Different Patterns Of Disease Progression Research Articles

Brain-first forms of Parkinson's disease are over-represented in patients with non-responsive resting tremor

Motor subtypes in Parkinson's Disease (PD) are unstable over time, limiting mechanistic insights and biomarker discovery. We focused on Rest Tremor (RT) as a symptom to test for phenotype stability and link it to specific circuits and disease mechanisms. Using the PPMI cohort data over 5 years we found that RT is more stable than classical Tremor-Dominant definitions, a stability also seen for RT response to therapy. At time of diagnosis, the population of therapy-resistant RT patients was enriched with a brain-first PD profile as predicted by a-Synuclein origin site and connectome (SOC) model. Resistant-RT patients have lower gastrointestinal and cardiovascular symptoms, lower prevalence of probable REM-Sleep behaviour disorder, and higher dopaminergic asymmetry compared to therapy-responsive or no tremor patients. Treating RT as a distinct phenomenon revealed a relative phenotypic stability with treatment response being linked to different patterns of disease progression.

Hyposecretory Progression Pattern Indicates Inferior Survival of Multiple Myeloma

Introduction: The application of novel drugs has significantly enhanced the prognosis of patients with MM. However, most patients will inevitably experience disease progression and relapse. At progressive disease (PD), patients always exhibit distinct features characterized by varying levels of M protein and plasma cells in the bone marrow (BMPC), even in the presence of end-organ damage. Notably, a subgroup of patients initially diagnosed with secretory MM exhibits a higher proportion of BMPC but a lower level of M protein when PD, rendering identification of this subgroup challenging without conducting bone marrow evaluations, leading to many patients experiencing PD but without timely treatment. The identification and comprehension of the hyposecretion at progression remain unclear and require further investigation. Thus, in this study, we aimed to assess the impact of different patterns of disease progression according to M protein and BMPC percentage on the survival and describe the features of the subgroup. Methods: We retrospectively analyzed the baseline and progression clinical features of 268 patients in our hospital between January 1, 2013 to July 1, 2023. We classified the PD patterns into three categories based on the elevated level of M protein and clonal plasma cells in bone marrow at progression: a. hyposecretory progression (HypoP) means >10% increase of the absolute percentage of BMPCs but serum M-protein increase <5g/L (or urine M protein increase < 200 mg/24h) and patients with the non-secretory subtype at diagnosis were excluded.; b. extramedullary progression (EMP) means appearance of a new extramedullary lesion; c. classic progression (ClaP) means any one or more of the other PD criteria according to International Myeloma Working Group (IMWG) criteria. High burden refers to the percentage of BMPC > 50%. Time from the first relapse to death as overall survival (OS) after the first progression (pro-OS). Results: There were 268 patients included in the study, and according to their features of M protein and BMPC at progression, 206 (76.8%) patients were classified in the ClaP group, 39 (14.6%) patients in EMP group and 23 (8.6%) patients in HypoP group. The percentage of female in HypoP group was 52.2%, which was much higher than that in other two groups (36.5% in ClaP and 30.8% in EMP). In general, the patients with MM are predominantly of the IgG subtype. Interestingly, for patients featured by hyposecretion in progression, the M protein types were mainly IgA (47.9%) and light chain type (43.5%) ( P<0.001). Compared to the ClaP and EMP group, there were more patients in HypoP presenting t(11;14) (36.8% vs 16.7% vs 11.8%) and 1q21+ (70% vs 53.8% vs 53.8%) both at diagnosis and progression. And at disease progression, the proportion of patients with t(4;14) in the HypoP group was as high as 50%. Besides, in terms of clinical manifestations, HypoP patients were more likely to suffer from hypercalcemia, renal dysfunction, and lower serum M protein level and EMP experienced high level of lactate dehydrogenase (LDH) both at diagnosis and progression. The median follow-up was 67.0m (7.6-123.0m). Figure 1 demonstrates the progression-free survival (PFS), OS and pro-OS of patients with different progression patterns. Patients in ClaP and EMP groups experienced similar PFS whereas HypoP patients had significantly shorter median PFS ( P=0.003, 23.9m vs. 22.6m vs. 14.1m). We also found that patients with ClaP and HypoP feature had inferior median OS ( P=0.007, 71.4m vs. 48.0m vs. 53.9m for ClaP vs. EMP vs, HypoP) and pro-OS ( P=0.012, 34.2m vs. 17.3m vs. 23.4m for ClaP vs, EMP vs. HypoP). Then we refer to these two as non-ClaP. In the Cox-regression, multivariate analysis showed ISS-III, ASCT and non-ClaP were associated with shorter pro-OS and OS ( Figure 1). Conclusions: In conclusion, our results indicate that the hyposecretory progression pattern is a valuable indicator of inferior survival. In such cases, bone marrow testing plays a crucial role in identifying and detecting this special group. Patients presenting with EMP or HypoP features tend to have a poorer prognosis, representing unmet clinical need. Therefore, it is important to recognize these particular patients as early as possible and to intensify treatment strategies.

Exploring the Complex and Multifaceted Interplay between Melanoma Cells and the Tumor Microenvironment.

Malignant melanoma is a very aggressive skin cancer, characterized by a heterogeneous nature and high metastatic potential. The incidence of melanoma is continuously increasing worldwide, and it is one of the most common cancers in young adults. In the past twenty years, our understanding of melanoma biology has increased profoundly, and disease management for patients with disseminated disease has improved due to the emergence of immunotherapy and targeted therapy. However, a significant fraction of patients relapse or do not respond adequately to treatment. This can partly be explained by the complex signaling between the tumor and its microenvironment, giving rise to melanoma phenotypes with different patterns of disease progression. This review focuses on the key aspects and complex relationship between pathogenesis, genetic abnormalities, tumor microenvironment, cellular plasticity, and metabolic reprogramming in melanoma. By acquiring a deeper understanding of the multifaceted features of melanomagenesis, we can reach a point of more individualized and patient-centered disease management and reduced costs of ineffective treatments.

STMO-3 Mid- to long-term outcome of supratotal resection of IDH1 wild-type glioblastoma based on 11C-methionine PET: a retrospective, single-center study

PurposeMid- to long-term outcome in glioblastoma (GBM) patients following supratotal resection (SupTR), involving complete resection both of contrast-enhancing enhanced (CE) tumors and areas of methionine (Met) uptake on 11C-Met positron emission tomography (Met-PET), are not clarified.MethodsA retrospective, single-center review was performed in newly diagnosed, IDH1 wild-type GBM patients, comparing SupTR with gross total resection (GTR), in which only CE tumor tissue was completely resected. Only patients who were operated on until November 2019 were included for evaluation of mid- to long-term outcome. Following resection, all patients underwent standard radiotherapy and temozolomide treatment, and were followed for progression-free survival (PFS) and overall survival (OS).ResultsAmong the 30 patients included in this study, 7 underwent SupTR and 23 underwent GTR. Awake craniotomy with cortical and subcortical mapping was more frequently performed in the SupTR group than in the GTR group. During the follow-up period, significantly different patterns of disease progression were observed between groups. Although more than 80% of recurrences were local in the GTR group, all recurrences in the SupTR group were distant. Median PFS in the GTR and SupTR groups was 8.8 months (95% confidence interval [CI], 5.2–14.9) and 27.8 months (95% CI, 6.0-not estimable) respectively (p=0.08 by log-rank test). Median OS was 17.7 months (95% CI, 14.2–35.1) in GTR and not reached (95% CI, 30.5-not estimable) in SupTR, respectively; this difference was statistically significant (p=0.03 by log-rank test). No postoperative neurocognitive impairment was observed in SupTR patients.ConclusionCompared to GTR alone, SupTR strategy with aggressive resection of both CE tumors and Met uptake area in GBM patients under awake craniotomy with functional preservation results in a survival benefit associated with better local control.

The Natural History of Lower Risk MDS: Factors Predicting Progression to High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia in Patients with Very Low and Low Risk MDS According to the R-IPSS Criteria

The Natural History of Lower Risk MDS: Factors Predicting Progression to High-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia in Patients with Very Low and Low Risk MDS According to the R-IPSS Criteria

Oncological and functional outcomes of supratotal resection of IDH1 wild-type glioblastoma based on 11C-methionine PET: a retrospective, single-center study

The oncological and functional outcomes in glioblastoma (GBM) patients following supratotal resection (SupTR), involving complete resection of contrast-enhancing enhanced (CE) tumors and areas of methionine (Met) uptake on 11C-met positron emission tomography (Met-PET), are unknown. We conducted a retrospective review in newly diagnosed, IDH1 wild-type GBM patients, comparing SupTR with gross total resection (GTR), in which only CE tumor tissue was resected. All patients underwent standard radiotherapy and temozolomide treatment, and were followed for tumor recurrence and overall survival (OS). Among the 30 patients included in this study, 7 underwent SupTR and 23 underwent GTR. Awake craniotomy with cortical and subcortical mapping was more frequently performed in the SupTR group than in the GTR group. During the follow-up period, significantly different patterns of disease progression were observed between groups. Although more than 80% of recurrences were local in the GTR group, all recurrences in the SupTR group were distant. Median OS in the GTR and SupTR groups was 18.5 months (95% confidence interval [CI] 14.2–35.1) and not reached (95% CI 30.5-not estimable), respectively; this difference was statistically significant (p = 0.03 by log-rank test). No postoperative neurocognitive decline was evident in patients who underwent SupTR. Compared to GTR alone, aggressive resection of both CE tumors and areas with Met uptake (SupTR) under awake craniotomy with functional mapping results in a survival benefit associated with better local control and neurocognitive preservation.

Changing Times for CLN2 Disease: The Era of Enzyme Replacement Therapy.

Neuronal ceroid lipofuscinosis type 2 (CLN2 disease) is a progressive neurodegenerative disease that results in early-onset, severe, progressive, neurological disabilities, leading to death in late childhood or early adolescence. Management has relied on symptomatic care, and supportive and palliative strategies, but the approval of the enzyme replacement therapy cerliponase alfa in the USA and Europe in 2017 brought different treatment opportunities. We describe the natural history of CLN2 disease, its diagnosis and management, and the preclinical and clinical development of cerliponase alfa. A PubMed search was undertaken for cerliponase alfa and rhTPP1 to identify preclinical and clinical studies. The hallmark-presenting symptoms of CLN2 disease are unprovoked seizures and a history of language delay, and progression involves motor dysfunction, and cognitive and visual decline. Cerliponase alfa has shown efficacy and tolerability in mouse and canine models of CLN2 disease when delivered intracerebroventricularly. Administration of cerliponase alfa in patients with CLN2 disease has led to significant reductions in the rate of decline of motor and language functions in comparison with a natural history population. The approval of cerliponase alfa has brought a new era for CLN2 disease, highlighting the need to understand different patterns of disease progression and clinical needs in treated patients.

Recent Advances in Nuclear Imaging of Receptor Expression to Guide Targeted Therapies in Breast Cancer.

Breast cancer remains the most frequent cancer in women with different patterns of disease progression and response to treatments. The identification of specific biomarkers for different breast cancer subtypes has allowed the development of novel targeting agents for imaging and therapy. To date, patient management depends on immunohistochemistry analysis of receptor status on bioptic samples. This approach is too invasive, and in some cases, not entirely representative of the disease. Nuclear imaging using receptor tracers may provide whole-body information and detect any changes of receptor expression during disease progression. Therefore, imaging is useful to guide clinicians to select the best treatments for each patient and to evaluate early response thus reducing unnecessary therapies. In this review, we focused on the development of novel tracers that are ongoing in preclinical and/or clinical studies as promising tools to lead treatment decisions for breast cancer management.

Options for treating different soft tissue sarcoma subtypes.

Management of soft tissue sarcoma is increasingly subtype-dependent. Surgery is recommended for uterine leiomyosarcoma, with trabectedin being the preferred option for advanced disease when the treatment goal is long-term tumor stabilization. Liposarcoma subgroups are characterized by distinctive morphologies and genetics, different patterns of disease progression and clinical behavior, and variable responses to treatment. Genetic analysis of sarcomas has provided insights into pathogenesis with potential for developing new molecular targets. At the cytogenetic level, soft tissue sarcomas are categorized into specific, balanced translocations and those due to massive chromosomal rearrangements. For subtypes such as undifferentiated sarcomas, angiosarcomas, alveolar soft part sarcomas and clear cell sarcomas, evidence is especially limited, although it is known that these tumors display markedly different sensitivities to chemotherapeutic and targeted agents.

Periodontal progression based on radiographic records: An observational study in chronic and aggressive periodontitis

ObjectivesThe current classification assumes that aggressive periodontitis (AgP) has a faster rate of progression than chronic periodontitis (CP). However, this has not been clearly proven and difficulties exist in establishing progression. This study aimed to assess the feasibility of retrospectively utilising previous records for clinical diagnosis of periodontal diseases and to assess if two different patterns of disease progression exist between AgP and CP. Materials and methodsPrevious radiographic records of a cohort of 235 patients clinically diagnosed with AgP or CP were requested from the referring general dental practitioners (GDPs). Comparable radiographic records were analysed in order to assess progression patterns and associate these with clinical diagnosis, by multilevel analysis. Results43 patients out of the initial 235 had comparable radiographs retrieved from the GDPs. 858 sites were followed for an average 6.6 years. Radiographically, AgP showed a faster linear pattern of progression than CP (0.31mm/year vs. 0.20mm/year, p<0.001). ConclusionThis study provides evidence for a faster disease progression in untreated AgP compared to CP as assessed by radiographic bone levels. Furthermore, it shows that retrievability of previous radiographs from GDPs is unpredictable and GDPs should be encouraged to send them along with their referral. Clinical significanceThe importance of differentially diagnosing AgP and CP might be useful in establishing a clinically relevant definition for periodontal disease progression and may have an impact on the clinical management of aggressive periodontitis, since our findings show that there is continuous destruction in patients with aggressive periodontitis if left untreated.

High-throughput characterization of Echinococcus spp. metacestode miRNomes

Echinococcosis is a worldwide zoonosis of great public health concern, considered a neglected disease by the World Health Organisation. The cestode parasites Echinococcus granulosus sensu lato (s. l.) and Echinococcus multilocularis are the main aetiological agents. In the intermediate host, these parasites display particular developmental traits that lead to different patterns of disease progression. In an attempt to understand the causes of these differences, we focused on the analysis of microRNAs (miRNAs), small non-coding regulatory RNAs with major roles in development of animals and plants. In this work, we analysed the small RNA expression pattern of the metacestode, the stage of sanitary relevance, and provide a detailed description of Echinococcus miRNAs. Using high-throughput small RNA sequencing, we believe that we have carried out the first experimental identification of miRNAs in E. multilocularis and have expanded the Echinococcus miRNA catalogue to 38 miRNA genes, including one miRNA only present in E. granulosus s. l. Our findings show that although both species share the top five highest expressed miRNAs, 13 are differentially expressed, which could be related to developmental differences. We also provide evidence that uridylation is the main miRNA processing mechanism in Echinococcus spp. These results provide detailed information on Echinococcus miRNAs, which is the first step in understanding their role in parasite biology and disease establishment and/or progression, and their future potential use as drug or diagnostic targets.

Salvage Therapy beyond Targeted Therapy in Lung Adenocarcinoma

Targeted therapy in lung adenocarcinoma has evolved rapidly over the last few years, especially in the application of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs). Although many patients with advanced EGFR-mutated or ALK-rearranged lung adenocarcinoma do benefit from treatment with a specific TKI, the duration of disease control is notoriously short. Different patterns of disease progression have been recognized that may require distinct treatment approaches. Isolated progressive disease in the central nervous system requires additional local therapy (radiotherapy or surgery) and an exploratory pulsatile regimen of TKI. Oligoprogressive disease at extracranial sites, representing resistant tumor clones in isolated lesions, requires local ablative therapy (radiotherapy or surgery) and continuation of the existing TKI. Multifocal progressive disease is a key therapeutic challenge to overcome because of widespread acquired resistance due to heterogeneous mechanisms. It is now known that EGFR TKI-acquired resistance is mostly (50-60%) due to a single resistance mutation in exon 20 (T790M) and occasionally (5-10%) due to c-MET amplification. On the contrary, the acquired resistance mechanisms to ALK TKI appear more diverse. Specific therapeutic strategies are being developed to overcome various acquired resistance mechanisms and may further improve the overall prognosis of advanced lung adenocarcinoma with actionable driver mutations.

Dynamic features of the selective pressure on the human immunodeficiency virus type 1 (HIV-1) gp120 CD4-binding site in a group of long term non progressor (LTNP) subjects

The characteristics of intra-host human immunodeficiency virus type 1 (HIV-1) env evolution were evaluated in untreated HIV-1-infected subjects with different patterns of disease progression, including 2 normal progressor [NP], and 5 Long term non-progressor [LTNP] patients. High-resolution phylogenetic analysis of the C2-C5 env gene sequences of the replicating HIV-1 was performed in sequential samples collected over a 3–5 year period; overall, 301 HIV-1 genomic RNA sequences were amplified from plasma samples, cloned, sequenced and analyzed. Firstly, the evolutionary rate was calculated separately in the 3 codon positions. In all LTNPs, the 3rd codon mutation rate was equal or even lower than that observed at the 1st and 2nd positions (p = 0.016), thus suggesting strong ongoing positive selection. A Bayesian approach and a maximum-likelihood (ML) method were used to estimate the rate of virus evolution within each subject and to detect positively selected sites respectively. A great number of N-linked glycosylation sites under positive selection were identified in both NP and LTNP subjects. Viral sequences from 4 of the 5 LTNPs showed extensive positive selective pressure on the CD4-binding site (CD4bs). In addition, localized pressure in the area of the IgG-b12 epitope, a broad neutralizing human monoclonal antibody targeting the CD4bs, was documented in one LTNP subject, using a graphic colour grade 3-dimensional visualization. Overall, the data shown here documenting high selective pressure on the HIV-1 CD4bs of a group of LTNP subjects offers important insights for planning novel strategies for the immune control of HIV-1 infection.

Biological and Genetic Evolution of HIV Type 1 in Two Siblings with Different Patterns of Disease Progression

To investigate the immunological and virological factors that may lead to different patterns of disease progression characteristic of HIV-1-infected children, two HIV-1-infected siblings, a slow and a fast progressor, were followed prospectively before the onset of highly active antiretroviral therapy. Viral coreceptor usage, including the use of CCR5/CXCR4 chimeric receptors, macrophage tropism, and sensitivity to the CC-chemokine RANTES, has been studied. An autologous and heterologous neutralizing antibody response has been documented using peripheral blood mononuclear cells- and GHOST(3) cell line-based assays. Viral evolution was investigated by env C2-V3 region sequence analysis. Although both siblings were infected with HIV-1 of the R5 phenotype, their viruses showed important biological differences. In the fast progressor there was a higher RANTES sensitivity of the early virus, an increased trend to change the mode of CCR5 receptor use, and a larger genetic evolution. Both children developed an autologous neutralizing antibody response starting from the second year with evidence of the continuous emergence of resistant variants. A marked viral genetic and phenotypic evolution was documented in the fast progressor sibling, which is accompanied by a high viral RANTES sensitivity and persistent neutralizing antibodies.

Toxoplasma gondii: Inconsistent dissemination patterns following oral infection in mice

Since Toxoplasma gondii is transmitted in the wild through the ingestion of infective cysts, oral infection is a preferred model for studying the natural mode of parasite dissemination and pathogenesis. Using luciferase-expressing strains of T. gondii and in vivo imaging, we observed different patterns of disease progression in mice depending of the method of oral infection. Oral gavage of infective cysts (e.g., bradyzoites) resulted in an inconsistent pattern of parasite dissemination; in the majority (20/29) of infected mice, luciferase-derived signal (indicating high numbers of Toxoplasma tachyzoites) was first observed in the right chest area. At later time points this signal spread to other parts of the mouse, including the abdominal area. In the remaining mice (9/29), parasites were first observed replicating in the abdominal area, as might be expected. In contrast, when mice were infected naturally (either via ingestion of whole brains from previously infected mice or brain cyst homogenate-soaked bread), parasites were first observed replicating in the abdominal area in all mice examined (10/10). Based on the inconsistency of infections initiated with oral gavage, it is recommended that natural feeding be used to infect mice when a consistent oral infection is desired.

P1-139: Patterns of cognitive decline during long-term treatment of Alzheimer’s disease in relation to cognitive reserve

Some patients treated for Alzheimer's disease (AD) do better than others but the factors that underlie different patterns of disease progression are poorly understood. Variability in cognitive reserve offers one explanation for why patients with similar treatments show variable disease expression. To identify patterns of disease progression in relation to initial conditions. Data come from long term follow–up of patients enrolled in European/Canadian trials of galantamine (Gal–Int 13). Of 240 patients with mild–moderate AD at baseline (age 74.5+/–7.8; 61% women) who were treated with galantamine for 48 months, 188 completed the study. The Alzheimer's Disease Assessment Scale–cognitive subscale (ADAS–cog) and Disability Assessment in Dementia (DAD), were assessed throughout. The Mini–Mental State Examination (MMSE) was available only at baseline. Patients were classified by iterative K–means clustering in three distinct groups according to their pattern of disease progression. The three groups of patients were identified as “least progression” (n=82), “intermediate” (n=82), and “persistent progression”(n=75) based on their ADAS–cog trajectories. The between–group differences in baseline characteristics were much higher than the within–group differences in the maximal rates of change. Of note, these differences do not diminish during the course of disease progression; rather they tend to increase: on average, over 48 months the ADAS–cog increased (representing decline) by 13 points in those with least progression, by 17 points in the intermediate group, and by 21 points for the persistent progression group (p<0.01). The maximal annual changes are 6, 8 and 10, respectively (p for trend <0.05). The baseline MMSE and ADAS–cog were significantly different between the three groups. For example, patients with the least progression had a baseline ADAS–cog of 15+/–8, those in the intermediate group had ADAS–cog 20+/–9 and those with persistent progression had ADAS–cog 30+/–10 (p<0.001). This is also reflected in the MMSE but not the DAD. Of note, only 10.8% of patients with the least progression dropped out, compared with 26.7% of persistent progressors (p<0.001). Differences in patterns of decline appear to arise from differences in the initial (baseline) state. These differences in initial conditions are consistent with differences in cognitive reserve.

Inverse correlation of telomerase activity/proliferation of CD4+ T lymphocytes and disease progression in simian immunodeficiency virus-infected nonhuman primates.

Both increased lymphocyte renewal with subsequent exhaustion of the immune system and impaired T-cell renewal have been put forth to account for CD4+ T-cell depletion and development of AIDS in HIV-1-infected humans and SIV-infected nonhuman primates. In the present study, telomeric terminal restriction fragment length and telomerase activity were used as measures of proliferative activity of T lymphocytes from three nonhuman primate species before and after being infected with SIV. In peripheral blood T cells, our data show both species and T-cell-subset-specific differences in proliferative activity accompanied by different patterns of disease progression. A significant postinfection increase in telomerase/proliferative activity in CD4+ T cells from seropositive sooty mangabeys and from normal progressor rhesus macaques was associated with asymptomatic infection or delayed disease progression, respectively, whereas a decrease in telomerase/proliferative activity detected in CD4+ T cells postinfection from SIVsmmPBj14-infected pigtailed macaques was associated with rapid CD4+ T-cell depletion and disease progression. The levels of telomerase activity observed in CD4+ T cells from peripheral blood closely parallelled those seen in CD4+ T cells in lymph node samples from selected animals. Our data suggest that an increase in proliferative activity of T lymphocytes in vivo may be associated with a favorable course of SIV infection in nonhuman primates.

Viral phenotype in mother-to-child HIV-1 transmission and disease progression of vertically acquired HIV-1 infection.

Human immunodeficiency virus-1 (HIV-1) primary isolates differ in replicative capacity on peripheral blood mononuclear cells, tropism for primary monocyte-derived macrophages (MDM) and T-cell lines and syncytium-inducing (SI) capability on MT-2 cells in vitro. To assess the role of viral phenotype in mother-to-child HIV-1 transmission and the progression of vertically acquired HIV-1 infection, we studied 57 HIV-1-infected women at the time of delivery and 24 HIV-1-infected infants. Eight mothers transmitted the infection to their children. Primary isolates, obtained from 7 and 33 transmitting and non-transmitting mothers, respectively, differed in replicative capacity and SI activity, and no significant differences between the two groups were found regarding these viral properties. However, all primary isolates from transmitting mothers, but about half of those from non-transmitting mothers, were able to infect and replicate in MDM, regardless of their replicative capacity and/or SI activity; moreover, the monocyto-macrophage tropism of the maternal isolate correlated with an increased risk of transmission. Viral isolates from HIV-1-infected children were typed before 2 months of age; all but four showed a tropism for MDM, further supporting the notion that monocyto-macrophage tropic variants are selectively transmitted from mother to child and/or selectively replicated upon transmission. Clinical follow-up disclosed that 7/11 infants with a rapid/high replicating virus but none of the 17 with a slow replicating virus developed severe symptoms of disease and/or severe immunodepression by 1 year of age. By means of competitive RNA-polymerase chain reaction (PCR), a relationship was found between viral phenotype and dynamics of HIV-1 replication early in life in children who experienced different patterns of disease progression.

Type 1 cytokine production and low prevalence of viral isolation correlate with long-term nonprogression in HIV infection.

Cytokine production, prevalence of viral isolation, and surface marker expression of peripheral blood mononuclear cells (PBMCs) were analyzed in HIV+ individuals with different patterns of disease progression to establish correlations between these parameters. Thus, mitogen-stimulated in vitro production of interferon gamma (IFN-gamma) and interleukin 2 (IL-2) (type 1 cytokines), and of IL-4 and IL-10 (type 2 cytokines) as well as prevalence of viral isolation were evaluated in 26 HIV+ long-term nonprogressors (LTNPs), in 28 HIV+ patients with progressive HIV infection (PI), and in 24 HIV-seronegative controls (HCs). Surface expression of activation and nonactivation markers was also analyzed in a group of these donors. We report that (1) IL-2 and IFN-gamma production is reduced and IL-4 and IL-10 production is increased in PI patients compared to HCs and LTNPs; (2) prevalence of HIV isolation is lower in LTNPs compared to PI, and the primary viral isolates in LTNPs show a slow/low (S/L) phenotype; and (3) the elevated production of type 2 cytokines is paralleled by an increase in CD57+CD4+CD7- lymphocytes. Thus, whereas a high IL-2, high IFN-gamma/low IL-4, low IL-10 cytokine production pattern is present in HC and in LTNP HIV+, progression of HIV infection is associated with a low IL-2 low IFN-gamma/high IL-4, high IL-10 cytokine profile; increased prevalence of HIV isolation; and an augmented percentage of CD57+CD4+CD7- lymphocytes. These findings further confirm that a dominant type 1 cytokine profile together with reduced prevalence of virus isolation is associated with lack of progression in HIV infection.

Immunologic characterization of children vertically infected with human immunodeficiency virus, with slow or rapid disease progression

Cytokine production of unstimulated and mitogen-stimulated peripheral blood mononuclear cells of 31 children vertically infected with human immunodeficiency virus type 1 (HIV) and with different patterns of disease progression was evaluated to establish possible correlations between the immunologic and the clinical findings. Production of interferon gamma and interleukin-2 (type 1 cytokines), and of interleukin-4 and interleukin-10 (type 2 cytokines), was analyzed in seven symptom-free patients (Centers for Disease Control and Prevention class P-1B), 10 patients with mild symptoms (class P-2A), and 14 patients with severe symptoms (class P-2B-F). Cytokine production was compared with that of 10 age- and sex-matched control subjects who were seronegative for HIV. The HIV-infected patients produced significantly fewer type 1 cytokines and significantly more type 2 cytokines than the uninfected control subjects. No differences in the production of interferon gamma and interleukin-2 were detected among the different clinical categories of HIV-infected patients. In contrast, interleukin-4 production was augmented in the patients with class P-2A ( p <0.05) and class P-2B-F HIV infection ( p <0.03), in comparison with the children with class P-1B infection. The increase in interleukin-4 production was paralleled by an increase in the number of children with hyperimmunoglobulinemia E in each of the clinical groups (0% in class P-1B; 40% in class P-2A; and 71% in class P-2 B-F infection). Similarly, interleukin-10 production was increased both in patients with class P-2A and in those with class P-2B-F infection, in comparison with the children with class P-1B disease ( p<0.006 and <0.04, respectively). These data indicate (1) that vertically acquired HIV infection results in decreased production of type 1 cytokines and in increased production of type 2 cytokines, and (2) that an increased production of type 2 cytokines correlates with hyperimmunoglobulinemia E and is present in, and may be characteristic of, the symptomatic phases of childhood HIV infection. (J P EDIATR 1995;126:368-74)