Subclinical cardiovascular disease in HIV controller and long-term nonprogressor populations.

OBJECTIVES: Elite controllers (ECs), viraemic controllers (VCs), and long-term nonprogressors (LTNPs) control HIV viral replication or maintain CD4 T-cell counts without antiretroviral therapy, but may have increased cardiovascular disease (CVD) risk compared to HIV-uninfected persons. We evaluated subclinical carotid and coronary atherosclerosis and inflammatory biomarker levels among HIV controllers, LTNPs and noncontrollers and HIV-uninfected individuals in the Multicenter AIDS Cohort Study (MACS) and the Women's Interagency HIV Study (WIHS). METHODS: We measured carotid plaque presence and common carotid artery intima-media thickness (IMT) in 1729 women and 1308 men, and the presence of coronary artery calcium and plaque in a subgroup of men. Associations between HIV control category and carotid and coronary plaque prevalences were assessed by multivariable regression analyses adjusting for demographics and CVD risk factors. Serum inflammatory biomarker concentrations [soluble CD163 (sCD163), soluble CD14 (sCD14), galectin-3 (Gal-3), galectin-3 binding protein (Gal-3BP) and interleukin (IL)-6] were measured and associations with HIV control category assessed. RESULTS: We included 135 HIV controllers (30 ECs) and 135 LTNPs in the study. Carotid plaque prevalence and carotid IMT were similar in HIV controllers, LTNPs and HIV-uninfected individuals. HIV controllers and LTNPs had lower prevalences of carotid plaque compared to viraemic HIV-infected individuals. The prevalence of coronary atherosclerosis was similar in HIV controllers/LTNPs compared to HIV-uninfected and viraemic HIV-infected men. Controllers and LTNPs had higher concentrations of sCD163 and sCD14 compared to HIV-uninfected persons. CONCLUSIONS: Subclinical CVD was similar in HIV controllers, LTNPs and HIV-uninfected individuals despite elevated levels of some inflammatory biomarkers. Future studies of HIV controllers and LTNPs are needed to characterize the risk of CVD among HIV-infected persons.

Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy.

Combination therapy for HIV-1 infection can reduce plasma virus to undetectable levels, indicating that prolonged treatment might eradicate the infection. However, HIV-1 can persist in a latent form in resting CD4+ T cells. We measured the decay rate of this latent reservoir in 34 treated adults whose plasma virus levels were undetectable. The mean half-life of the latent reservoir was very long (43.9 months). If the latent reservoir consists of only 1 x 10(5) cells, eradication could take as long as 60 years. Thus, latent infection of resting CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective anti-retroviral therapy.

Problems of neonatal tetanus as seen in Ghana.

An analysis of 249 cases of neontal tetanus admitted to Korle-Bu Teaching Hospital, Accra, between January 1971 and December 1974, has been presented. The overall case fatality was 64%. The unfavourable mortality trend over the period of study calls for urgent preventive measures on a largescale, to control the disease.

The CD28/B7 pathway costimulates the response of primary murine T cells to superantigens as well as to conventional antigens.

While the CD28/B7 pathway has been shown to play an important costimulatory role in the response of T cells to conventional antigens, its role in superantigen-mediated T cell activation has not been as clear. In this report, we used CD4+ T cells from ovalbumin-specific alpha beta-TCR-transgenic mice (DO11.10) to compare the ability of this pathway to costimulate the response of primary T cells to conventional antigens and superantigens. We show that either the addition of anti-CD28 monoclonal antibody or presentation with a B7 transfected cell line enhances the proliferative and interleukin-2 secretion response of DO11.10 CD4+ cells to both the conventional antigen, ovalbumin peptide (OVA 323-339), and the superantigen SEB. This implies that CD28-mediated costimulation plays a role in the response of murine T cells to superantigens as well as to conventional antigens.

Superantigens and conventional antigens induce different responses in alpha beta T-cell receptor transgenic mice.

While superantigens such as staphylococcal enterotoxin B (SEB) have been shown to induce both clonal deletion and clonal anergy, it is still not known why tolerance rather than memory is induced. To address this issue, we tested the proliferative capacity of T cells from ovalbumin (OVA)-specific alpha beta T-cell receptor transgenic mice primed with either SEB emulsified in complete Freund's adjuvant (CFA) or with OVA peptide, the specific antigen, in CFA. By contrast cells from mice primed with SEB in CFA appeared to be anergic in that they were hyporesponsive to OVA peptide as well as to SEB. The anergic cells could respond to phorbol myristate acetate (PMA) and ionomycin, suggesting that a proximal signal transduction step was affected. Cells from transgenic mice primed with OVA peptide and CFA were not anergic and in fact displayed an enhanced response when they were challenged with OVA in vitro. Thus, when the two antigens are emulsified in CFA and then injected subcutaneously, they behave very differently: the superantigen SEB induces anergy whereas the conventional antigen OVA induces a memory type of response.

Latent reservoirs for HIV-1.

Combination therapy for HIV-1 infection can reduce viremia to undetectable levels, suggesting that prolonged treatment might eradicate the infection. However, one potential mechanism for viral persistence involves the establishment of a state of latent infection. Recent studies have directly confirmed that HIV-1 establishes a state of latent infection in resting memory CD4(+) T cells in vivo. This reservoir is likely to frustrate current efforts to eradicate the infection with combination therapy.

Achieving treatment goals for schoolchildren with asthma.

OBJECTIVES: To identify problems in managing asthmatic children in school, which if dealt with would help reduce absenteeism and improve participation in school activities. DESIGN: A survey by questionnaire to headteachers. SETTING: Schools in Merthyr and Rhondda Cynon Taff, South Wales. SUBJECT: Asthmatic schoolchildren in areas studied. MAIN OUTCOME MEASURES: Facilities in schools to manage asthma, headteachers' perceptions of knowledge of asthma management by teachers, possession of written policies, and desire for further training. RESULTS: There are 216 schools in the area studied, with 55,166 schoolchildren. A total of 191 (88%) headteachers returned the completed questionnaire. Five hundred and twenty seven (17%) children were reported absent from school during one term because of asthma, with an average of nine days of schooling lost per asthmatic child per term (range 2-16 days). Only 76 (40%) schools allowed children to be responsible for their inhalers, and 12 (6%) schools required parents to administer inhalers. In 115 (60%) schools, headteachers believed their staff were familiar with the management of asthma. A total of 174 (91%) headteachers expressed interest in further training. CONCLUSION: This study highlights the need to train teachers and provide an agreed joint education and health policy on managing asthma in school.

Proliferative responses to human immunodeficiency virus type 1 (HIV-1) antigens in HIV-1-infected patients with immune reconstitution.

Cell-mediated immunity is affected early in human immunodeficiency virus type 1 (HIV-1) infection. HIV-1-specific CD4+ T cell proliferative responses are not measurable in most patients but have been reported in long-term nonprogressors and in patients treated with highly active antiretroviral therapy (HAART) during primary infection. However, treatment with HAART generally does not restore HIV-1-specific CD4+ T cell responses in chronically infected patients. In this study, HIV-1-specific CD4+ T cell responses in 10 HIV-1-infected patients who began HAART with low CD4 cell count nadirs and experienced significant immune reconstitution were studied. Surprisingly, 5 of these patients had proliferative responses to > or =1 HIV-1 gene product, compared with 0 of 8 chronically infected patients who started HAART when their CD4 cell counts were still relatively high. These results suggest that, in some patients with advanced HIV-1 infection, treatment with HAART can lead not only to significant increases in CD4 cell counts but also to the restoration of HIV-1-specific responses.

The Mamprobi Survey--a screening survey for cardiovascular disease and risk factors in Africa: methodology and validity.

The Mamprobi Survey is a cardiovascular disease prevalence sample survey in an African community in Ghana. This preliminary paper describes its methodology and validity. Response rate corrected for migration from the area was 73%. Subsequent sampling of non-respondents revealed only trivial reasons for non-attendance and only minor differences in health status, suggesting that estimates of disease prevalence by the survey were likely to be accurate.

Cardiovascular status and blood pressure in a population sample in Ghana--the Mamprobi survey.

In a medical survey of an urban population in Ghana, abnormal cardiovascular findings were present in 25% of the population aged from 15 to 64 years. This was largely due to hypertension and to cardiomegaly of obscure origin. The prevalence of valvular heart disease was comparatively low. Abnormal cardiovascular findings were commonest in the lowest third of the socio-economic stratum and next most frequent in the highest third. Abnormal findings were not related to smoking or drinking habits; these seem to be only marginally important in the population at present.

The nephrotic syndrome in Ghana: clinical and pathological aspects.

Clinical and pathological features of the nephrotic syndrome were studied in 36 adults and 25 children in Ghana. No evidence was found to implicate Plasmodium malariae as a cause and in the majority of patients the aetiology was not identified. Minimal change glomerulonephritis responsive to steroids was demonstrated in 14/25 children and 5/36 adults which was surprising as this lesion has been reported only rarely from tropical Africa. The other major histological lesions were focal segmental glomerulosclerosis (12/61), diffuse proliferative glomerulonephritis (11/61) and membranous glomerulonephritis (9/61).

Murine monoclonal antibodies specific for conserved and non-conserved antigenic determinants of the human and murine Ku autoantigens.

The Ku autoantigen is a DNA binding factor consisting of 70 and approximately 80 kDa proteins (p70 and p80, respectively) which form a heterodimer. The p70/p80 dimer appears to be crucial for the function of a 350 kDa DNA-dependent protein kinase (DNA-PK) that phosphorylates certain transcription factors in vitro. Previous studies have suggested that Ku is abundant in primate cells, but undetectable in most non-primate cells. However, it is unclear if this reflects low abundance of Ku (and possibly DNA-PK activity) in non-primate cells, a lack of antibodies crossreactive with non-primate Ku proteins, or both. Ku was first identified with human autoimmune sera, but the suitability of these sera for studying the distribution, abundance and function of Ku is limited by the polyclonal immune response to Ku and the presence of contaminating autoantibodies in most patients' sera. In the present studies, we determined the specificities of murine anti-Ku monoclonal antibodies (mAbs) using cellular Ku as well as recombinant human and murine Ku antigens. Immunofluorescence studies confirmed previous observations that Ku is undetectable in most nonprimate cells. However, small amounts of Ku could be detected in MOPC-315, but not L-929, cells by immunoprecipitating with mAb 162. In addition, autoantibodies to Ku were identified in the sera of approximately 1/3 of MRL/lpr mice. The murine autoantibodies also immunoprecipitated a small amount of Ku (comparable to that seen with 162) from MOPC-315, but not L-929, cell lysates. Characterization of the mAb specificities by immunoblot analysis with Ku fusion proteins revealed that mAbs 111, S10B1, and N9C1 bound to distinct epitopes of human p80 (amino acids 610-705, 8-221, and 1-374, respectively). All three mAbs were unreactive with murine p80. MAbs N3H10 and S5C11 bound immediately adjacent to the DNA binding site of p70 (amino acids 506-541). Only N3H10 displayed comparable reactivity with human and murine p70 on immunoblots, but it immunoprecipitated murine Ku poorly. S5C11 crossreacted more weakly with murine p70 on immunoblots, whereas 162 was completely unreactive with human or murine Ku on immunoblots, despite immunoprecipitating Ku efficiently. Studies with mAbs N3H10 and 162 suggest that the level of Ku is considerably lower in nonprimate cells than cells of primate origin, and that L-929 cells express little or no Ku protein.(ABSTRACT TRUNCATED AT 400 WORDS)

Characterization of chemokine receptor utilization of viruses in the latent reservoir for human immunodeficiency virus type 1.

Latently infected resting CD4(+) T cells provide a long-term reservoir for human immunodeficiency virus type 1 (HIV-1) and are likely to represent the major barrier to virus eradication in patients on combination antiretroviral therapy. The mechanisms by which viruses enter the latent reservoir and the nature of the chemokine receptors involved have not been determined. To evaluate the phenotype of the virus in this compartment with respect to chemokine receptor utilization, full-length HIV-1 env genes were cloned from latently infected cells and assayed functionally. We demonstrate that the majority of the viruses in the latent reservoir utilize CCR5 during entry, although utilization of several other receptors, including CXCR4, was observed. No alternative coreceptors were shown to be involved in a systematic fashion. Although R5 viruses are present in the latent reservoir, CCR5 was not expressed at high levels on resting CD4(+) T cells. To understand the mechanism by which R5 viruses enter latent reservoir, the ability of an R5 virus, HIV-1 Ba-L, to infect highly purified resting CD4(+) T lymphocytes from uninfected donors was evaluated. Entry of Ba-L could be observed when virus was applied at a multiplicity approaching 1. However, infection was limited to a subset of cells expressing low levels of CCR5 and markers of immunologic memory. Naive cells could not be infected by an R5 virus even when challenged with a large inoculum. Direct cell fractionation studies showed that latent virus is present predominantly in resting memory cells but also at lower levels in resting naive cells. Taken together, these findings provide support for the hypothesis that the direct infection of naive T cells is not the major mechanism by which the latent infection of resting T cells is established.

Biphasic decay of latently infected CD4+ T cells in acute human immunodeficiency virus type 1 infection.

Latent infection of resting CD4(+) T cells represents a major barrier to eradication of human immunodeficiency virus type 1 (HIV-1). The establishment and rate of decay of latent HIV-1 in resting CD(+) T cells from 9 acute seroconverters, 7 of whom began to receive highly active antiretroviral therapy (HAART) shortly after presentation, were studied. Before the initiation of therapy, these patients had very high frequencies of latently infected CD4(+) T cells, with a median frequency of 205 infectious units per million resting CD4(+) T cells. These values are > or =1 log higher than those seen in chronically infected patients who are not undergoing HAART. The number of latently infected cells declined dramatically after initiation of HAART but then tended to level off at a low but stable level. The biphasic decay of latent HIV in resting CD4(+) T cells in acute seroconverters supports current models of pre- and postintegration latency.