rate (ESR), CD4+count, and total lymphocyte count. Tuberculin skin test data were not available.Results:There were 198 prevalent and 144 incident cases of tuberculosis in the cohort of 1206 patients. The incidence rate of tuberculosis risk was 10.4/100 person years. WHO clinical stages 3 and 4 (risk ratio [RR], 3.4; 95% confidence interval [CI], 1.8–6.4), ESR >75 mm/hour (RR, 3.5; CI, 1.8–6.5) and being a member of a high-prevalence tuberculosis community (RR, 2.5; CI, 1.2–5.1) were independently associated with the risk of developing tuberculosis.Conclusions:HIV-infected adults in Cape Town are at high risk of developing tuberculosis irrespective of tuberculin skin testing. The risk increases markedly with HIV disease progression. Patients at extremely high risk can be identified on the basis of demographic and clinical features. Such individuals would be suitable for targeted tuberculosis prophylaxis.

ISSN:1525-4135    

出版商:OVID    

年代:2000

数据来源: OVID