Studies in Subjects with Long-Term Nonprogressive Human Immunodeficiency Virus Infection

Pantaleo, Giuseppe; Menzo, Stefano; Vaccarezza, Mauro; Graziosi, Cecilia; Cohen, Oren J.; Demarest, James F.; Montefiori, David C.; Orenstein, Jan M.; Fox, Cecil H.; Schrager, Lewis K.; Margolick, Joseph B.; Buchbinder, Susan; Giorgi, Janis V.; Fauci, Anthony S.

doi:10.1056/nejm199501263320402

Cited by 672 publications

(318 citation statements)

References 31 publications

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“…Recent data on LTNP indicate that they have low levels of HIV-1 in the presence of strong virus-specific immune responses, combined with some degree of viral attenuation (Cao et al, 1995). Similar observations concerning low plasma levels of HIV-1 RNA and viral burden in PBMC from LTNP have been reported by Pantaleo et al, who also showed that lymph-node architecture and immune function appear to remain intact in these subjects (Pantaleo et al, 1995). Accordingly, the main aims of this study were the following: (i) to ascertain whether PBMC from LTNP have a different tendency to undergo apoptosis either spontaneously or after treatment with a mitogen (pokeweed mitogen, PWM), or with anti-CD95 monoclonal antibodies, in comparison with cells from subjects who show signs of progression of the infection (HIV+P) and from seronegative controls; (ii) to identify the phenotype of apoptotic cells, in order to see whether in LTNP different lymphocyte subsets have a different propensity to cell death; (iii) to ascertain whether spontaneous or induced apoptosis can be modulated by agents such as growth factors (interleukin-2, IL-2), molecules able to inhibit poly(ADPribosyl)polymerase (nicotinamide, NAM; 3-aminobenzamide, 3-ABA), or to increase intracellular reduced glutathione (GSH) content (N-acetyl-L-cysteine, NAC) or energy charge (L-acetyl-carnitine, LAC).…”

Section: Introductionsupporting

confidence: 68%

Phenotypic characteristics and tendency to apoptosis of peripheral blood mononuclear cells from HIV+ long term non progressors

Franceschi

Franceschini

Boschini³

et al. 1997

Cell Death Differ

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The aim of this study was to analyze (i) phenotype, (ii) in vitro spontaneous and induced apoptosis, (iii) glutathione (GSH) intracellular content and (iv) inhibitors of apoptosis of potential therapeutical use in peripheral blood mononuclear cells (PBMC) from HIV+ long term non progressors (LTNP), in comparison with progressors (HIV+P) and seronegative controls (HIV7). Three groups of subjects were studied: 15 HIV+P (patients losing 4150 CD4+/year), 9 LTNP (subjects infected by HIV for at least 7 years without clinical and immunological signs of progression, with a mean of 898 CD4+/mL) and 18 HIV7. All subjects were living in a large community for former drug addicts, and were matched for age and sex.We used flow cytometry for analyzing PBMC phenotype and apoptosis; high performance liquid chromatography for measuring intracellular GSH content. PBMC phenotype of LTNP shared characteristics with those of both HIV7 and HIV+P. Indeed, LTNP showed a normal number CD4+ cells (an inclusioncriteria),butsignificantlyincreasednumbersofCD8+ lymphocytes, activated T cells, CD19+, CD5+ B lymphocytes and CD57+ cells, as well as a decrease in CD19+, CD57 B lymphocytes and CD16+ cells. In LTNP, spontaneous apoptosis was similar to that of HIV7 and significantly lower than that of HIV+P. Adding interleukin-2 (IL-2) or nicotinamide (NAM)significantlydecreasedspontaneousapoptosisinLTNP and HIV+P. Pokeweed mitogen-induced apoptosis was also similar in LTNP and HIV7, but significantly lower than that of HIV+P. In HIV+P, but also in LTNP, spontaneous apoptosis was inversely correlated to the absolute number and percentage of CD4+ cells and directly correlated to the number and percentageofactivatedTcellspresentinperipheralblood.GSH intracellular content was greatly decreased in PBMC from HIV+P and slightly, but significantly, reduced in LTNP. Adding 2-deoxy-D-ribose, an agent provoking apoptosis through GSH depletion, to quiescent PBMC resulted in similar levels of massive cell death in the three groups. This phenomenon was equally prevented in the three groups by N-acetyl-cysteine but not by IL-2.A complex immunological situation seems to occur in LTNP. Indeed, PBMC from LTNP are characterized by a normal in vitro tendencytoundergoapoptosisdespitethepresenceofastrong activation of theirimmune system,unexpectedly similar tothat of HIV+P. Our data suggest that NAM and IL-2 are possible candidates for reducing spontaneous apoptosis in HIV infection.

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Section: Introductionsupporting

confidence: 68%

Phenotypic characteristics and tendency to apoptosis of peripheral blood mononuclear cells from HIV+ long term non progressors

Franceschi

Franceschini

Boschini³

et al. 1997

Cell Death Differ

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“…This population of children probably included a highly selected group of patients who had minimal to no progression of HIV disease such as the cohort of adult nonprogressors described in recent studies. 16,17 All patients in the survey were long-term survivors based exclusively on their age. However, it is apparent that long-term survivors constitute a diverse patient population within the dynamic process of disease progression.…”

Section: Discussionmentioning

confidence: 99%

A Descriptive Survey of Pediatric Human Immunodeficiency Virus–infected Long-term Survivors

Nielsen

McSherry

Petru³

et al. 1997

Pediatrics

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ABSTRACT. Objective. To identify the population of human immunodeficiency virus-infected pediatric longterm survivors (LTS) followed in major medical institutions in California, Florida and New Jersey.Methods. A cross-sectional survey was performed with data collection forms sent to all investigators. Demographic, clinical, and laboratory data were obtained on all living patients 8 years infected in the perinatal period with human immunodeficiency virus.Results. A total of 143 perinatally infected and 54 children infected by neonatal transfusion were identified. Fifty-four children (27%) had absolute CD4 counts 500 cells/mm 3 (group 1: mean age 9.8 years), 54 children (27%) had CD4 counts between 200 and 500 cells/mm 3 (group 2: mean age 10.1 years), and 89 children (45%) had CD4 counts <200 cells/mm 3 (group 3: mean age 10.4 years). Ninety-five (48%) patients had developed AIDS defining conditions; 14 (26%) in group 1, 26 (48%) in group 2, and 55 (62%) in group 3. Ninety-two percent of patients had received antiretrovirals. Perinatally human immunodeficiency virus-infected children tended to be younger (mean age 9.8 years) than children infected via a blood transfusion (mean age 11 years). Generalized lymphadenopathy was the most prevalent clinical finding. Lymphoid interstitial pneumonia and recurrent bacterial infections were the most prevalent acquired immune deficiency syndrome-defining conditions. Twenty percent of LTS had CD4 counts 500 cells/mm 3 and no immune deficiency syndrome-defining conditions.Conclusions. Pediatric LTS were in variable stages of disease progression. The proportion of children within each CD4 strata did not differ by mode of acquisition of infection. Increased CD4 counts were inversely proportional to age. Only 20% of pediatric LTS had minimal to no disease progression. Pediatrics 1997;99(4). URL: http: //www.pediatrics.org/cgi/content/full/99/4/e4; HIV, pediatric long-term survivors, slow disease progression.

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“…Although the ultimate reasons for that especially favourable behaviour of an otherwise fatal disease are not clear at the moment, some important points have been recently addressed. These subjects are characterized by very low levels of viral burden in the plasma, by a strong neutralizing antibody response, and by vigorous inhibitory CD8 lymphocytes [6,7].…”

Section: Introductionmentioning

confidence: 99%

CD8+ lymphocyte phenotype and cytokine production in long-term non-progressor and in progressor patients with HIV-1 infection

Zanussi¹,

Simonelli

D'Andrea³

et al. 1996

Clinical and Experimental Immunology

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SUMMARYIn most HIV-1-infected patients, clinical and immunological progression develops within a few years. Few infected people, termed long-term non-progressors (LTNP), remain healthy and immunologically stable for a long time. The factors governing the maintenance of this condition are not well known, but it is conceivable that CD8 lymphocytes, cells that play a central role in controlling in vitro HIV replication, may have a part in vivo in this process. The aim of this study was to characterize the phenotypic profile and the cytokine production of CD8 cells in a group of LTNP patients who had stable CD4 cell counts (>500/mm 3 ) for at least 7 years. Their CD8 absolute numbers were similar to a control group composed of HIV-1 patients who have a progressive decline of their CD4 cell counts. However, our multiparameter immunofluorescence studies show that a clinical and immunologically stable condition is associated with the presence of a CD28 , CD95 strongly positive CD8 population, while disease progression is marked by the CD28 ÿ CD95 CD8 subset. Purified CD8 cells from LTNP retain their ability to produce IL-2, interferon-gamma (IFN-°) and, to a lesser degree, to produce IL-10 and IL-4. In contrast, CD8 cells from progressors are unable to secrete IL-2 and IL-10. Although CD8 cytokine profile does not fit with the proposed T helper (Th)1/Th2 switch in progressive HIV infection, LTNP CD8 T cells maintain their capacity to produce IL-2 and IL-10 (Th0-like), a pattern very similar to that observed in normal HIV healthy controls. We suggest that CD8 cells expressing CD28, CD95 and having a Th0-like profile may be considered to be associated with long-term survival.

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Studies in Subjects with Long-Term Nonprogressive Human Immunodeficiency Virus Infection

Abstract: In persons who remain free of disease for many years despite HIV infection the viral load is low, but viral replication persists. Lymph-node architecture and immune function appear to remain intact.

Cited by 672 publications

References 31 publications

Phenotypic characteristics and tendency to apoptosis of peripheral blood mononuclear cells from HIV+ long term non progressors

Phenotypic characteristics and tendency to apoptosis of peripheral blood mononuclear cells from HIV+ long term non progressors

A Descriptive Survey of Pediatric Human Immunodeficiency Virus–infected Long-term Survivors

CD8+ lymphocyte phenotype and cytokine production in long-term non-progressor and in progressor patients with HIV-1 infection

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