Bone marrow somatic mutation after genotoxic cancer therapy

Clinical and Experimental Immunology, 1999

This study presents the immunophenotypic and functional analysis of lymphocyte subsets obtained from peripheral blood and lymphoid tissue from HIV+ individuals treated with highly active anti-retroviral therapy (HAART) alone or in combination with 6 million units international (MUI) s.c. IL-2. Before treatment, the HIV+ patients had reduced CD4 and increased CD8 values in the peripheral blood and lymphoid tissue and impaired cytokine production by peripheral blood mononuclear cells (PBMC). After 24 weeks of treatment, all the HIV+ patients demonstrated increased CD4 values in peripheral blood and lymphoid tissue. The use of IL-2 did not promote an additional CD4 expansion compared with HAART alone; increased ‘naive’ and CD26+ CD4 cells and reduced CD8 cells were found in the peripheral blood and lymphoid tissue of the IL-2-treated, but not of the HAART-treated patients. Both types of treatment induced a significant reduction of the CD8/CD38+ cells. While HAART alone had negligible e...

Immunity, 2004

ment, was measured in peripheral blood-mononuclear cells (PBMCs). This ratio has the virtue that it is a Jean-Pierre Routy, 6 Zvi Grossman, 7,8 Rafick-Pierre Sé kaly, 1,2,3,4, * and Ré mi Cheynier 1,9 "signature" of thymic emigrants throughout their entire life and, thus, can be measured in peripheral cell 1 Laboratoire d'Immunologie Centre de Recherches du CHUM populations that are easy to obtain. Using the new assay, we evaluated the effect of HIV infection on intra-Hô tel-Dieu Montré al, Qué bec H2X 1P1 thymic precursor T cell proliferation by longitudinal analysis of PBMCs from recently infected individuals. Canada 2 Department of Microbiology and Immunology Our findings reveal a substantial reduction in intrathymic proliferation. The analysis also indicates the McGill University Montré al, Qué bec H2X 1P1 existence of a compensatory mechanism acting to sustain the numbers of recent thymic emigrants Canada 3 Department of Medicine (RTEs) in the periphery. Division of Experimental Medicine McGill University Introduction Montré al, Qué bec H2X 1P1 Canada HIV infection leads to sustained immune activation and 4 Dé partement de Microbiologie et Immunologie to major alterations in T cell homeostasis (Douek, 2003; Faculté de Mé decine Roederer et al., 1997; Silvestri and Feinberg, 2003). In Université de Montré al particular, naive cells, CD4 ϩ and CD8 ϩ alike, are pro-Montré al, Qué bec H2X 1P1 gressively depleted (Roederer et al., 1997), possibly as Canada a consequence of their frequent activation and differen-5 Laboratoire d'Immunologie Cellulaire tiation into memory cells (Hazenberg et al., 2000a). Be-Institut National de la Santé et de la Recherche Mé dicale cause the division of naive T cells is normally minimal Unite 543 and remains quite low in HIV-infected persons (Hazen-Groupe Hospitalier Pitié-Salpetriè re berg et al., 2000c; Sachsenberg et al., 1998), their main-75651 Paris, Cedex 13 tenance may critically depend on input from the thymus France (Douek, 2003; Tanchot and Rocha, 1997). Thymic func-6 Immunodeficiency Service and Division of Hematology tion may, however, be impaired in HIV infection (Douek Royal Victoria Hospital et al., 2001; Hatzakis et al., 2000; Richardson et al., McGill University Health Centre 2000). It has been difficult to assess the extent of such Montré al, Qué bec H3A 1A1 impairment (Aladdin et al.,

Clinical & Experimental Immunology

We examined the secretion and expression by peripheral blood mononuclear cells (PBMC) of TNF-alpha and TNF-related molecules with regard to Th1/Th2-type cytokine production. In 76 HIV+ patients at different disease stages and in 25 controls we measured cytokine (TNF-alpha/beta, interferon-gamma (IFN-gamma), IL-2, IL-4, IL-10), and activation marker secretion (sCD4, sCD8, sCD30) in phytohaemagglutinin (PHA)-stimulated and unstimulated PBMC cultures by ELISA, and membrane-bound TNF-alpha and CD30 expression by flow cytometry. We found an expansion of the TNF system in HIV+ individuals, that positively correlated with TNF-alpha, IFN-gamma and sCD8, probably representing activation of the cytotoxic compartment. In advanced disease these correlations disappeared, and TNF-alpha and TNF-related molecules positively correlated with IL-10. Our results are in line with the hypothesis that an expanded TNF system is immunopathological in conjunction with Th2-type immunity in the advanced stage ...

Clinical and Experimental Immunology, 2001

Despite its potent antiviral activity, highly active antiretroviral therapy (HAART) only exerts a marginal effect on CD4 1 T-cell regeneration in HIV-infected subjects. Combination therapies aimed at boosting T-cell activity and maturation may provide an important contribution to the restoration of immune function. Here, we report the results obtained by a two-year follow-up of a cohort of HIV-infected patients treated with a combination of HAART and interleukin-2 (IL-2). In these patients, in addition to a series of quantitative virological and immunological parameters, we investigated T-cell regeneration by an immunophenotypic assay monitoring CD4 1 naõ Ève T cells, and by analysis of thymic function, through the quantification of the excision DNA products of T-cell receptor rearrangement (TRECs) in lymphocytes. Compared with HAART alone, we found that the IL-2 combination therapy was equally effective in reducing the levels of viremia and marginally more effective in decreasing proviral DNA load. Strikingly, the IL-2 combination produced a marked increase in the number of CD4 1 T cells bearing a naõ Ève phenotype (CD45RA 1 , CD62L 1 ), which was apparent for over 96 weeks after therapy. To assess whether these cells were the product of improved T-cell generation, we exploited a competitive quantitative molecular assay to quantify TRECs in peripheral blood lymphocytes. Surprisingly, we found that the levels of these molecules were unchanged in these patients. These findings indicate that improved thymic function does not account for the early rise of CD4 naõ Ève cells in HIV-positive patients treated with IL-2, and suggest that alternative mechanisms of T-cell maturation and differentiation are responsible for this event.

European Journal of Immunology, 1989

Longitudinal study of leukocyte functions in homosexual men seroconverted for HIV: rapid and persistent loss of B cell function after HIV infection* The early effects of infection with human immunodeficiency virus (HIV) were investigated in homosexual men who had seroconverted for anti-HIV antibodies. Leukocyte functional activities were determined in longitudinally collected peripheral blood mononuclear cell samples. During the first 10 months following seroconversion, anti-CD3 monoclonal antibody-induced T cell proliferation, monocyte accessory function and T helper activity on B cell differentiation in a pokeweed mitogen-driven system were not affected. In contrast, from the moment of seroconversion on, B cells of seroconverted men failed to produce immunoglobulin in the pokeweed mitogendriven system. This defect was not restored by addition of normal CD4' T cells. Immunoglobulin synthesis induced by Staphylococcus aurem and interleukin 2 decreased gradually, until it was completely lost 10 months after seroconversion. In addition, proliferation in response to anti-IgM or Staphylococcus aureus by B cells from HIV seroconverted men was decreased. The lack of inducible in v i m B cell activity was not accompanied by elevated spontaneous Ig synthesis by B cells of the seroconverted men. In the second group of men studied during the 2nd year following seroconversion, T helper activity on normal B cell differentiation significantly decreased, whereas anti-CD3-induced T cell proliferation and monocyte accessory function were not significantly affected. Our results demonstrate that in almost all HIV-infected individuals B cell functional defects are the first leukocyte abnormalities observed preceding defects in T helper activity.

Asian Pacific journal of allergy and immunology / launched by the Allergy and Immunology Society of Thailand

To determine if the immunopathologic alterations of HIV-infected lymph nodes have any correlation with clinical stages in the northern Thai patients, we conducted a comparative analysis of immunopathologic features of lymph nodes between 25 HIV-infected patients from various clinical categories and 25 non-HIV individuals of reactive hyperplasia morphology of lymph node biopsies. The risk factors for HIV infection were all heterosexual. The majority of patients in clinical category A (PGL) showed a histopathologic pattern of explosive follicular hyperplasia, while category C (AIDS) patients demonstrated follicular involution and lymphocyte depletion on lymph node sections. Interestingly, weak reactivity for HIV p24 gag protein was detected within the germinal centers and scattering interfollicular lymphocytes in only 20% of the HIV-infected cases. Morphologically, the presence of MGCs was specific for HIV-infected lymph nodes. MGCs (hematoxylin & eosin stain) were found in 64% of the...

Journal of Clinical Investigation, 1988

To investigate the effect of persistent HIV infection on the immune system, we studied leukocyte functions in 14 asymptomatic homosexual men (CDC group Il/III) who were at least two years seropositive, but who still had normal numbers of circulating Cfl4+ T cells. Compared with age-matched heterosexual men and HIV-negative homosexual men, the CD4' and CD8' T cells from seropositive men showed decreased proliferation to anti-CD3 monoclohal antibody and decreased CD4' T-helper activity on PWM-driven differentiation of normal donor B cells. Monocytes of HIV-infected homosexual men showed decreased accessory function on normal T cell proliferation induced by CD3 monoclonal antibody. The most striking defect in leukocyte functional activities was observed in the B cells of HIV-infected men. B cells of 13 out of 14 seropositive men failed to produce Ig in response to PWM in the presence of adequate allogeneic T-helper activity. These findings suggest that HIV induces severe immunological abnormalities in T cells, B cells, and antigen-presenting cells early in infection before CD4' T cell numbers start to decline. Impaired immunological function in subclinically HIV-infected patients may have clinical implications for vaccination strategies, in particular the use of live vaccines in groups with a high prevalence of HIV seropositivity.

AIDS Research and Human Retroviruses, 2001

Understanding how highly HIV-exposed individuals remain HIV uninfected may be useful for HIV vaccine design and development of new HIV prevention strategies. To elucidate mechanisms associated with resistance to HIV infection, immunologic and genetic factors were examined in 14 HIV-exposed but persistently seronegative (HEPS) female sex workers from Chiang Rai, northern Thailand and in ethnically matched, HIVpositive (n 5 9) and HIV-negative women (n 5 9). The HEPS women were identified in a study of commercial sex workers who had an HIV-1 incidence of 20.3 per 100 person-years. A high frequency of HLA-A11 was observed in HEPS women (86%) compared with northern Thai controls (56%). HIV-specific cytotoxic T lymphocyte (CTL) lytic responses were detected in cryopreserved peripheral blood mononuclear cells (PBMCs), using HLA-A-matched subtype E HIV-1 peptides in four of seven (57%) HEPS women, eight of eight HIV-positive women, and zero of nine HIV-negative unexposed controls (p 5 0.019 HEPS women vs. HIV-negative controls). CTL lysis levels were low, but responses were detected to peptides from Nef, Pol, Gag, and Env. Nef responses predominated in HEPS women. Compared with controls, HEPS women tended to have higher frequencies of CCR5 promotor 59402GG and SDF-1 39UTR 801A genotypes known to influence HIV transmission or course of disease. HEPS women also had higher levels of spontaneous RANTES production by PBMCs than other groups. Each of these factors could potentially contribute to HIV resistance. As most HEPS women had one or more of these factors, they may prevent HIV infection synergistically by blocking HIV cell entry, delaying its dissemination, or killing HIV-infected cells.

AIDS, 2009

Masaaki Miyazawa reviewed the literature on genetic correlates of resistance and wrote this part of the manuscript.

Annals of Internal Medicine, 1987

There are few reports of the natural history of human immunodeficiency virus (HIV) infection from Asia. In a retrospective analysis of 594 patients (72.9% male; baseline CD4 cell count, 216 cells/mL) receiving care at YRG Center for AIDS Research and Education, a tertiary HIV referral center in southern India, the mean duration of survival from serodiagnosis was 92 months. Ninety-three percent of the patients acquired infection through heterosexual contact. The most common acquired immune deficiency syndrome-defining illnesses were pulmonary tuberculosis (49%; median duration of survival, 45 months), Pneumocystis carinii pneumonia (6%; median duration of survival, 24 months), cryptococcal meningitis (5%; median duration of survival, 22 months), and central nervous system toxoplasmosis (3%; median duration of survival, 28 months). Persons with a CD4 lymphocyte count of !200 cells/mL were 19 times (95% confidence interval [CI], 5.56-64.77) more likely to die than were those with CD4 cell count of 1350 cells/mL. Patients who had у1 opportunistic infection were 2.6 times more likely to die (95% CI, 0.95-7.09) than were those who did not have an opportunistic infection. Antiretroviral therapy for patients with low CD4 lymphocyte counts improved the odds of survival (odds ratio, 5.37; 95% CI, 1.82-15.83). The first case of HIV infection in India was detected in 1986 [1], and early reports suggested that the epidemic was most prevalent in female sex workers, truck drivers, and patients attending sexually transmitted disease clinics [2]. Subsequently, the prevalence of HIV infection among women attending antenatal clinics and married monogamous women was reported from India [3-5]. It is estimated that the number of people living with HIV infection in India could be 3-4 million [6].