T cells isolated from patients with checkpoint inhibitor-resistant melanoma are functional and can mediate tumor regression.

Background: Almost half of the patients with metastatic melanoma obtain only short-term or no benefit at all from checkpoint inhibitor (CPI) immunotherapy. In this study, we investigated whether the immune system of patients progressing following CPI treatment was able to generate functional tumor-specific immune responses. Materials and methods: Tumor-infiltrating lymphocytes (TILs) were isolated and expanded from metastatic melanoma lesions which progressed during or after anti-programmed cell death protein 1 (PD)-1 and anti-Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4) treatment. Tumor-specific immune responses were assessed with co-culture assays of TILs and autologous tumor cells. Results: TILs from 23 metastases of individual patients could be assessed for T cells recognition of autologous tumor cells. All metastases were progressive on or following anti-PD-1 (23/23, 100%), and the majority also after anti-CTLA-4 (17/23, 74%). Functional antitumor immune responses were detected in 19/23 patients (83%). Both CD8+ (in 18/23 patients, 78%) and CD4+ (in 16/23 patients, 70%) TILs were able to recognize autologous tumors. A large fraction of CD8+ TILs (median 23%, range 1.0%-84%) recognized tumor cells. This is similar to the cohorts of unselected patient populations with metastatic melanoma presented in previous studies. The localization of intratumoral immune infiltrates was heterogeneous among samples. In a phase I/II clinical trial, TILs were administered with lymphodepleting chemotherapy, pegIFNα2b and interleukin-2 to 12 patients with CPI-resistant melanoma. Out of 12 patients who previously failed CPI therapy, treatment with TILs resulted in two partial responses, of which one is ongoing. Conclusions: Tumor-reactive T cells appear to heavily infiltrate the tumor microenvironment of patients who failed previous CPI treatment. These patients can still respond to an infusion of unselected autologous TILs. Our results warrant further testing of novel immune re-activation strategies in melanoma patients who failed multiple CPI therapy.

Genomic analysis of Fas and FasL genes and absence of correlation with disease progression in AIDS.

Apoptosis has been suggested as a major mechanism for the CD4(+) T-lymphocyte depletion observed in patients infected with human immunodeficiency virus 1 (HIV-1). To evaluate the impact of genetic variations to apoptosis during progression of acquired immunodeficiency syndrome (AIDS), we have performed an extensive genetic analysis of Fas and Fas ligand ( FasL) genes. The coding regions and promoters of these genes were resequenced in a cohort of 212 HIV-1-seropositive patients presenting extreme disease phenotypes and 155 healthy controls of Caucasian origin. Overall, 33 single nucleotide polymorphisms (SNPs) with an allele frequency >1% were identified and evaluated for their association with disease progression. Among them, 14 polymorphisms were newly characterized. We did not find any statistically significant association of Fas and FasL polymorphisms and haplotypes with AIDS progression.

Genomic analysis of Th1-Th2 cytokine genes in an AIDS cohort: identification of IL4 and IL10 haplotypes associated with the disease progression.

Polymorphisms of Th1-Th2 cytokine genes have previously been implicated in the rate of progression to AIDS in seropositive patients. To evaluate further the impact of these genes in the development of AIDS, we have performed an extensive genetic analysis of IL2, IL4, IL6, IL10, IL12p35 and p40, IL13 and IFNgamma. The coding regions and promoters of these genes were sequenced in a Caucasian cohort of 337 HIV-1 seropositive extreme patients (the GRIV cohort) consisting of patients with slow progression and rapid progression, and up to 470 healthy controls. In all, 64 single nucleotide polymorphisms (SNPs) and four deleterious polymorphisms with frequency >1% were identified and evaluated for their association with disease. Statistically significant associations were observed with haplotypes of the IL4 and IL10 genes, but no relation was found with variants of other genes. The catalogue of SNP and haplotypes presented here will facilitate further genetic investigations of Th1-Th2 cytokines in AIDS and other immune-related disorders.

Genomic studies in AIDS: problems and answers. Development of a statistical model integrating both longitudinal cohort studies and transversal observations of extreme cases.

Genomic studies developed to understand HIV-1 infection and pathogenesis have often lead to conflicting results. This is linked to various factors, including differences in cohort design and selection, the numbers of patients involved, the influence of population substructure, the ethnic origins of the participants, and phenotypic definition. These difficulties in the interpretation of results are examined through published studies on the role of polymorphisms in HLA and the chemokine receptors genes in AIDS. Our analysis suggests that the use of haplotypes will strengthen the results obtained in a given cohort, and meta-analysis including multiple cohorts to gather large-enough numbers of patients should also allow clarification of the genetic associations observed. A P-value of 0.001 appears to be a good compromise for significance on candidate genes in a genetic study. Due to the generally limited size of available cohorts, results will have to be validated in other cohorts. We developed a model to fit transversal case studies (extreme case-control studies) with longitudinal cohorts (all-stages patients) for observations on two gene polymorphisms of CCR5 and NQO1. Interestingly, we observe a protective effect for the CCR5-Delta32 mutant allele in 95% of the simulations based on that model when using a population of 600 subjects; however, when using populations of 250 subjects we find a significant protection in only 59% of the simulations. Our model gives thus an explanation for the discrepancies observed in the various genomic studies published in AIDS on CCR5-Delta32 and other gene polymorphisms: they result from statistical fluctuations due to a lack of power. The sizes of most seroconverter cohorts presently available seem thus insufficient since they include less than a few hundred subjects. This result underlines the power and usefulness of the transversal studies involving extreme patients and their complementarity to longitudinal studies involving seroconverter cohorts. The transposition approach of extreme case-control data into longitudinal analysis should prove useful not only in AIDS but also in other diseases induced by chronic exposure to a foreign agent or with chronic clinical manifestations.

Endoscopic retrograde cholangiopancreatography causes reduced myocardial blood flow.

BACKGROUND AND STUDY AIMS: Previous studies have shown that up to 50% of healthy patients may develop ST-segment changes during upper gastrointestinal endoscopy. The aim of the study was to evaluate myocardial blood flow in patients during endoscopic retrograde cholangiopancreatography (ERCP). PATIENTS AND METHODS: 11 patients scheduled for ERCP were monitored with a Holter tape recorder and underwent myocardial perfusion scintigraphies, to evaluate myocardial perfusion at rest and during ERCP. RESULTS: Ten patients completed the study. Eight patients had no sign of myocardial ischemia with either of the two methods, while two patients developed signs of ischemia during ERCP with both the Holter tape recording and on myocardial scintigraphy (P = 0.02). CONCLUSIONS: Patients undergoing ERCP may develop true myocardial ischemia with reduced myocardial blood flow. Although this is a small-scale study, these findings strongly support the use of alternative methods for diagnostic evaluation of the pancreatic duct and biliary tree.

Accelerated postoperative recovery programme after colonic resection improves physical performance, pulmonary function and body composition.

BACKGROUND: Postoperative organ dysfunction contributes to morbidity, hospital stay and convalescence. Multimodal rehabilitation with epidural analgesia, early oral feeding, mobilization and laxative use after colonic resection has reduced ileus and hospital stay. METHODS: Fourteen patients receiving conventional care (group 1) and 14 patients who had multimodal rehabilitation (group 2) were studied before and 8 days after colonic resection. Outcome measures included postoperative mobilization, body composition by whole-body dual X-ray absorptiometry, cardiovascular response to treadmill exercise, pulmonary function and nocturnal oxygen saturation. RESULTS: Defaecation occurred earlier (median day 1 versus day 4) and hospital stay was shorter (median 2 versus 12 days) in patients who had multimodal treatment. Lean body and fat mass decreased in group 1 but not in group 2. Exercise performance decreased by 44 per cent in group 1 but was unchanged in group 2. A postoperative increase in heart rate (HR) response to exercise was avoided in group 2. Pulmonary function decreased in group 1 but not in group 2. There was less nocturnal postoperative hypoxaemia in group 2. Cardiac demand-supply (HR/oxygen saturation ratio) increased in group 1 but not in group 2. CONCLUSION: Multimodal rehabilitation prevents reduction in lean body mass, pulmonary function, oxygenation and cardiovascular response to exercise after colonic surgery.

Minor long-term changes in weight have beneficial effects on insulin sensitivity and beta-cell function in obese subjects.

AIM: To evaluate the long-term effect of changes in body composition induced by weight loss on insulin sensitivity (SI), non-insulin mediated glucose disposal, glucose effectiveness (SG)and beta-cell function. DESIGN: Glucose metabolism was evaluated before and after participation in a two-year weight loss trial of Orlistat vs. placebo, combined with an energy and fat restricted diet. SUBJECTS: Twelve obese patients (11 women, 1 man), age 45.8 +/- 10.5 years, body weight (BW) 99.7 +/- 13.3 kg, BMI 35.3 +/- 2.8 kg/m(2). MEASUREMENTS: At inclusion and 2 years later an oral glucose tolerance test (OGTT) and a frequently sampled intravenous glucose tolerance test (FSIGT) were performed. Body composition was estimated by a dual-energy X-ray absorptiometry (DXA) whole body scanning. RESULTS: The patients obtained varying changes in BW ranging from a weight loss of 17.8 kg to a weight gain of 6.0 kg. Corresponding changes in fat mass (FM) varied from a 40% reduction to a19% increase. A significant decrease in both fasting (p = 0.038) and 2 h (p = 0.047) blood glucose at OGTT was found. The improvement in insulin sensitivity (SI) estimated by means of Bergmans Minimal Model, was significantly and linearly correlated to change in total FM (r = - 0.83,p = 0.0026). A multiple regression analysis showed that changes in truncal FM was the strongest predictor of change in S(I) explaining 67% of the variation. First phase insulin response (AIRg)remained unchanged whereas insulin disposition index increased significantly (p = 0.044). At inclusion five patients had impaired glucose tolerance of which four, who lost weight, were normalized at the retest 2 years later. CONCLUSION: In obese subjects long-term minimal or moderate changes in weight were found to be linearly associated with changes in insulin sensitivity. In obese subjects with impaired glucose tolerance even a minor weight loss was able to normalize glucose tolerance.

Influence of orlistat on bone turnover and body composition.

OBJECTIVE: To investigate the influence of the pancreas lipase inhibitor orlistat (OLS) on calcium metabolism, bone turnover, bone mass, bone density and body composition when given for obesity as adjuvant to an energy- and fat-restricted diet. DESIGN: Randomized controlled double-blinded trial of treatment with OLS 120 mg three times daily or placebo for 1 y. SUBJECTS: Thirty obese subjects with a mean body mass index (BMI) of 36.9+/-3.7 kg/m(2) and a mean age of 41+/-11 y. Sixteen patients were assigned to OLS and 14 to placebo. MEASUREMENTS: Dual energy X-ray absorptiometry (DXA) measurements of bone mineral and body composition included total bone mineral content (TBMC), total bone mineral density (TBMD), lumbar spine BMC and BMD, forearm BMC and BMD, fat mass (FM), fat free-mass (FFM), percentage fat mass (FM%) as well as a DXA estimate of the body weight. Body composition (FM, FFM and FM%) was estimated by total body potassium (TBK). Indices of calcium metabolism and bone turnover included serum values of ionized calcium (Ca(++)), iPTH (parathyroid hormone), alkaline phosphatase, 25(OH)-vitamin D, 1,25(OH)(2) vitamin D and osteocalcin as well as fasting urinary ratios of hydroxyproline/creatinine and Ca/creatinine (fU-OHpr/creat, fUCa/creat). RESULTS: There were no significant differences between OLS and placebo groups as to any of the body composition variables (FFM, FM, FM%) at baseline or after 1 y treatment. Weight loss was of 11.2+/-7.5 kg in the OLS group and 8.1+/-7.5 kg in the placebo group (NS). The changes in FM and FM% were significant in both groups determined by DXA as well as by TBK, but the group differences between these changes were not significant. The composition of the weight loss was approximately 80% fat in both groups. FFM only changed significantly by DXA in the OLS group (-1.3 kg), but the difference from the placebo group was not significant. Forearm BMD in both groups, forearm BMC in the OLS group and TBMD in the placebo group fell discretely but significantly, but there were no significant group differences between the OLS and the placebo-treated group. All biochemical variables except s-osteocalcin changed significantly after 1 y in the OLS group, disclosing a pattern of an incipient negative vitamin D balance, a secondary increase in PTH-secretion, and an increase in bone turnover with the emphasis on an increase in resorption parameters (fU-OHpr/creat, fUCa/creat). In the placebo group, only s-25(OH)vitamin D and fU-OHpr/creat changed significantly, but the pattern was also that of a deteriorated vitamin D status and an increase in PTH levels and bone turnover. The only biochemical variable which was significantly different between OLS and placebo groups after one year was the fU-OHpr/creat ratio, which increased from 12.0 to 20.1 in the OLS group but only from 10.9 to 1 3.2 in the placebo group. CONCLUSION: One year's treatment with OLS induces a lipid malabsorption which enhances a dietary weight loss without any significant deleterious effects on body composition. OLS induces a relative increase in bone turnover in favour of resorption, possibly due to malabsorption of vitamin D and/or calcium. However, no changes in bone mass or density are seen after 1 y of OLS treatment apart from those explained by the weight loss itself. Thus 1 y of OLS treatment seems safe from a 'bone preserving' point of view. A vitamin D and calcium supplement should be taken during the treatment.

Validation of genetic case-control studies in AIDS and application to the CX3CR1 polymorphism.

New polymorphisms have been recently identified in CX3CR1, a coreceptor for some HIV-1 strains, one of which was associated with a strong acceleration of HIV disease progression. This effect was observed both by a case-control study involving 63 nonprogressors (NP) from the asymptomatic long-term (ALT) cohort and Kaplan-Meier analysis of 426 French seroconverters (SEROCO cohort). These results prompted us to analyze these polymorphisms in 244 nonprogressors (NPs) and 80 rapid progressors (RPs) from the largest case-control cohort known to date, the GRIV cohort. Surprisingly, the genetic frequencies found were identical for both groups under all genetic models (p >.8). The discrepancy with the previous work stemmed only from the difference between GRIV NPs versus ALT NPs. We hypothesized this might be due to the limited number of NPs in ALT (n = 63) and in this line we reanalyzed the data previously collected on GRIV for over 100 different genetic polymorphisms: we effectively observed that the genetic frequencies of some polymorphisms could vary by as much as 10% (absolute percentage) when computing them on the first 50 NP subjects enrolled, on the first 100, or on all the NPs tested (240 study subjects). This observation emphasizes the need for caution in case-control studies involving small numbers of subjects: p values should be low or other control groups should be used.However, the association of the CX3CR1 polymorphism with progression seems quite significant in the Kaplan-Meier analysis of the SEROCO cohort (426 individuals), and the difference observed with GRIV might be explained by a delayed effect of the polymorphism on disease. Further studies on other seroconverter cohorts are needed to confirm the reported association with disease progression.

A common stromal cell-derived factor-1 chemokine gene variant is associated with the early onset of type 1 diabetes.

Type 1 diabetes results from the autoimmune destruction of pancreatic beta-cells. Although the disease shows a strong association with HLA class II alleles, other genes may influence the initiation or the rate of progression of the autoimmune process. The recruitment of mononuclear cells within the islets of Langerhans is a critical step in the pathogenesis of the disease. Because chemokines are cytokines that promote migration of mononuclear cells, we hypothesized that polymorphisms in chemokine receptor or chemokine genes, CCR5 and SDF1, may be involved in susceptibility to or clinical expression of type 1 diabetes. The frequencies of the CCR5-delta32 and SDF1-3'A (801G-->A in the 3' untranslated region) variants were similar in 208 unrelated Caucasian patients with type 1 diabetes and in 120 Caucasian control subjects. They were not modified after stratification for the predisposing HLA-DR3 and -DR4 haplotypes. However, the SDF1-3'A variant was strongly associated with early onset (< 15 years) of the disease (odds ratio 2.6, P = 0.0019). On average, the presence of the SDF1-3'A allele was associated with a 5-year reduction in the age at onset of diabetes (P = 0.0067). Our results suggest that stromal cell-derived factor-1 may be implicated in the aggressiveness of the autoimmune process leading to type 1 diabetes. These preliminary data require replication in other populations.

Autoantibodies to TNFalpha in HIV-1 infection: prospects for anti-cytokine vaccine therapy.

Tumor necrosis factor alpha (TNFalpha) is a proinflammatory cytokine principally involved in the activation of lymphocytes in response to viral infection. TNFalpha also stimulates the production of other cytokines, activates NK cells and potentiates cell death and/or lysis in certain models of viral infection. Although TNFalpha might be expected to be a protective component of an antiviral immune response, several lines of evidence suggest that TNFalpha and other virally-induced cytokines actually may contribute to the pathogenesis of HIV infection. Based on the activation of HIV replication in response to TNFalpha, HIV appears to have evolved to take advantage of host cytokine activation pathways. Antibodies to TNFalpha are present in the serum of normal individuals as well as in certain autoimmune disorders, and may modulate disease progression in the setting of HIV infection. We examined TNFalpha-specific antibodies in HIV-infected non-progressors and healthy seronegatives; anti-TNFalpha antibody levels are significantly higher in GRIV seropositive slow/non-progressors (N = 120, mean = 0.24), compared to seronegative controls (N= 12, mean = 0.11). TNFalpha antibodies correlated positively with viral load, (P = 0.013, r = 0.282), and CD8+ cell count (P = 0.03, r = 0.258), and inversely with CD4+ cell count (P = 0.003, r = - 0.246), percent CD4+ cells (P = 0.008, r = -0.306), and CD4 :CD8 ratio (P = 0.033, r = - 0.251). TNFalpha antibodies also correlated positively with antibodies to peptides corresponding to the CD4 binding site of gp160 (P = 0.001, r = 0.384), the CD4 identity region (P = 0.016, r = 0.29), the V3 loop (P = 0.005, r = 0.34), and the amino terminus of Tat (P = 0.001, r = 0.395); TNFalpha antibodies also correlated positively with antibodies to Nef protein (P = 0.008, r = 0.302). The production of anti-TNFalpha antibodies appears to be an adaptive response to HIV infection and suggests the potential utility of modified cytokine vaccines in the treatment of HIV infections as well as AIDS-related and unrelated autoimmune and CNS disorders.

Analysis of telomere length and thymic output in fast and slow/non-progressors with HIV infection.

There are two models for CD4+ T-cell depletion leading to AIDS: a kinetic model and an immune suppression model. In the kinetic model, direct cell killing due to viral replication results in a continuous demand for CD4+ T-cells, which eventually exhausts their capacity for renewal by proliferative mechanisms. In the immune suppression model, CD4+ T-cell decline is due to an indirect global inhibitory effect of the virus on uninfected immune cell function. In order to address differences in the two models, we investigated proliferative history and thymic output in PBMC from the GRIV cohort of fast (FP) and slow/non-progressors (S/NP), and uninfected controls. Proliferative history and thymic output were assessed by measurement of mean telomeric restriction fragment (TRF) length and T-cell receptor Rearrangement Excision Circles (TREC) levels, respectively. Mean TRF lengths were significantly shorter in S/NP (n = 93, 7.59 +/- 0.11 kb) and FP (n = 42, 7.25 +/- 0.15 kb) compared to controls (n = 35, 9.17 +/- 0.19 kb). Mean TRF length in PBMC (n = 9, 7.32 +/- 0.31 kb) and CD4+ enriched fractions (n = 9, 7.41 +/- 0.30 kb) from a subset of non-GRIV HIV-1 infected samples were also significantly smaller than PBMC (n = 8, 9.77 +/- 0.33 kb) and CD4+ fractions (n = 8, 9.41 +/- 0.32 kb) from uninfected controls. Rates of telomeric shortening, however, were similar among S/NP (n = 93, -45 +/- 20 bp/yr), FP (n = 42, -41 +/- 14 bp/yr) and controls (-29 +/- 17 bp/yr). Paralleling differences observed in mean TRF length, TREC levels were significantly reduced in S/NP (n = 10, 3,433 +/- 843 mol/mu and FP (n = 8, 1,193 +/- 413) compared to controls (n = 15, 22,706 +/- 5,089), indicative of a defect in thymopoiesis in HIV-1 infection. When evaluated in the context of reduced thymopoiesis, the difference in mean TRF length between S/NP and controls (1.58 +/- 0.30 kb) is similar to that observed between memory and naïve T-cells (1.4 +/- 0.1 kb), and may reflect perturbations in the peripheral T-cell population due to a decline in thymic output of naïve T-cells rather than increased turnover. Based on the different clinical criteria used to select S/NP and FP, the sight difference in TREC between these two groups suggests the threshold for pathogenesis as a result of naïve T-cell depletion may be quite low, and incremental increases in thymic output may yield substantial clinical results. Future studies regarding therapeutic vaccination, specifically with HIV-1 Tat targeted anti-immunosuppressive vaccines, should address the defect in thymic output in HIV-1 infection by using TREC analysis as a rapid method for biological evaluation.

New class I and II HLA alleles strongly associated with opposite patterns of progression to AIDS.

The genetics of resistance to infection by HIV-1 cohort consists of 200 slow and 75 rapid progressors to AIDS corresponding to the extremes of HIV disease outcome of 20,000 Caucasians of European descent. A comprehensive analysis of HLA class I and class II genes in this highly informative cohort has identified HLA alleles associated with fast or slow progression, including several not described previously. A quantitative analysis shows an overall HLA influence independent of and equal in magnitude (for the protective effect) to the effect of the CCR5-Delta32 mutation. Among HLA class I genes, A29 (p = 0.001) and B22 (p < 0.0001) are significantly associated with rapid progression, whereas B14 (p = 0.001) and C8 (p = 0.004) are significantly associated with nonprogression. The class I alleles B27, B57, C14 (protective), and C16, as well as B35 (susceptible), are also influential, but their effects are less robust. Influence of class II alleles was only observed for DR11. These results confirm the influence of the immune system on disease progression and may have implications on peptide-based vaccine development.

Distinctive effects of CCR5, CCR2, and SDF1 genetic polymorphisms in AIDS progression.

The Genetics of Resistance to Infection by HIV-1 (GRIV) cohort represents 200 nonprogressor/slow-progressor (Slowprog) and 90 fast-progressor (Fastprog) HIV-1-infected patients. Using this unique assembly, we performed genetic studies on three recently discovered polymorphisms of CCR5, CCR2, and SDF1, which have been shown to slow the rate of disease progression. The increased prevalence of mutant alleles among Slowprogs from the GRIV cohort was significant for CCR5 (p < .0001) but not for CCR2 (p = .09) or SDF1 (p = . 12), emphasizing the predominant role of CCR5 as the major HIV-1 coreceptor. However, the prevalence of the CCR2 mutant allele (64I) was significantly increased among Slowprogs homozygous for wild-type CCR5 compared with Fastprogs (p = .04). The prevalence of double mutants SDF1-3'A/3'A genotypes was also increased among Slowprogs homozygous for wild-type CCR5 compared with Fastprogs (p = .05). The effects of the CCR2 and SDF1 mutations are overshadowed by the protective effects of the CCR5 deletion. Predictive biologic markers such as CD4 cell counts or viral load in the Slowprog population did not show significant differences between Slowprog groups with wild-type or mutant alleles for the three genes. Thus, our data suggest that the effects of these genes are exerted earlier in infection and no longer evident in the Slowprog of the GRIV cohort whose average duration of HIV infection is 12 years. We conclude that these genes, whose products serve as viral coreceptors or their ligands, may play a role early in infection and delay the onset of disease. However, among Slowprogs, whose duration of infection is >8 years, they are no longer influential for maintenance of their longterm nonprogression status. Other genetic determinants may be responsible for late protective effects.

Fasting gall bladder volume and lithogenicity in relation to glucose tolerance, total and intra-abdominal fat masses in obese non-diabetic subjects.

OBJECTIVE: To investigate whether total body fat mass or fat distribution and associated metabolic disturbances in glucose and lipid metabolism influence the well known gallstone pathogenetic factors in obese subjects in order to explain why some obese subjects develop gallstones and some do not. DESIGN: Cross sectional study of gallstone pathogenetic factors, body composition, fat distribution, glucose and lipid metabolism. SUBJECTS: 57 healthy overweight subjects (aged 26-64y, body mass index (BMI) 30-45 kg/m2). MEASUREMENTS: Total and intra-abdominal fat masses were measured by dual X-ray absorptiometry and abdominal CT scanning, respectively. The lithogenic index was measured in aspirated bile. The gallbladder volume was determined by ultrasound and the gallbladder ejection fraction% by dynamic cholescintigraphy. Plasma cholecystokinin (CCK) concentrations during a meal were measured with a specific radioimmunoassay. Insulin sensitivity was measured by the Minimal Model and glucose tolerance by an oral glucose tolerance test (OGTT). Serum lipid concentrations were measured by standard methods. RESULTS: The gallbladder volume in the fasting state increased with increasing intra-abdominal fat mass (P=0.006) and was increased in subjects with impaired glucose tolerance (41 vs 27 ml, P=0.001). The lithogenic index was > 1 in all subjects and correlated with total fat mass (P=0.04). CONCLUSION: Gallstone pathogenesis in obesity seems to be influenced by the total body fat mass and its regional distribution possibly via mutual association with the glucose tolerance.

Antibodies to the HIV-1 Tat protein correlated with nonprogression to AIDS: a rationale for the use of Tat toxoid as an HIV-1 vaccine.

OBJECTIVES: To investigate which immune parameters, such as antibodies against HIV-1 specificities, or viral parameters, such as p24 antigenemia, are predictive of disease progression. STUDY DESIGN: We performed studies on serum collected from individuals exhibiting two extremes of disease evolution--67 fast progressors (FP) and 182 nonprogressors (NP)--at their enrollment. After a 1- to 2-year clinical follow-up of 104 nonprogressors after their enrollment, we could determine the best serologic predictors for disease progression. METHODS: We investigated levels of antibodies to tetanus toxoid and to HIV antigens including Env, Gag, Nef, and Tat proteins, as well as p24 antigenemia, viremia, CD4 cell count, and interferon-alpha (IFN-alpha) titers in FPs and NPs, and we correlated these data with clinical and biologic signs of progression. RESULTS: p24 Antigenemia, a marker of viral replication, and anti-Tat antibodies were highly and inversely correlated in both groups (P < .001). Furthermore, anti-p24 antibodies and low serum IFN-alpha levels were correlated to the NP versus the FP cohort. Finally, among NPs, only antibodies to Tat and not to the other HIV specificities (Env, Nef, Gag) were significantly predictive of clinical stability during their follow-up. CONCLUSION: Antibodies toward HIV-1 Tat, which are inversely correlated to p24 antigenemia, appear as a critical marker for a lack of disease progression. This study strongly suggests that rising anti-Tat antibodies through active immunization may be beneficial in AIDS vaccine development to control viral replication.