The role of HIV-specific CD8 T cell activity in the course of HIV infection and the way it affects the virus that resides in the latent reservoir resting memory cells is debated. The PBMC of ...HIV-infected patients contain HIV-specific CD8 T cells and their potential targets, CD4 T cells latently infected by HIV. CD4 T cells and CD8 T cells procured from PBMC of HIV-infected patients were co-incubated and analyzed: Formation of CD8 T cells and HIV-infected CD4 T cell conjugates and apoptosis of these CD4 T cells were observed by fluorescence microscopy with
PCR of HIV LTR DNA. Furthermore, conjugation of CD8 T cells with CD4 T cells and apoptosis of CD4 T cells was observed and quantified by imaging flow cytometry using anti-human activated caspase 3 antibody and TUNEL assay. The conjugation activity and apoptosis were found to be much higher in patients with acute HIV infection or AIDS compared to patients in chronic infection on antiretroviral therapy (ART) or not. Patients on ART had low grade conjugation and apoptosis of isolated CD69, CD25, and HLA-DR-negative CD4 T cells (latent reservoir cells) by CD8 T cells. Using
PCR The latent reservoir CD4 T cells were shown to contain most of the HIV DNA. We demonstrate in HIV-infected patients, that CD8 T cells conjugate with and kill HIV-infected CD4 T cells, including HIV-infected resting memory CD4 T cells, throughout the course of HIV infection. We propose that in HIV-infected patients CD4 T cell annihilation is caused in part by ongoing activity of HIV-specific CD8 T cells. HIV Nef protein interacts with ASK 1 and inhibits its pro-apoptotic death signaling by Fas/FasL, thus protecting HIV-infected cells from CD8 T cells killing. A peptide that interrupts Nef-ASK1 interaction that had been delivered into CD4 T cells procured from patients on ART resulted in the increase of their apoptosis inflicted by autologous CD8 T cells. We suggest that elimination of the HIV-infected latent reservoir CD4 T cells can be achieved by Nef inhibition.
Global HIV-1 genetic diversity forms a major obstacle to the development of an HIV vaccine. It may be necessary to employ subtype-specific HIV-1 vaccines in individual countries according to their ...HIV-1 subtype distribution. We estimated the global and regional need for subtype-specific HIV-1 vaccines. We took into account the proportions of different HIV-1 variants circulating in each country, the genetic composition of HIV-1 recombinants, and the different genome segments (
,
,
) that may be incorporated into vaccines. We modeled different scenarios according to whether countries would employ subtype-specific HIV-1 vaccines against (1) the most common subtype; (2) subtypes contributing more than 5% of HIV infections; or (3) all circulating subtypes. For therapeutic vaccines targeting the most common HIV-1 subtype in each country, 16.5 million doses of subtype C vaccine were estimated globally, followed by subtypes A (14.3 million) and B (4.2 million). A vaccine based on
required 2.6 million subtype E doses, and a vaccine based on
required 4.8 million subtype G doses. For prophylactic vaccines targeting the most common HIV-1 subtype in each country, 1.9 billion doses of subtype A vaccine were estimated globally, followed by subtype C (1.1 billion) and subtype B (1.0 billion). A vaccine based on
required 1.2 billion subtype E doses, and a vaccine based on
required 0.3 billion subtype G doses. If subtype-specific HIV-1 vaccines are also directed against less common subtypes in each country, vaccines targeting subtypes D, F, H, and K are also needed and would require up to five times more vaccine doses in total. We conclude that to provide global coverage, subtype-specific HIV-1 vaccines need to be directed against subtypes A, B, and C. Vaccines targeting
also need to include subtype E and those targeting
need to include subtype G.
Background.Musculoskeletal manifestations (MMs) are considered to be rare in cat scratch disease (CSD) and are not well characterized. We aimed to study MMs of CSD. Methods.A surveillance study ...performed over 11 years identified patients with CSD on the basis of compatible clinical presentation and confirmatory serological test or PCR results for Bartonella henselae. Patients with CSD who had MMs (i.e., myalgia, arthritis, arthralgia, tendinitis, osteomyelitis, and neuralgia) were compared with patients with CSD who did not have MMs (control subjects). Results.Of 913 patients with CSD, 96 (10.5%) had MMs. Myalgia (in 53 patients 5.8%) was often severe, with a median duration of 4 weeks (range, 1–26 weeks). Arthropathy (arthralgia and/or arthritis; in 50 patients 5.5%) occurred mainly in the medium and large joints and was classified as moderate or severe in 26 patients, with a median duration of 5.5 weeks (range, 1–240 weeks). In 7 patients, symptoms persisted for ⩾1 year; 5 developed chronic disease. Tendinitis, neuralgia, and osteomyelitis occurred in 7, 4, and 2 patients, respectively. Patients with MMs were significantly older than patients in the control group (median age, 31.5 years vs. 15.0 years; P < .001). In multivariate analysis, age >20 years was associated with having any MM (relative risk RR, 4.96; 95% confidence interval CI, 2.79–8.8), myalgia (RR, 4.69; 95% CI, 2.22–9.88), and arthropathy (RR, 11.0; 95% CI, 4.3–28.2). Arthropathy was also associated with female sex (RR, 1.89; 95% CI, 1.01–3.52) and erythema nodosum (RR, 4.07; 95% CI, 1.38–12.02). Conclusions.MMs of CSD are more common than previously thought and affect one-tenth of patients with CSD. MMs occur mostly in patients aged >20 years and may be severe and prolonged. Osteomyelitis, the most well known MM of CSD is, in fact, the rarest.
HIV in Israel started with a subtype-B epidemic among men who have sex with men, followed in the 1980s and 1990s by introductions of subtype C from Ethiopia (predominantly acquired by heterosexual ...transmission) and subtype A from the former Soviet Union (FSU, most often acquired by intravenous drug use). The epidemic matured over the last 15 years without additional large influx of exogenous infections. Between 2005 and 2013 the number of infected men who have sex with men (MSM) increased 2.9-fold, compared to 1.6-fold and 1.3-fold for intravenous drug users (IVDU) and Ethiopian-origin residents. Understanding contemporary spread is essential for effective public health planning.
We analyzed demographic and virologic data from 1,427 HIV-infected individuals diagnosed with HIV-I during 1998-2012. HIV phylogenies were reconstructed with maximum-likelihood and Bayesian methods.
Subtype-B viruses, but not A or C, demonstrated a striking number of large clusters with common ancestors having posterior probability ≥0.95, including some suggesting presence of transmission networks. Transmitted drug resistance was highest in subtype B (13%). MSM represented a frequent risk factor in cross-ethnic transmission, demonstrated by the presence of Israeli-born with non-B virus infections and FSU immigrants with non-A subtypes.
Reconstructed phylogenetic trees demonstrated substantial grouping in subtype B, but not in non-MSM subtype-A or in subtype-C, reflecting differences in transmission dynamics linked to HIV transmission categories. Cross-ethnic spread occurred through multiple independent introductions, with MSM playing a prevalent role in the transmission of the virus. Such data provide a baseline to track epidemic trends and will be useful in informing and quantifying efforts to reduce HIV transmission.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A highly specific enzyme immunoassay (EIA) was recently described for use in the diagnosis of cat scratch disease (CSD). However, data regarding EIA antibody kinetics or its correlation with ...long-term clinical follow-up data are lacking. The association between antibody kinetics, clinical spectrum, and disease duration were studied in 98 patients with CSD. The median duration of follow-up was 35.3 weeks (range, 2–211.3 weeks). Results of EIA testing for detection of anti-Bartonella henselae immunoglobulin M (IgM) antibodies (detected in 53% of the patients) remained positive for ⩽3 months. Therefore, the presence of IgM indicated acute infection. Titers of immunoglobulin G (IgG) also decreased over time; 25% of the patients remained seropositive for >1 year after the onset of CSD. Onset of CSD in patients with an IgG titer with an optical density of ⩾1.0 occurred within the prior 12 months. No association was found between antibody titers or their kinetics and the clinical manifestations or duration of disease. EIA allows for the identification of atypical manifestations of CSD that were unrecognized before the use of serological assays. Complete recovery from these manifestations may take months. Results of this study provide additional data supporting the utility of EIA in the serodiagnosis of CSD.
HIV subtypes A and CRF01_AE (A/AE) became prevalent in Israel, first through immigration of infected people, mostly intravenous-drug users (IVDU), from Former Soviet-Union (FSU) countries and then ...also by local spreading. We retrospectively studied virus-transmission patterns of these subtypes in comparison to the longer-established subtype B, evaluating in particular risk-group related differences. We also examined to what extent distinct drug-resistance patterns in subtypes A/AE versus B reflected differences in patient behavior and drug-treatment history.
Reverse-transcriptase (RT) and protease sequences were retrospectively analyzed along with clinical and epidemiological data. MEGA, ClusalX, and Beast programs were used in a phylogenetic analysis to identify transmission networks.
318 drug-naive individuals with A/AE or patients failing combination antiretroviral therapy (cART) were identified. 61% were IVDU. Compared to infected homosexuals, IVDU transmitted HIV infrequently and, typically, only to a single partner. 6.8% of drug-naive patients had drug resistance. Treatment-failing, regimen-stratified subtype-A/AE- and B-patients differed from each other significantly in the frequencies of the major resistance-conferring mutations T215FY, K219QE and several secondary mutations. Notably, failing boosted protease-inhibitors (PI) treatment was not significantly associated with protease or RT mutations in either subtype.
While sizable transmission networks occur in infected homosexuals, continued HIV transmission among IVDU in Israel is largely sporadic and the rate is relatively modest, as is that of drug-resistance transmission. Deviation of drug-naive A/AE sequences from subtype-B consensus sequence, documented here, may subtly affect drug-resistance pathways. Conspicuous differences in overall drug-resistance that are manifest before regimen stratification can be largely explained in terms of treatment history, by the different efficacy/adherence limitations of older versus newer regimens. The phenomenon of treatment failure in boosted-PI-including regimens in the apparent absence of drug-resistance to any of the drugs, and its relation to adherence, require further investigation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background. Cat-scratch disease (CSD) is mostly contracted by children and young adults. To our knowledge, CSD in elderly patients has never been characterized, and it may be underrecognized in this ...age group. Methods. The study population included all patients with CSD diagnosed at our reference laboratory during 1991–2002. Demographic, clinical, and laboratory data for patients with CSD aged ⩾60 years (elderly group) were compared with data for patients with CSD aged <60 years (nonelderly group). Results. There were 846 immunocompetent patients with CSD included in this study. Fifty-two patients (6%) were ⩾60 years old. Lymphadenopathy was less common in elderly patients than in nonelderly patients (76.5% vs. 94.4%; P < .001), and general malaise was more frequent in elderly patients (70.8% vs. 51.4%; P = .009). Atypical CSD was more common in elderly patients than in nonelderly patients (32.7% vs. 13.6%), including endocarditis (odds ratio OR, 61.6; P < .001), encephalitis (OR, 6.3; P = .013), and fever of unknown origin (OR, 7.3; P < .001). The time period from onset of symptoms to diagnosis was >6 weeks for 29.5% of elderly patients versus 13.3% of nonelderly patients (P = .003). Conclusions.CSD affects elderly persons as well as nonelderly persons, but clinical features differ between the patient groups. Atypical CSD, including endocarditis, is more frequent in elderly than in nonelderly patients. Conversely, lymphadenitis, the hallmark of typical CSD, is often absent in elderly patients. Lack of awareness among clinicians may delay the diagnosis of CSD in elderly persons and result in unnecessary and often invasive diagnostic procedures.
The objective of the present study was to determine the prevalence of high-risk (HR) human papillomavirus (HPV) genotypes in a group of Israeli Jewish women referred for colposcopic examination. ...Scrape specimens were prospectively collected from 84 women referred for colposcopic examination. All the women underwent Papanicolaou (Pap) smears and colposcopies, and some also underwent cervical or loop electrosurgical excision procedure biopsy. HR HPV was detected in scrape specimens (Amplicor HPV test; Roche Molecular Systems), and the individual genotypes in these specimens were identified (HPV GenoArray test kit; Hybribio Ltd., Hong Kong). Forty-one (49%) specimens were positive by the Amplicor HPV test. Sixty-four samples (41 positive and 23 negative by the Amplicor HPV test) were also assayed by use of the HPV GenoArray kit. The overall level of agreement between the two assays was 93.8% (Cohen's kappa = 0.98). HR genotypes were found in 37/41 (90%) HPV-positive samples. The prevalences of the HR HPV genotypes in the 37 HPV-positive samples were 41% of patients for HPV type 16 (HPV-16), 22% for HPV-39, 19% for HPV-52, and 14% for HPV-18. Forty-one percent of these patients were infected with a single HR genotype, whereas 59% were infected with mixtures of HR genotypes. The presence of a relatively high percentage of HPV types 39 and 52 and the relatively high incidence of infections with mixtures of genotypes may be one of the reasons for the low rate of conversion from high-grade squamous intraepithelial lesions to invasive carcinoma in Israeli women. Larger and more comprehensive studies are warranted to investigate this issue in greater detail.
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