p16(INK4a) Expression and Immunologic Aging in Chronic HIV Infection

Chronic HIV infection is characterized by increased immune activation and immunosenescence. p16(INK4a) (p16) is a member of the cyclin-dependent kinase antagonist family that inhibits cellular proliferation, and its protein expression increases during normal chronological aging. However, some infectious diseases can increase the expression of this anti-proliferative protein, potentially accelerating immunological aging and dysfunction. In order to investigate the immunological aging in HIV patients, p16 protein expression was evaluated by flow cytometry, in T cell subsets in a cohort of chronically HIV-infected patients on and off ART as well as age-matched healthy controls. Results showed that untreated HIV-infected subjects exhibited increased per-cell p16 protein expression that was discordant with chronological aging. ART restored p16 protein expression to levels comparable with HIV-negative subjects in the CD4 compartment, but not in CD8 T cells, which can be an indicative of an irreversible activation/exhaustion status on these cells. Additionally, the frequency of activated CD4+ and CD8+ T cells was positively correlated with p16 expression in CD4+ and CD8+ T cells in untreated subjects. In contrast to healthy controls, untreated HIV-infected individuals had increased p16 levels within the effector memory (T-EM) subset, indicating a possible role for this marker in impaired clonal expansion during antiviral effector function. Taken together, these data demonstrate that chronic HIV infection is associated with elevated expression of the cellular aging marker p16 in T cells. ART restored normal p16 levels in the CD4+ T cell compartment, indicating that use of therapy can be of fundamental importance to normal cell cycling and maintaining immune homeostasis

Imbalanced expression of functional surface molecules in regulatory and effector T cells in systemic lupus erythematosus

Regulatory T (TREG) cells play an important role in maintaining immune tolerance and avoiding autoimmunity. We analyzed the expression of membrane molecules in TREG and effector T cells in systemic lupus erythematosus (SLE). TREG and effector T cells were analyzed for the expression of CTLA-4, PD1, CD28, CD95, GITR, HLA-DR, OX40, CD40L, and CD45RO in 26 patients with active disease, 31 with inactive disease, and 26 healthy controls. TREG cells were defined as CD25+/highCD127Ø/lowFoxP3+, and effector T cells were defined as CD25+CD127+FoxP3Ø. The ratio of TREG to effector T cells expressing GITR, PD1, HLA-DR, OX40, CD40L, and CD45RO was determined in the three groups. The frequency of TREG cells was similar in patients with SLE and controls. However, SLE patients had a decreased frequency of CTLA-4+TREG and CD28+TREG cells and an increased frequency of CD40L+TREG cells. There was a decrease in the TREG/effector-T ratio for GITR+, HLA-DR+, OX40+, and CD45RO+ cells, and an increased ratio of TREG/effector-T CD40L+ cells in patients with SLE. In addition, CD40L+TREG cell frequency correlated with the SLE disease activity index (P=0.0163). In conclusion, our findings showed several abnormalities in the expression of functionally critical surface molecules in TREG and effector T cells in SLE that may be relevant to the pathogenesis of this disease.

Systemic lupus erythematosus exhibits a dynamic and continuum spectrum of effector/regulatory T cells.

OBJECTIVE: The identification of regulatory T cells (Treg cells) as CD4(+)CD25(high) cells may be upset by the increased frequency of activated effector T cells (Teff cells) in inflammatory diseases such as systemic lupus erythematosus (SLE). This study aimed to evaluate the frequency of T-cell subsets according to the expression of CD25 and CD127 in active (A-SLE) and inactive SLE (I-SLE). METHODS: Peripheral blood mononuclear cells (PBMCs) from 26 A-SLE patients (SLE Disease Activity Index (SLEDAI) = 10.17 ± 3.7), 31 I-SLE patients (SLEDAI = 0), and 26 healthy controls (HC) were analysed by multicolour flow cytometry. RESULTS: CD25(high) cell frequency was increased in A-SLE (5.2 ± 5.7%) compared to I-SLE (3.4 ± 3.4%) and HC (1.73 ± 0.8%) (p < 0.01). However, the percentage of FoxP3(+) cells in the CD25(high) subset was decreased in A-SLE (24.6 ± 16.4%) compared to I-SLE (33.7 ± 16) and HC (45 ± 25.1%) (p < 0.01). This was partly due to the increased frequency of Teff cells (CD25(high)CD127(+)FoxP3(Ø)) in A-SLE (10.7 ± 7.3%) compared to I-SLE (8.5 ± 6.5) and HC (6.1 ± 1.8%) (p = 0.02). Hence the frequency of Treg cells (CD25(+/high)CD127(low/Ø)FoxP3(+)) was equivalent in A-SLE (1.4 ± 0.8%), I-SLE (1.37 ± 1.0%), and HC (1.13 ± 0.59%) (p = 0.42). A-SLE presented an increased frequency of CD25(+)CD127(+)FoxP3(+) and CD25(Ø)FoxP3(+)CD127(low/Ø) T cells, which may represent intermediate phenotypes between Treg and Teff cells. CONCLUSIONS: The present study has provided data supporting normal Treg cell frequency in A-SLE and I-SLE as well as increased frequency of Teff cells in A-SLE. This scenario reflects a Treg/Teff ratio imbalance that may favour the inflammatory phenotype of the disease. In addition, the increased frequency of T cells with putative intermediate phenotypes may be compatible with a highly dynamic immune system in SLE.

HIV Seroprevalence and Risk Factors in a Brazilian Prison.

The burden of the AIDS epidemic in Brazil is characterized by high prevalence rates in specific groups, including prison populations. Reports o HIV seroprevalence rates from several, prisons in different countries have varied widely. Those rates have usually reflected the HIV seroprevalence in the community served by the correctional facility studied and the risk factors of inmates for HIV infection. The present study was designed: 1) to determine the HIV seroprevalence among inmates of Casa de Detenção de São Paulo; 2) to identify independent risk factors for HIV acquisition; and 3) to determine the relevance of transmission of HIV infection within the prison. From December 20, 1993, through January 5, 1994, 780 inmates were interviewed using a standardized questionnaire and had their blood drawn for HIV testing by ELISA with confirmatory Western Blot. Out of 766 inmates tested, 637 (83.1%) were negative for HIV, 105 (13.7%) were positive, and 24 (3.1%) had indeterminate test results. Multivariate logistic regression analysis identified the following variables as independent risk factors for HIV seropositivity: 1) age less than 29 years-old; 2) previous incarceration in Casa de Detençã; 3) more than one sexual partner in the last year in Casa de Detençã; and 4) intravenous drug use before admission to Casa de Detençã. We conclude from this study that HIV infection among prisoners is high (13.7%) and that several risk factors are responsible. Of these, intravenous drug use before imprisonment is the most likely factor, but HIV transmission can also occur during incarceration.

Disseminated Strongyloides stercoralis Infection in an AIDS Patient: The Role of Suppressive Therapy.

Patients with AIDS are prone to develop infections caused by opportunistic pathogens. Unusual agents, such as Strongyloides stercoralis, are being described in this syndrome, resulting in disseminated disease which is always severe and, in some cases, fatal. We describe a case of a patient with AIDS and Strongyloides stercoralis infection involving the gastrointestinal tract and the lungs. Therapy with thiabendazole for ten days led to resolution of the acute episode. Preventive therapy with 3g of thiabendazole once a week was then prescribed, and repeated fecal examinations were negative for larvae. Following discontinuation of treatment, however, the patient again had a positive fecal examination for Strongyloides stercoralis larvae, even though reinfection was considered to be very unlikely. The patient was retreated with a shorter course of therapy and once per week preventive therapy was reintroduced. After four months of follow-up, repeated fecal examinations were negative. When the treatment was changed to thiabendazole given once every two weeks, however, pulmonary Strongyloides stercoralis recurred. Subsequently, because of intolerance to thiabendazole, the patient was treated with cambendazole. The patient died three months later due to Pseudomonas aeruginosa pneumonia. Prolonged therapy for Strongyloides stercoralis infection may be necessary. Although further evaluation is needed, 3g of thiabendazole once a week may be adequate for this purpose. Cambendazole may be a useful alternative for disseminated Strongyloides stercoralis.