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We present a case of a necrotising disease of the orofacial tissues, the so-called noma, in a female patient with AIDS in a stage of severe immune deficiency. To our knowledge, this is the first time a case like that has been reported in Bulgaria. The patient received an antibiotic course of treatment with a triple combination to good effect on the inflammatory process, and began also HAART. Within 3 weeks, the patient’s general condition improved. However, despite the treatment, a demarcation line was formed, and a defect on the lower lip occurred. Noma is a manifestation of severe immune deficiency with lasting adverse consequences for the patient: severe deformation of the maxilo-facial region and functional impairment (i.e. difficulties eating and speaking, and salivary leak).

Objective: To determine the incidence of osteopenia and osteoporosis in Bulgarian human immunodeficiency virus (HIV)-infected patients.

Diarrhea is the most common gastrointestinal symptom in HIV-infected patients. The incidence and severity of diarrhea increase with progression of the immune defi ciency. In the literature, 30-60% of the patients with diarrhea among HIV-infected individuals remain without specified etiological agent. The aim of this article is to present the incidence of enterocolitis among hospitalized HIV-infected patients over a 3-year period and the degree of etiological clarifi cation of the cause. The results of our analyses showed that 63% of the hospitalized HIV-infected patients for this period were with enterocolitis. Only in 30% of these patients etiological agent was isolated. The reasons for this are mainly financial constraints and, therefore, virological investigations and further endoscopic and histopathological examination of the patients with negative for bacteria and parasites stool samples, were not performed. In the cases with isolated pathogen, an etiological treatment was carried out in parallel with highly active antiretroviral therapy, while in unsubstantiated cases an empirical treatment was carried out. Advanced immune defi ciency was associated with more severe course and worse prognosis of the enterocolitis. The treatment with highly active antiretroviral therapy, which leads to improvement of the immune status of the patients, is essential for the output of enterocolitis in HIV-infected patients.

Demonstrates that the c-Jun transcription factor is necessary for transformation by `ras.' Experimental methods; Results; Discussion.

The increased life expectancy of PLHIV (People Living with HIV) and the successful highly combined antiretroviral therapy (cART) poses new clinical challenges regarding aging and its co-morbid condition. It is commonly believed that HIV infection "accelerates" aging. Human immunodeficiency virus type 1 (HIV-1) infection is characterized by inflammation and immune activation that persists despite cART, and that may contribute to the development of co-morbid conditions. In this regard, we aimed to compare current cART regimens in light of premature aging to evaluate differences in their ability to reduce immune activation and inflammation in virologically suppressed patients. We studied a panel of biomarkers (IFN-γ, IL-1β, IL-12p70, IL-2, IL-4, IL-5, IL-6, IL-13, IL-18, GM-CSF, TNF-α, C-reactive protein, D-dimer, soluble CD14), which could provide a non-invasive and affordable approach to monitor HIV-related chronic inflammation. The results of the current study do not provide hard evidence favoring a particular cART regimen, although they show a less favorable regimen profile containing a protease inhibitor. Our data suggest an incomplete reduction of inflammation and immune activation in terms of the effective cART. It is likely that the interest in various biomarkers related to immune activation and inflammation as predictors of clinical outcomes among PLHIV will increase in the future.

Background: The aim of the study was to assess socio-demographical characteristics, clinical presentation, and outcomes in patients diagnosed with mpox., Methods: A survey on patients diagnosed with mpox was performed in 14 countries from Central and Eastern Europe. Data was compared according to HIV status and country of origin (EU vs. non-EU). Mpox diagnosis was confirmed by RT-PCR from oropharyngeal swabs, skin lesions, and other body fluids., Results: Out of 154 patients confirmed with mpox in 2022, 99.3% were males, with a median age (years) of 35 (IQR 30-39), 90.2% MSM and 48.7% PLWH. Compared to HIV-negative subjects, PLWH had more frequent high-risk behaviours:chemsex (p = 0.015), group sex (p = 0.027), and a history of sexually transmitted infections (STIs) (p = 0.004). Persons from EU were more often PLWH (p = 0.042), MSM (p < 0.0001), had multiple sexual partners (p = 0.025), practiced chemsex (p = 0.008) or group-sex (p = 0.005) and had more often history of STIs (p < 0.0001). The median CD4 cell count/mL at mpox diagnosis was 713 (IQR 486-996) and 73.5% had undetectable HIV VL. The commonest clinical features were fever (108 cases), lymphadenopathy (78), and vesiculo-pustular rash: penile (76), perianal (48), limbs (67). Fifty-one (31%) persons were hospitalized due to complications or epidemiological reasons. Three patients received tecovirimat or cidofovir. The outcome was favorable for all patients, including 4 with severe forms., Conclusions: Mpox was diagnosed predominantly in young MSM, with high-risk behaviors and history of STIs. Effective contact tracing and vaccination are important strategic pillars to control mpox outbreaks., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Abstract: Microorganisms belonging to the Mycobacterium avium complex (MAC) are ubiquitous in the environment, but only a minority of infected persons develop disease. An underlying lung disease or immune deficiency is a prerequisite for clinical manifestation. However, disseminated MAC disease primarily manifests in people living with human immunodeficiency virus (HIV) in the severe immunodeficiency stage with a whole host of clinical symptoms. We present two cases of disseminated M. avium infection in people living with HIV in the stage of severe immunodeficiency. Both patients exhibited distinct disease progression, with the absence of pulmonary symptoms being a common characteristic. The first patient predominantly experienced high fever, accompanied by diarrhea and severe anemia. The normothermia in the second patient was incongruent with the presence of marked cachexia, severe abdominal pain, and magnetic resonance imaging evidence of abdominal lymph node involvement. The causative agent was isolated from both sputum and stools. The patients underwent treatment that comprised aminoglycoside, macrolide, ethambutol, and rifampicin. Although both patients achieved optimal viral suppression of HIV, the immunologic response to antiretroviral therapy was suboptimal. The first patient died in the setting of severe immunodeficiency due to the development of decompensated liver cirrhosis, while the second patient demonstrated a slight reverse course of the disease., (Copyright © 2024 Copyright: © 2024 International Journal of Mycobacteriology.)

Introduction: Surging HIV prevalence across countries of Central and Eastern Europe (CEE) is largely a result of poor HIV care engagement and a lack of comprehensive support for key populations. This is fostered by widespread stigma across healthcare, community, and legislative settings., Discussion: Throughout CEE, HIV stigma and intersectional stigma are serious obstacles to providing adequate medical care to people living with HIV. Anticipated and enacted (experienced) stigma from healthcare professionals, and fears of breaches in confidentiality, deter individuals from having an HIV test and engaging in HIV care. Furthermore, negative connotations surrounding HIV infection can lead to discrimination from family, friends, colleagues, and the public, leading to internalized stigma and depression. Key populations that have higher HIV prevalence, such as men who have sex with men, people who inject drugs, transgender individuals, and sex workers, experience additional stigma and discrimination based on their behaviour and identities. This contributes to the concentrated HIV epidemics seen in these populations in many CEE countries. The stigma is exacerbated by punitive legislation that criminalizes HIV transmission and penalizes sexual orientation, drug use, gender identities, and sex work. Despite high levels of HIV stigma and intersectional stigma, there are many evidence-based interventions that have reduced stigma in other parts of the world. Here, we discuss the interventions that are currently being enacted in various countries of CEE, and we suggest additional effective, evidence-based interventions that will tackle stigma and lead to increased HIV care engagement and higher rates of viral suppression. We cover the promotion of the undetectable = untransmittable (U = U) message, stigma-reduction education and training for healthcare professionals, patient-centric approaches for testing and treatment, and advocacy for non-discriminatory legislation, policies, and practices. We also consider targeted stigma-reduction interventions that acknowledge the wider challenges faced by marginalized populations., Conclusions: HIV stigma and intersectional stigma in CEE drive poor engagement with HIV testing services and care. Widespread adoption of evidence-based interventions to tackle stigma highlighted in this review will improve the quality of life of people living with HIV, improve HIV care engagement, and ultimately slow the surging HIV prevalence and concentrated epidemics occurring throughout CEE., (© 2023. The Author(s).)

(1) Background: Viral hepatitis C (HCV) and viral hepatitis B (HBV) are common co-infections in people living with HIV (PLWH). All PLWH should be vaccinated against HBV and hepatitis A (HAV) and treated for HBV and HCV. We aimed to compare testing, prophylaxis and treatment of viral hepatitis in PLWH in Central and Eastern Europe (CEE) in 2019 and 2022. (2) Methods: Data was collected through two on-line surveys conducted in 2019 and 2022 among 18 countries of the Euroguidelines in CEE (ECEE) Network Group. (3) Results: In all 18 countries the standard of care was to screen all PLWH for HBV and HCV both years; screening of HAV was routine in 2019 in 54.5% and in 2022 47.4% of clinics. Vaccination of PLWH against HAV was available in 2019 in 16.7%, in 2022 in 22.2% countries. Vaccination against HBV was available routinely and free of charge in 50% of clinics both in 2019 and 2022. In HIV/HBV co-infected the choice of NRTI was tenofovir-based in 94.4% of countries in both years. All clinics that responded had access to direct-acting antivirals (DAAs) but 50% still had limitations for treatment. (4) Conclusions: Although testing for HBV and HCV was good, testing for HAV is insufficient. Vaccination against HBV and especially against HAV has room for improvement; furthermore, HCV treatment access needs to overcome restrictions.

Transmitted HIV drug resistance in Bulgaria was first reported in 2015 using data from 1988-2011. We determined the prevalence of surveillance drug resistance mutations (SDRMs) and HIV-1 genetic diversity in Bulgaria during 2012-2020 using polymerase sequences from 1053 of 2010 (52.4%) antiretroviral therapy (ART)-naive individuals. Sequences were analyzed for DRM using the WHO HIV SDRM list implemented in the calculated population resistance tool at Stanford University. Genetic diversity was inferred using automated subtyping tools and phylogenetics. Cluster detection and characterization was performed using MicrobeTrace. The overall rate of SDRMs was 5.7% (60/1053), with 2.2% having resistance to nucleoside reverse transcriptase inhibitors (NRTIs), 1.8% to non-nucleoside reverse transcriptase inhibitors (NNRTIs), 2.1% to protease inhibitors (PIs), and 0.4% with dual-class SDRMs. We found high HIV-1 diversity, with the majority being subtype B (60.4%), followed by F1 (6.9%), CRF02&#95;AG (5.2%), A1 (3.7%), CRF12&#95;BF (0.8%), and other subtypes and recombinant forms (23%). Most (34/60, 56.7%) of the SDRMs were present in transmission clusters of different subtypes composed mostly of male-to-male sexual contact (MMSC), including a 14-member cluster of subtype B sequences from 12 MMSC and two males reporting heterosexual contact; 13 had the L90M PI mutation and one had the T215S NRTI SDRM. We found a low SDRM prevalence amid high HIV-1 diversity among ART-naive patients in Bulgaria during 2012-2020. The majority of SDRMs were found in transmission clusters containing MMSC, indicative of onward spread of SDRM in drug-naive individuals. Our study provides valuable information on the transmission dynamics of HIV drug resistance in the context of high genetic diversity in Bulgaria, for the development of enhanced prevention strategies to end the epidemic.

Immune memory to SARS-CoV-2 is key for establishing herd immunity and limiting the spread of the virus. The duration and qualities of T-cell-mediated protection in the settings of constantly evolving pathogens remain an open question. We conducted a cross-sectional study of SARS-CoV-2-specific CD4+ and CD8+ T-cell responses at several time points over 18 months (30-750 days) post mild/moderate infection with the aim to identify suitable methods and biomarkers for evaluation of long-term T-cell memory in peripheral blood. Included were 107 samples from 95 donors infected during the periods 03/2020-07/2021 and 09/2021-03/2022, coinciding with the prevalence of B.1.1.7 (alpha) and B.1.617.2 (delta) variants in Bulgaria. SARS-CoV-2-specific IFNγ+ T cells were measured in ELISpot in parallel with flow cytometry detection of AIM+ total and stem cell-like memory (T SCM ) CD4+ and CD8+ T cells after in vitro stimulation with peptide pools corresponding to the original and delta variants. We show that, unlike IFNγ+ T cells, AIM+ virus-specific CD4+ and CD8+ T SCM are more adequate markers of T cell memory, even beyond 18 months post-infection. In the settings of circulating and evolving viruses, CD8+ T SCM is remarkably stable, back-differentiated into effectors, and delivers immediate protection, regardless of the initial priming strain.

With no expected vaccine for HIV in the near future, we aimed to define the current situation and challenges for pre- and post-exposure prophylaxis (PrEP and PEP) in Central and Eastern Europe (CEE). The Euroguidelines CEE Network Group members were invited to respond to a 27-item survey including questions on PrEP (response rate 91.6%). PrEP was licensed in 68.2%; 95 centers offered PrEP and the estimated number on PrEP was around 9000. It was available in daily (40.1%), on-demand (13.3%), or both forms (33.3%). The access rate was <1−80%. Three major barriers for access were lack of knowledge/awareness among people who are in need (59.1%), not being reimbursed (50.0%), and low perception of HIV risk (45.5%). Non-occupational PEP was available in 86.4% and was recommended in the guidelines in 54.5%. It was fully reimbursed in 36.4%, only for accidental exposures in 40.9%, and was not reimbursed in 22.72%. Occupational PEP was available in 95.5% and was reimbursed fully. Although PrEP scale-up in the region has gained momentum, a huge gap exists between those who are in need of and those who can access PrEP. Prompt action is required to address the urgent need for PrEP scale-up in the CEE region.

The ECEE Network Group investigated early provision of HIV care to war refugees migrating from Ukraine in Central and Eastern Europe (CEE) through an online survey. Fourteen countries admitting war refugees from Ukraine on March 31, 2022, completed the survey. Most centers (86%) organized provision of same day antiretroviral therapy (ART) for at least 30 days (77%), but indicated that it may affect the local HIV care. CEE countries put effective emergency mechanisms, which need continuation with international support., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Chronic kidney disease (CKD) is a significant cause of morbidity and mortality among patients infected with human immunodeficiency virus (HIV). The Central and East Europe (CEE) region consists of countries with highly diversified HIV epidemics, health care systems and socioeconomic status. The aim of the present study was to describe variations in CKD burden and care between countries. The Euroguidelines in the CEE Network Group includes 19 countries and was initiated to improve the standard of care for HIV infection in the region. Information on kidney care in HIV-positive patients was collected through online surveys sent to all members of the Network Group. Almost all centres use regular screening for CKD in all HIV (+) patients. Basic diagnostic tests for kidney function are available in the majority of centres. The most commonly used method for eGFR calculation is the Cockcroft-Gault equation. Nephrology consultation is available in all centres. The median frequency of CKD was 5% and the main cause was comorbidity. Haemodialysis was the only modality of treatment for kidney failure available in all ECEE countries. Only 39% of centres declared that all treatment options are available for HIV+ patients. The most commonly indicated barrier in kidney care was patients' noncompliance. In the CEE region, people living with HIV have full access to screening for kidney disease but there are important limitations in treatment. The choice of dialysis modality and access to kidney transplantation are limited. The main burden of kidney disease is unrelated to HIV infection. Patient care can be significantly improved by addressing noncompliance.

Introduction: The COVID-19 pandemic has been challenging time for medical care, especially in the field of infectious diseases (ID), but it has also provided an opportunity to introduce new solutions in HIV management. Here, we investigated the changes in HIV service provision across Central and Eastern European (CEE) countries before and after the COVID-19 outbreak., Methods: The Euroguidelines in Central and Eastern Europe Network Group consists of experts in the field of ID from 24 countries within the CEE region. Between 11 September and 29 September 2021, the group produced an on-line survey, consisting of 32 questions on models of care among HIV clinics before and after the SARS-CoV-2 outbreak., Results: Twenty-three HIV centers from 19 countries (79.2% of all countries invited) participated in the survey. In 69.5% of the countries, there were more than four HIV centers, in three countries there were four centers (21%), and in four countries there was only one HIV center in each country. HIV care was based in ID hospitals plus out-patient clinics (52%), was centralized in big cities (52%), and was publicly financed (96%). Integrated services were available in 21 clinics (91%) with access to specialists other than ID, including psychologists in 71.5% of the centers, psychiatrists in 43%, gynecologists in 47.5%, dermatologists in 52.5%, and social workers in 62% of all clinics. Patient-centered care was provided in 17 centers (74%), allowing consultations and tests to be planned for the same day. Telehealth tools were used in 11 centers (47%) before the COVID-19 pandemic outbreak, and in 18 (78%) after ( p = 0.36), but were represented mostly by consultations over the telephone or via e-mail. After the COVID-19 outbreak, telehealth was introduced as a new medical tool in nine centers (39%). In five centers (28%), no new services or tools were introduced., Conclusions: As a consequence of the COVID-19 pandemic, tools such as telehealth have become popularized in CEE countries, challenging the traditional approach to HIV care. These implications need to be further evaluated in order to ascertain the best adaptations, especially for HIV medicine.

HIV-positive patients may present lungs with multiple infections, which may hinder differential diagnoses and the choice of treatment in the course of COVID-19, especially in countries with limited access to high-standard healthcare. Here, we aim to investigate the association between radiological changes and poor COVID-19 outcomes among HIV-positive patients from Central and Eastern Europe. Between November 2020 and May 2021, the Euroguidelines in Central and Eastern Europe Network Group started collecting observational data on HIV and COVID-19 co-infections. In total, 16 countries from Central and Eastern European submitted data (eCRF) on 557 HIV-positive patients. The current analyses included patients who had a radiological examination performed. Logistic regression models were used to identify the factors associated with death, ICU admission, and partial recovery (poor COVID-19 outcomes). Factors that were significant in the univariate models (p < 0.1) were included in the multivariate model. Radiological data were available for 224 (40.2%) patients, 108 (48.2%) had computed tomography, and 116 (51.8%) had a chest X-ray. Of these, 211 (94.2%) were diagnosed using RT-PCR tests, 212 (94.6%) were symptomatic, 123 (55.6%) were hospitalized, 37 (16.6%) required oxygen therapy, and 28 (13.1%) either died, were admitted to ICU, or only partially recovered. From the radiologist’s description, 138 (61.6%) patients had typical radiological changes, 18 (8.0%) atypical changes, and 68 (30.4%) no changes. In the univariate models, CD4 count (OR = 0.86 [95% CI: 0.76−0.98]), having a comorbidity (2.33 [1.43−3.80]), HCV and/or HBV co-infection (3.17 [1.32−7.60]), being currently employed (0.31 [0.13−0.70]), being on antiretroviral therapy (0.22 [0.08−0.63]), and having typical (3.90 [1.12−13.65]) or atypical (10.8 [2.23−52.5]) radiological changes were all significantly associated with poor COVID-19 outcomes. In the multivariate model, being on antiretroviral therapy (OR = 0.20 [95% CI:0.05−0.80]) decreased the odds of poor COVID-19 outcomes, while having a comorbidity (2.12 [1.20−3.72]) or either typical (4.23 [1.05−17.0]) or atypical (6.39 [1.03−39.7]) radiological changes (vs. no changes) increased the odds of poor COVID-19 outcomes. Among HIV patients diagnosed with symptomatic SARS-CoV-2 infection, the presence of either typical or atypical radiological COVID-19 changes independently predicted poorer outcomes.

Non-Langerhans cell histiocytosis is a rare disease which seldom affects adults. We report a case of a 32-year-old Bulgarian woman living with HIV. She developed severe anemia, extreme splenomegaly, requiring splenectomy and vertebral tumor formations leading to fracture. The diagnosis was confirmed by histological examination of the spleen, but subsequently questioned and a cumulative disease was discussed. After genetic testing, a cumulative disease was ruled out and the condition was determined to be Non-Langerhans cell histiocytosis. According to literature data, the disease has a high mortality rate. However, in our case, we should also note that there was a delay in diagnosis by several months due to difficulties in the clarification of the hematological disorder.

Background: There is currently no evidence suggesting that COVID-19 takes a different course in HIV-positive patients on antiretroviral treatment compared to the general population. However, little is known about the relation between specific HIV-related factors and the severity of the COVID-19 disease., Methods: We performed a retrospective analysis of cases collected through an on-line survey distributed by the Euroguidelines in Central and Eastern Europe Network Group. In statistical analyses characteristics of HIV-positive patients, asymptomatic/moderate and moderate/severe course were compared., Results: In total 34 HIV-positive patients diagnosed with COVID-19 were reported by 12 countries (Estonia, Czech Republic, Lithuania, Albania, Belarus, Romania, Serbia, Bosnia and Herzegovina, Poland, Russia, Hungary, Bulgaria). Asymptomatic courses of COVID-19 were reported in four (12%) cases, 11 (32%) patients presented with mild disease not requiring hospitalization, moderate disease with respiratory and/or systemic symptoms was observed in 14 (41%) cases, and severe disease with respiratory failure was found in five (15%) patients. The HIV-related characteristics of patients with an asymptomatic/mild course of COVID-19 were comparable to those with a moderate/severe course of COVID-19, except for the use of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in cART regimen (0.0% vs. 31.6% respectively, p = 0.0239)., Conclusions: In our analyses HIV viral suppression and immunological status were not associated with the course of COVID-19 disease. On the contrary the cART regimen could contribute to severity of SARS-CoV-2 infection. Large and prospective studies are necessary to further investigate this relationship., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

HIV-1 subtype CRF01&#95;AE is the second most predominant strain in Bulgaria, yet little is known about the molecular epidemiology of its origin and transmissibility. We used a phylodynamics approach to better understand this sub-epidemic by analyzing 270 HIV-1 polymerase ( pol ) sequences collected from persons diagnosed with HIV/AIDS between 1995 and 2019. Using network analyses at a 1.5% genetic distance threshold ( d ), we found a large 154-member outbreak cluster composed mostly of persons who inject drugs (PWID) that were predominantly men. At d = 0.5%, which was used to identify more recent transmission, the large cluster dissociated into three clusters of 18, 12, and 7 members, respectively, five dyads, and 107 singletons. Phylogenetic analysis of the Bulgarian sequences with publicly available global sequences showed that CRF01&#95;AE likely originated from multiple Asian countries, with Vietnam as the likely source of the outbreak cluster between 1988 and 1990. Our findings indicate that CRF01&#95;AE was introduced into Bulgaria multiple times since 1988, and infections then rapidly spread among PWID locally with bridging to other risk groups and countries. CRF01&#95;AE continues to spread in Bulgaria as evidenced by the more recent large clusters identified at d = 0.5%, highlighting the importance of public health prevention efforts in the PWID communities., Competing Interests: The authors declare no conflict of interest. The funding sponsors had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, and in the decision to publish the results.

HIV-associated lymphoma was first classified as an AIDS-defining disease by the American Center for Disease Control and Prevention (CDC) in 1985. Non-Hodgkin's lymphomas (NHLs) are frequent malignancies in AIDS patients. The risk of NHL in the case of an underlying HIV infection is estimated to be 100 times greater than in the general population, and it increases with the progression of the retrovirus-related immunosuppression. Cases of HIV-related non-Hodgkin's lymphoma are widely documented in the literature. In this article we present three cases of NHL and HIV hospitalized over a period of three years (2013-2016) at our specialized department for AIDS patients. Two of them were initially diagnosed with NHL and then with HIV infection. In one patient, NHL developed despite the patient's taking background antiretroviral therapy. The first case was a 38-year-old male diagnosed previously with HIV, who developed a palpable mass in the left zygomatic bone. The second case was a 52-year-old male who was first diagnosed with a cutaneous lymphoma, and subsequently with HIV infection. The third patient was a 63-year-old male who presented with two palpable masses: one in the left part of the mandible, and the other in the right inguinal region, the latter subsequently diagnosed as lymphoma. Following the latter diagnosis, the patient tested positive for HIV. The histological findings of the three lymphomas were as follows: an NHL plasmoblastic lymphoma, a cutaneous large B-cell anaplastic lymphoma, and a diffuse large B-cell lymphoma. The first patient received antiretroviral therapy (ART) and EPOCH (etoposide, pharmarubicin, vincristin, endoxane, uromitexan) plus radiotherapy, while the second received ART and CHOEP (endoxan, epirubicin, vincristin, etoposide, prednisolone). The third patient died a few days after beginning antiretroviral therapy.

The present investigation performed on Friend erythroleukemia cells provides evidence that the cellular reprogramming associated with transition of the cells from the growing to the resting state is accompanied by an intranuclear cycling of preexisting proteins migrating from the cytoplasm. The model system developed for this study affords an opportunity to follow these events in a conveniently short period. The flow microfluorometric analysis revealed that, with respect to DNA content, the quiescent nuclei exhibit distribution in G1, S and G2 phases, as do the nuclei of the control, exponentially growing cells. It was found further that the induction of quiescence arouses two waves of migration of preexisting cytoplasmic proteins toward the nucleus: an early one, during the transition to quiescence clearly showing density dependence, and a late one, in the established resting state. While the early-cycled proteins are undetectable in mass and once they have reached the nucleus have a short life time and, thus, could be considered as regulatory molecules, the late-cycled proteins accumulate within the nucleus and are associated most probably with structural reorganization of the resting nuclei; moreover, the late-cycled nonhistone proteins were found localized, at least partly, in the nuclear protein matrix structure. Control experiments confirmed that the early and late-cycled proteins have been synthesized in the cytoplasm in the proliferative state but are cycled intranuclearly only if the resting state has been induced. When finally the resting cells were stimulated to proliferate, the accumulated presynthesized and newly synthesized nonhistone proteins undergo a rapid degradation which suggests that the new cellular programme may require a complete elimination of the 'resting' nonhistone proteins.