Biomedical subjects
A Del Mistro
Publications and source records attributed to A Del Mistro.
Properties of tumors arising in SCID mice injected with PBMC from EBV-positive donors.
Groups of SCID mice were injected with different PBMC sub-populations, and established LCL cells. In about 80% of PBMC-injected animals, tumors developed in association with high levels of human Ig in mouse serum and detectable IL-6 levels. The tumors showed a histopathologic pattern reminiscent of large cell immunoblastic non-Hodgkin's lymphoma; in situ hybridization invariably evidenced EBV sequences in a minority of cells. Genotypic analysis of tumors arising in PBMC-injected mice showed the presence of different oligoclonal B cell populations in different tumor sites. Southern blot analysis disclosed the presence of both linear (replicating) and episomal (latent) EBV DNA forms; sequential analysis of LCL cells serially passaged into animals revealed the progressive selection of clonal cells with only the latent episomal form. Attempts to dissect the events underlying tumor development revealed that the presence of T cells within the injected population was essential for tumor generation; however, the putative T cell-derived factors involved are unclear, and IL-6 seems to play a minor role.
Human papillomavirus infections of the genital region in human immunodeficiency virus seropositive women: integration of type 16 correlates with rapid progression.
The efficacy of treatment of HPV infections was evaluated in 14 HIV-1 seropositive women. Disease evolution was evaluated at follow-up examinations, and findings were compared to those in 14 historic HIV-negative women who had received similar treatment. HPV sequences were demonstrated by Southern blot in 13/14 HIV-positive women and by in situ hybridization in 5/13 HIV-negative women. Types 6/11, 16, and 31/33/35 were equally distributed in both groups; type 18 was never detected. In all but one case, the same viral type was present in different lesions, and in recurrences. Among the HIV-positive women, integration of viral sequences had occurred in the dysplastic lesions in 2 of the 3 HPV-16-positive cases; both cases showed progression to carcinoma in situ within 1 to 2 years. Despite comparable treatment, the HIV-positive women showed lesion persistence or progression, while all HIV-negative women experienced regression.
Pattern of antibody response against the V3 loop in children with vertically acquired immunodeficiency virus type 1 (HIV-1) infection.
The principal neutralizing domain (PND) of HIV-1, located within the third variable region (V3) of the gp120 envelope protein, is related to the humoral and cellular immune response. We studied the V3 PND-specific antibody response in 30 children with vertically acquired HIV-1 infection by determining the antibodies that bound synthetic peptides derived from the PND of the HIV-1MN, HIV-1SF-2, HIV-1SC, HIV-1IIIB, HIV-1RF, HIV-1ELI, and HIV-1Z6 virus strains. At a standard antigen concentration, we found that most sera (90%) reacted against PNDMN peptide, but 73.3% also cross-reacted against multiple PNDs. A search for high-affinity/avidity antibodies was conducted in an antigen-limited assay; at lower peptide concentrations, cross-reactivity was restricted to PNDMN and PNDSC in 12 of 22 broadly reactive sera. Sequence analysis of the V3 region of HIV-1 isolates indicated that patients with high-affinity/avidity antibodies to PNDMN and PNDSC had a PND with an internal 12-amino acid sequence (serotype-specific domain, SSD) that was highly homologous (> 90%) with the MN and SC SSD. Broadly reactive sera with low-affinity/avidity antibodies showed a lower degree of homology with the SSD sequence of all tested viral strains. The role of anti-PND antibodies in vertical transmission was further studied in 49 children born to HIV-1-seropositive mothers. No statistical correlation emerged between V3 antibodies and HIV-1 transmission, but we found that maternal V3 antibodies were lost soon after birth. This finding may be relevant to a new serological approach to the early diagnosis of vertically transmitted HIV-1 infection.
Detection of human T lymphotropic virus type II/b in human immunodeficiency virus type 1-coinfected persons in southeastern Italy.
A preliminary screening of 511 persons at risk for AIDS living in southeastern Italy disclosed 20 cases of seroreactivity to human T lymphotropic viruses (HTLV). To verify and type the HTLV infection among these subjects, confirmatory serologic tests, polymerase chain reaction (PCR), and virus culture were done. No evidence of HTLV-I infection was found. HTLV-II infection was confirmed in 8 cases by HTLV-specific, synthetic peptide EIAs and PCR on uncultured cells; restriction analysis of the PCR-amplified env regions revealed the presence of HTLV-II/b strains in all 8 cases. Four sera were nontypeable by EIA. The finding of such indeterminate reactivities in a geographic area in which HTLV variants were previously described indicates the need for more extensive surveys among the healthy population. HTLV-II was isolated in 5 cases, and virus isolation was mostly dependent on the presence of an actively replicating human immunodeficiency virus type 1 in culture.
Lymphoproliferative disease in human peripheral blood mononuclear cell-injected SCID mice. I. T lymphocyte requirement for B cell tumor generation.
Mechanisms of tumor development were studied in SCID mice injected with human lymphoid cells from Epstein-Barr virus-positive (EBV+) donors. About 80% of peripheral blood mononuclear cell (PBMC)-injected animals developed a lymphoproliferative disease associated with oligoclonal EBV+ tumors of human B cell origin. No change in tumor development rate occurred when monocyte-depleted PBMC were inoculated. No tumors developed when purified B cells were injected. B cell lymphoproliferative disease was also prevented in most cases when PBMC-injected animals were treated with agents that prevent T cell activation, such as cyclosporin A. Both CD4+ and CD8+ T cell subpopulations were able to provide putative factor(s) necessary for EBV+ B cell expansion and progression to tumors. These data suggest that the transfer alone of potentially tumorigenic human cells into an immunodeficient environment, such as the SCID mouse, might not be sufficient for cell progression to tumor, and raise the possibility that chronic activation events could play a major role in the pathogenesis of some EBV+ lymphomas in the immunocompromised host.
Lymphoma induction by human B cells in scid mice.
Lymphoma development was studied in scid mice injected i.p. with PBMC from EBV-positive donors. Most injected mice developed oligo/monoclonal B-cell tumors within 4 months after the inoculation; EBV genome was found in tumor cells. Removal of T lymphocytes from the injected cell populations prevented lymphoma development in all mice, suggesting that T-cell-derived factors are involved in the expansion of the latently EBV-infected B-cell population within the immunodeficient host.
HIV-1 and HIV-2 seroprevalence rates in mother-child pairs living in The Gambia (west Africa).
A seroepidemiological study was conducted, during 1988 and 1989, of mother-child pairs living in The Gambia (West Africa) in order to determine the distribution of the human immunodeficiency viruses type 1 (HIV-1) and type 2 (HIV-2). Specimens were obtained from 931 children (age range, 14-17, months) and 923 mothers (age range, 14-17 years) using village-based cluster samples; the children are participating in The Gambia Hepatitis Intervention Study (GHIS), a large-scale HBV vaccination program. Large numbers of indeterminate Western blot patterns were observed among the mothers, mainly for HIV-1 antibodies; HIV-1 infected subjects were not found, whereas an HIV-2 seroprevalence rate of 0.75% was observed. The children born to the seven HIV-2 positive women were seronegative for HIV-2 antibodies, and none of the children showed HIV-2 or HIV-1 seropositively.
No evidence of HIV-2 infection in subjects at risk for AIDS living in north-east Italy.
Sera samples from 1134 individuals (824 HIV-1 seropositive and 310 HIV-1 seronegative), collected from January 1988 to April 1990, were tested for HIV-2 antibodies by whole virus assays and synthetic peptide-based assays to determine the prevalence of HIV-2 infection in populations at risk for AIDS in North-East Italy (Veneto Region). Partial reactivities on HIV-2 Western Blot were a common finding in HIV-1 seropositive samples. None of the sera fulfilled the criteria for HIV-2 seropositivity, since only low-level reactivity was observed with an HIV-2 competitive ELISA test, and no reactivity occurred with an HIV-2 specific peptide. Therefore, there is no evidence of HIV-2 infection in this geographical area, to date.
Serological and molecular evidence of infection by human T-cell lymphotropic virus type II in Italian drug addicts by use of synthetic peptides and polymerase chain reaction.
Infection with human T lymphotropic virus type I (HTLV-I) is associated with specific forms of tumours and neurological disorders, but the pathogenic activity of HTLV-II is not yet established. Moreover, due to high crossreactivity between the two viruses, differential diagnosis is not readily achieved. To discriminate between HTLV-I and HTLV-II infections, we employed synthetic peptides specific for HTLV-I and HTLV-II env regions, and the polymerase chain reaction (PCR). In a series of 962 intravenous drug addicts (IVDAs) and 50 patients with haematological malignancies, 51 and 2 samples, respectively, were reactive against HTLV-I proteins; among these, HTLV-I infection was confirmed only in 1 patient with adult T-cell lymphoma, while HTLV-II infections were identified in 6 out of 14 PCR-tested IVDAs. These findings provide evidence of HTLV-II infection among Italian IVDAs. The differentiation between HTLV-I and HTLV-II infections may contribute to a better understanding of HTLV-II pathogenicity in man.
Prevalence of HIV infection in a cohort of patients with congenital coagulation defects of the prothrombin complex factors.
Twenty-seven patients suffering from congenital coagulation defects of the prothrombin complex factors were investigated: six had haemophilia B; 14, factor VII defect; four, factor X defect; and three, factor II defect. Nineteen patients (70.3%) had previously received plasma and/or clotting factors concentrates. Among these, markers of hepatitis B infection (HBV) were present in five cases (26.3%) and hepatitis C (HCV) antibodies were found in seven cases (36.8%). The HIV1 prevalence was similarly high. In fact, five patients (26.3%), previously infused with factor IX or prothrombin complex factors concentrates, developed HIV1 infection. No patient with factor VII deficiency became HIV1 positive, despite the administration of unheated factor VII concentrates and the consequent HBV and HCV contamination. In the HIV1 positive group, three patients showed a false positivity for HIV2 antibodies. Five years after seroconversion, three patients developed AIDS (stage IV) and died, one had persistent generalized lymphadenopathy (stage III), and one with post-hepatitis liver cirrhosis was asymptomatic (stage II) for HIV infection. The significant decrease in total white cells, T4 lymphocytes and platelet counts and increase of beta 2-microglobulin and neopterin levels confirmed the prognostic value of these markers for the progression of HIV1 disease. Only one HIV1 negative transfused patient developed anti-HTLV-I p19 antibodies.
Antigen detection, virus culture, polymerase chain reaction, and in vitro antibody production in the diagnosis of vertically transmitted HIV-1 infection.
Polymerase chain reaction (PCR), virus culture (V), antigen detection (Ag), and in vitro antibody production (IVAP) assays may be useful for the early detection of vertically transmitted HIV-1 infection in infants under 18 months of age, when a diagnosis cannot be based on seropositivity because of maternal antibody persistence. To assess the reliability of these procedures and to correlate diagnostic results with infection status, 101 children born to HIV-1-seropositive mothers were evaluated by all these techniques within the first 6 months of life. The children were then followed up to the age of at least 18 months, when diagnosis was made on the basis of AIDS or AIDS-related complex (ARC) onset or persistence of HIV-1 seropositivity. Out of 27 children classified as infected according to the above criteria, 25 (92.5%) were repeatedly positive in IVAP test, 22 (81.5%) in the first PCR analysis, and only 19 (70.3%) in the initial V assay. On further testing, a total of 24 children (88.9%) were found positive in PCR assay, and 23 (85.2%) in V test. All these assays were found to be more sensitive than antigen detection for HIV-1 infection diagnosis, but the antigenaemia was shown to be a useful prognostic marker of disease onset. We also found that both Ag and IVAP assays could give false-positive results in the first 2 months of life, which severely limits their diagnostic value during this period of time. False-positive results in PCR assay could occur at any time of the tested period and were unrelated to the child's age.(ABSTRACT TRUNCATED AT 250 WORDS)
Recurrent oral condylomata acuminata and hairy leukoplakia: an early sign of myelodysplastic syndrome in an HIV-seronegative patient.
Oral hairy leukoplakia (OHL) has been observed in all risk groups seropositive for HIV infection. Recently, this lesion has also been described in HIV-seronegative patients with immunosuppression of iatrogenic origin. We report on a HIV-1 and HIV-2 seronegative, heterosexual man affected by refractory anemia with ringed sideroblasts (myelodysplastic syndrome), who developed recurrent oral condylomata acuminata and OHL as an early clinical manifestation. The diagnosis of OHL was confirmed by identifying Epstein-Barr viral particles by electron microscopy and by in situ DNA hybridization. HIV infection was ruled out using polymerase chain reaction and testing for HIV-1 and HIV-2 antibodies.
Human retroviruses in NHL.
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How frequent and how early does the neurological involvement in HIV-positive children occur? Preliminary results of a prospective study.
To study the natural history of the neurological involvement in pediatric human immunodeficiency virus (HIV) infection, 77 children born to seropositive mothers have been followed up since birth. The median follow-up time has been 17.5 months. Fourteen children were classified as infected, 34 as not infected, and 21 as indeterminable. Only two children with full-blown acute immune deficiency syndrome had severe neurological manifestations. "Soft" neurological signs were found in six infected, and ten non-infected children (chi 2, P < 0.05). The mean development quotient and IQ scores in the infected and the non-infected children were 82.22, and 93.15, respectively (Mann-Whitney test, P > 0.05). These data suggest that neurological and developmental abnormalities do not occur early in the course of vertical HIV infection and that they are associated with severe immunodeficiency.
Primary lymphoma of the central nervous system in two children with acquired immune deficiency syndrome.
Postmortem examination disclosed central nervous system non-Hodgkin's lymphoma in two children who died of acquired immune deficiency syndrome (AIDS) at 6 and 14 months of age, respectively. Systemic signs of lymphoma were not present. The B-cell origin and clonality of the neoplastic cells were established by immunohistochemistry in one case and by molecular analysis of immunoglobulin gene rearrangement in the other. Moreover, in the latter case the neoplastic cells were characterized by the presence of a single episomal EBV genome. According to these data, the monoclonal B-cell proliferation occurred after EBV infection, thus suggesting a possible pathogenetic role of EBV in the early stages of lymphomagenesis.
HIV-1-specific B cell activation. A major constituent of spontaneous B cell activation during HIV-1 infection.
B cell activation is a well known consequence of HIV-1 infection, and seropositive subjects show high numbers of spontaneously activated Ig-secreting cells in circulation. To better define the importance of the HIV-1-specific response in this phenomenon, we first studied whether in vitro spontaneous anti-HIV-1 antibody production was accompanied by reactivation of memory B lymphocytes. Unstimulated PBL from HIV-1-infected individuals with prior history of hepatitis B and/or EBV infection did not consistently show spontaneous in vitro synthesis of anti-hepatitis B core Ag or anti-EBV antibodies; in addition, PWM-induced synthesis of anti-hepatitis B virus and anti-EBV antibodies was decreased compared to HIV-1-seronegative subjects. Moreover, in comparing the frequencies of activated HIV-1-specific B cell precursors and activated Ig-secreting precursors in limiting dilution experiments, a sizable fraction (20 to 40%) of circulating cells spontaneously secreting Ig produced antibody against HIV-1 determinants. The ratio between the two frequencies fitted in very well with the amount of Ig removed from unstimulated culture supernatants after HIV-1-specific antibody absorption with solid-phase HIV-1. These findings indicate that B cell activation during HIV-1 infection is mainly oriented toward a specific response to HIV-1 determinants; the possible relevance of this phenomenon to lymphomagenesis in AIDS patients is discussed.
Condylomata acuminata of the urinary bladder. Natural history, viral typing, and DNA content.
Three patients with condylomata acuminata of the urinary bladder are reported. Two of the patients were immunosuppressed, and one had longstanding extensive condylomata acuminata of the external genitalia and adjacent areas. All lesions recurred at least once and were difficult to treat. The diagnosis was confirmed by in situ hybridization on archival material with human papillomavirus (HPV) DNA probes under stringent conditions. In two of the patients, probes for HPV types 6 and 11 were positive; HPV 11 only was identified in one patient. Probes for HPV types 16 and 18 and pBR322 vector controls were negative. In one patient with a strong hybridization signal, the lesion was also positive for common papillomavirus antigen. DNA content measured by cytophotometry of Feulgen-stained whole nuclei isolated from lesions in two patients revealed a markedly aneuploid DNA pattern. Whether this is a factor in the behavior of the lesions is not known at this time. Although rare, HPV infection of the urinary bladder may result in widespread condylomatosis and may mimic giant condylomas of Buschke-Löwenstein or even verrucous carcinomas, sometimes necessitating radical treatment. Nevertheless, until there is proof to the contrary, the lesions must be considered benign and should not be confused with squamous cancer of the bladder.