Acquired Immunodeficiency Syndrome: Estaquier J

Hurtrel B, Petit F, Arnoult D, Müller-Trutwin M, Silvestri G, Estaquier J. · Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, Paris, cedex 15, France. · Cell Death Differ. · Pubmed #15818408 links to  free full text

Abstract: Pathogenic human immunodeficiency virus (HIV)/Simian immunodeficiency virus (SIV) infection is associated with increased T-cell apoptosis. In marked contrast to HIV infection in humans and SIV infection in macaques, the SIV infection of natural host species is typically nonpathogenic despite high levels of viral replication. In these nonpathogenic primate models, no observation of T-cell apoptosis was observed, suggesting that either SIV is less capable of directly inducing apoptosis in natural hosts (likely as a result of coevolution/coadaptation with the host) or, alternatively, that the indirect T-cell apoptosis plays the key role in determining the HIV-associated T-cell depletion and progression to acquired immune deficiency syndrome (AIDS). Understanding the molecular and cellular mechanisms responsible for the disease-free equilibrium in natural hosts for SIV infection, including those determining the absence of high levels of T-cell apoptosis, is likely to provide important clues regarding the mechanisms of AIDS pathogenesis in humans.

Petit F, Arnoult D, Viollet L, Estaquier J. · Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, 28, rue du Dr Roux, 75724 Paris cedex 15, France. · Biochimie. · Pubmed #14585547 No free full text.

Abstract: Infection with human immunodeficiency virus (HIV) is characterized by the gradual depletion of CD4+ T lymphocytes. The incorporation of the concept of apoptosis as a rationale to explain progressive T cell depletion has led to growing research in this field during the last 10 years. In parallel, the biochemical pathways implicated in programmed cell death have been extensively studied. Thus, the influence of mitochondrial control in the two major apoptotic pathways-the extrinsic and intrinsic pathways-is now well admitted. In this review, we summarized our current knowledge of the different pathways involved in the death of T cells in the course of HIV infection.

Arnoult D, Petit F, Lelièvre JD, Estaquier J. · EMI-U 9922 INSERM/Université Paris 7, IFR02, AP-HP, Hôpital Bichat-Claude Bernard, Paris, France. · Biochem Biophys Res Commun. · Pubmed #12729591 No free full text.

Abstract: It is now well admitted that HIV infection leading to AIDS is associated with an abnormal susceptibility of T cells to undergo apoptosis. Recent progress in research into programmed cell death has resulted in the identification of the principal pathways involved in this process. Thus the "extrinsic" as well as the "intrinsic" pathways converge to the mitochondria considered as the main sensor of programmed cell death. This review summarizes our knowledge of the influence of mitochondrial control on T cell death during HIV and SIV infections.

Elbim C, Monceaux V, François S, Hurtrel B, Gougerot-Pocidalo MA, Estaquier J. · Centre de Recherche des Cordeliers, Université Pierre et Marie Curie, UMR, Paris, France. · Retrovirology. · Pubmed #19317901 links to  free full text

Abstract: Polymorphonuclear neutrophils (PMN) from chronically HIV-infected individuals have been reported to be more prone to die. However, although non-human primates models have been extensively used for improving our knowledge on T cell immunity, the impact of SIV-infection on PMN, in relationships with disease severity, has never been assessed. In our study, we demonstrate that PMN from Rhesus macaques (RMs) of Chinese origin chronically infected with the virulent strain SIVmac251 display increased susceptibility to undergo apoptosis as compared to PMN from RMs infected with the non-pathogenic SIVDeltanef strain. PMN apoptosis was significantly increased in RMs progressing faster to AIDS as compared to non-progressors RMs. Furthermore, the percentage of apoptotic cells correlated with PMN activation state reflected by increased CD11b expression and reactive oxygen species production. Interestingly, whereas inflammatory cytokines IL-8 and IL-1beta prevent in vitro PMN death, the levels of those cytokines were low in RMs progressing towards AIDS. Altogether, increased PMN death during SIV infection is a new pathogenic effect associated with AIDS progression, adding to the long list of markers associated with disruption of defense against infection.

Estaquier J, Hurtrel B. · Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, Paris, France. · Med Sci (Paris). · Pubmed #19116114 No free full text.

Abstract: The identification of human immunodeficiency virus type 1 (HIV-1) reservoir has been the center of extensive research for 25 years. In a recent work published in Cell Death and Differentiation, we show that mesenteric lymph nodes which drain intestine could represent the main reservoir for the virus. This concept has been established in a rhesus macaque model. Moreover, among the mechanisms associated with the lack of viral control, we suggest a major role of apoptosis in the death of CD8 T cells. This programmed cell death is associated with increased expression of immunosuppressive factors in lymph nodes such as TGF-b and two molecules regulating lymphocyte metabolism, IDO and PD-1. In this context, the virus benefits from the immune suppression which prevails within this "sanctuary", which offers optimal conditions for its persistence.

Elbim C, Monceaux V, Mueller YM, Lewis MG, François S, Diop O, Akarid K, Hurtrel B, Gougerot-Pocidalo MA, Lévy Y, Katsikis PD, Estaquier J. · Faculté de Médecine, Service d'Immunologie et d'Hématologie,Assistance Publique-Hôpitaux de Paris, Centre Hospitalier Universitaire Xavier Bichat, Université Paris 7-Denis Diderot, Paris, France. · J Immunol. · Pubmed #19050281 No free full text.

Abstract: We used pathogenic and nonpathogenic simian models of SIV infection of Chinese and Indian rhesus macaque (RMs) and African green monkeys (AGMs), respectively, to investigate the relationship between polymorphonuclear neutrophil (PMN) death and the extent of viral replication and disease outcome. In this study, we showed that PMN death increased early during the acute phase of SIV infection in Chinese RMs and coincided with the peak of viral replication on day 14. The level of PMN death was significantly more severe in RMs that progressed more rapidly to AIDS and coincided with neutropenia. Neutropenia was also observed in Indian RMs and was higher in non-Mamu-A*01 compared with Mamu-A*01 animals. In stark contrast, no changes in the levels of PMN death were observed in the nonpathogenic model of SIVagm-sab (sabaeus) infection of AGMs despite similarly high viral replication. PMN death was a Bax and Bak-independent mitochondrial insult, which is prevented by inhibiting calpain activation but not caspases. We found that BOB/GPR15, a SIV coreceptor, is expressed on the PMN surface of RMs at a much higher levels than AGMs and its ligation induced PMN death, suggesting that SIV particle binding to the cell surface is sufficient to induce PMN death. Taken together, our results suggest that species-specific differences in BOB/GPR15 receptor expression on PMN can lead to increased acute phase PMN death. This may account for the decline in PMN numbers that occurs during primary SIV infection in pathogenic SIV infection and may have important implications for subsequent viral replication and disease progression.

Monceaux V, Viollet L, Petit F, Cumont MC, Kaufmann GR, Aubertin AM, Hurtrel B, Silvestri G, Estaquier J. · Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris cedex 15, France. · J Virol. · Pubmed #17898067 links to  free full text

Abstract: Simian immunodeficiency virus (SIV) infection of rhesus macaques (RMs) provides a reliable model to study the relationship between lentivirus replication, cellular immune responses, and CD4+ T-cell dynamics. Here we investigated, using SIVmac251-infected RMs of a Chinese genetic background (which experience a slower disease progression than Indian RMs), the dynamics of CD4+ CCR5+ T cells, as this subset of memory/activated CD4+ T cells is both a preferential target of virus replication and a marker of immune activation. As expected, we observed that the number of circulating CD4+ CCR5+ T cells decreases transiently at the time of peak viremia. However, at 60 days postinfection, i.e., when set-point viremia is established, the level of CD4+ CCR5+ T cells was increased compared to the baseline level. Interestingly, this increase correlated with faster disease progression, higher plasma viremia, and early loss of CD4+ T-cell function, as measured by CD4+ T-cell count, the fraction of memory CD4+ T cells, and the recall response to purified protein derivative. Taken together, these data show a key difference between the dynamics of the CD4+ CCR5+ T-cell pool (and its relationship with disease progression) in Chinese RMs and those described in previous reports for Indian SIVmac251-infected RMs. As the SIV-associated changes in the CD4+ CCR5+ T-cell pool reflect the opposing forces of SIV replication (which reduces this cellular pool) and immune activation (which increases it), our data suggest that in SIV-infected Chinese RMs the impact of immune activation is more prominent than that of virus replication in determining the size of the pool of CD4+ CCR5+ T cells in the periphery. As progression of HIV infection in humans also is associated with a relative expansion of the level of CD4+ CCR5+ T cells, we propose that SIV infection of Chinese RMs is a very valuable and important animal model for understanding the pathogenesis of human immunodeficiency virus infection.

Cumont MC, Monceaux V, Viollet L, Lay S, Parker R, Hurtrel B, Estaquier J. · CNRS URA 1930; Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris cedex 15, France. · Cell Death Differ. · Pubmed #17612589 links to  free full text

Abstract: SIV-infected macaques exhibit distinct rates of progression to AIDS and despite significant increases in CD8+ T cells, immune cells fail to control and eradicate SIV in vivo. Here, we investigated the interplay between viral reservoir sites, CD8+ T-cell activation/death and outcome. Our data provide strong evidence that mesenteric (Mes) lymph nodes represent major reservoirs not only for SIV-infected macaques progressing more rapidly toward AIDS but also in controllers. We demonstrate that macaques progressing faster display greater expression of TGF-beta and Indoleamine 2,3 dioxygenase in particular in intestinal tissues associated with a phosphorylation of the p53 protein on serine 15 in CD8+ T cells from Mes lymph nodes. These factors may act as a negative regulator of CD8+ T-cell function by inducing a Bax/Bak/Puma-dependent death pathway of effector/memory CD8+ T cells. Greater T-cell death and viral dissemination was associated with a low level of TIA-1+ expressing cells. Finally, we provide evidence that abrogation of TGF-beta in vitro enhances T-cell proliferation and reduces CD8+ T-cell death. Our data identify a mechanism of T-cell exhaustion in intestinal lymphoid organs and define a potentially effective immunological strategy for the modulation of progression to AIDS.

Viollet L, Monceaux V, Petit F, Ho Tsong Fang R, Cumont MC, Hurtrel B, Estaquier J. · Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, Paris, France. · J Immunol. · Pubmed #17082581 links to  free full text

Abstract: Immunological and virological events that occur during the earliest stages of SIV infection are now considered to have a major impact on subsequent disease progression. In the present study, we demonstrate a clear correlation between progression to AIDS and the rate of in vitro CD4+ (but not CD8+) T cell death in lymph nodes. The dying CD4+ T cells were effector memory T cells, which are critical for the immune response to pathogens. However, there was no correlation between the rate of the viral replication within lymph nodes and the extent of Fas ligand-mediated death, despite the increased sensitivity of CD4+ T cells to death in response to recombinant human Fas ligand. CD4+ T cell death was caspase and apoptosis-inducing factor independent but was clearly associated with mitochondrion damage. Interestingly, higher expression levels of the active form of Bak, a proapoptotic molecule involved in mitochondrial membrane permeabilization, were observed in SIV-infected macaques progressing more rapidly to AIDS. Finally, we demonstrated that the strain of SIV we used requires CCR5 and BOB/GRP15 molecules as coreceptors and caused death of unstimulated noncycling primary CD4+ T cells. Altogether, these results demonstrate that CD4+ T cell death occurring early after SIV infection is a crucial determinant of progression to AIDS and that it is mediated by the intrinsic death pathway.

Beq S, Nugeyre MT, Ho Tsong Fang R, Gautier D, Legrand R, Schmitt N, Estaquier J, Barré-Sinoussi F, Hurtrel B, Cheynier R, Israël N. · Unité de Régulation des Infections Rétrovirales, Institut Pasteur, Paris, France. · J Immunol. · Pubmed #16393976 links to  free full text

Abstract: Despite efficient antiretroviral therapy (ART), CD4+ T cell counts often remain low in HIV-1-infected patients. This has led to IL-7, a crucial cytokine involved in both thymopoiesis and peripheral T cell homeostasis, being suggested as an additional therapeutic strategy. We investigated whether recombinant simian IL-7-treatment enhanced the T cell renewal initiated by ART in rhesus macaques chronically infected with SIVmac251. Six macaques in the early chronic phase of SIV infection received antiretroviral treatment. Four macaques also received a 3-wk course of IL-7 injections. Viral load was unaffected by IL-7 treatment. IL-7 treatment increased the number of circulating CD4+ and CD8+ memory T cells expressing activation (HLA-DR+, CD25+) and proliferation (Ki-67+) markers. It also increased naive (CD45RAbrightCD62L+) T cell counts by peripheral proliferation and enhanced de novo thymic production. The studied parameters returned to pretreatment values by day 29 after the initiation of treatment, concomitantly to the appearance of anti-IL-7 neutralizing Abs, supporting the need for a nonimmunogenic molecule for human treatment. Thus, IL-7, which increases T cell memory and de novo renewal of naive T cells may have additional benefits in HIV-infected patients receiving ART.

Monceaux V, Viollet L, Petit F, Ho Tsong Fang R, Cumont MC, Zaunders J, Hurtrel B, Estaquier J. · Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, Paris, France. · J Immunol. · Pubmed #15905532 links to  free full text

Abstract: Immunological and virological events that occur during the earliest stages of HIV-1 infection are now considered to have a major impact on subsequent disease progression. We observed changes in the frequencies of CD8(bright) T cells expressing different chemokine receptors in the peripheral blood and lymph nodes of rhesus macaques during the acute phase of the pathogenic SIVmac251 infection; the frequency of CD8(bright) T cells expressing CXCR4 decreased, while the frequency of those expressing CCR5 increased. These reciprocal changes in chemokine receptor expression were associated with changes in the proportion of cycling (Ki67(+)) CD8(bright) T cells, and with the pattern of CD8(bright) T cell differentiation as defined by expression of CCR7 and CD45RA. In contrast, during the primary phase of the attenuated SIVmac251Deltanef infection, no major change was observed. Whereas during the acute phase of the infection with pathogenic SIV (2 wk postinfection) no correlate of disease protection was identified, once the viral load set points were established (2 mo postinfection), we found that the levels of cycling and of CCR5- and CXCR4-positive CD8(bright) T cells were correlated with the extent of viral replication and therefore with SIV-infection outcome. Our data reveal that, during primary SIV infection, despite intense CD8 T cell activation and an increase in CCR5 expression, which are considered as essential for optimal effector function of CD8(+) T cells, these changes are associated with a poor prognosis for disease progression to AIDS.

Ho Tsong Fang R, Khatissian E, Monceaux V, Cumont MC, Beq S, Ameisen JC, Aubertin AM, Israël N, Estaquier J, Hurtrel B. · Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, Paris, France. · AIDS. · Pubmed #15821392 No free full text.

Abstract: BACKGROUND: An attenuated immunodeficiency virus has been long considered innocuous. Nevertheless, converging data suggest that low levels of viral replication can still provoke AIDS. Pathogenesis of these attenuated infections is not understood. OBJECTIVES: To determine the pathogenicity of a long-term attenuated infection and to delineate T-cell dynamics during such an infection. METHODS: This is a cross-sectional study of 12 rhesus macaques infected with SIV Delta nef for 8 years. We evaluated apoptosis (annexin V), activation (HLA-DR, Ki67), and newly generated T cells (TCR excision circle: TREC). RESULTS: Infection with SIV Delta nef induced pathological CD4 T-cell depletion after 8 years of infection. Virus replication and CD8 T-cell activation positively correlated with the rate of disease progression. The frequency of TREC within CD8+CD45RA+ cells increased in SIV Delta nef-infected animals compared to age-matched non-infected controls. Moreover, in the cohort of infected animals, TREC+CD45RA+CD4+ T-cell counts correlated strongly with non-progression to AIDS. The animal with the lowest rate of disease progression exhibited a 115-fold increase in TREC+CD45RA+CD4+ T-cell counts compared to age-matched non-infected controls. In contrast, the animal showing the fastest rate of progression to AIDS displayed 600-fold lower TREC+CD45RA+CD4+ T-cell counts compared to age-matched non-infected controls. CONCLUSIONS: Our results suggest that the thymus plays a major role in the pathogenesis of an attenuated SIV infection and that a sustained thymic output could maintain CD4 T-cell homeostasis in the context of low viral loads.

Kornfeld C, Ploquin MJ, Pandrea I, Faye A, Onanga R, Apetrei C, Poaty-Mavoungou V, Rouquet P, Estaquier J, Mortara L, Desoutter JF, Butor C, Le Grand R, Roques P, Simon F, Barré-Sinoussi F, Diop OM, Müller-Trutwin MC. · Unité de Biologie des Rétrovirus, Institut Pasteur, Paris, France. · J Clin Invest. · Pubmed #15761496 links to  free full text

Abstract: T cell activation levels in HIV infection are predictive of AIDS progression. We searched for the immunological correlates of protection against disease progression by studying the early stages of nonpathogenic SIV infection in African green monkeys (SIVagm). The African green monkeys (AGMs) displayed high peak viremias and a transient decline in levels of blood CD4(+) and CD8(+) T cells between days 5 and 17 after infection. A concomitant increase in levels of CD4(+)DR(+), CD8(+)DR(+), and CD8(+)CD28(-) cells was detected. After the third week, T cell activation returned to baseline levels, which suggested a protective downregulation of T cell activation. A very early (24 hours after infection) and strong induction of TGF-beta1 and FoxP3 expression was detected and correlated with increases in levels of CD4(+)CD25(+) and CD8(+)CD25(+) T cells. This was followed by a significant increase in levels of IL-10, whereas IFN-gamma gene upregulation was more transient, and levels of TNF-alpha and MIP-1alpha/beta transcripts did not increase in either blood or tissues. The profiles were significantly different during primary SIV infection in macaques (SIVmac); that is, there was a delayed increase in IL-10 levels accompanied by moderate and persistent increases in TGF-beta levels. Together, our data show that SIVagm infection is associated with an immediate antiinflammatory environment and suggest that TGF-beta may participate in the generation of Tregs, which may prevent an aberrant chronic T cell hyperactivation.

Lelièvre JD, Mammano F, Arnoult D, Petit F, Grodet A, Estaquier J, Ameisen JC. · EMI-U 9922 INSERM/Université Paris 7, IFR02, AP-HP, Faculté de Médecine Xavier Bichat, 16 rue Henri Huchard, 75018 Paris, France. · Cell Death Differ. · Pubmed #15118766 links to  free full text

Abstract: CD4+ T-cell death is a crucial feature of AIDS pathogenesis, but the mechanisms involved remain unclear. Here, we present in vitro findings that identify a novel process of HIV1 mediated killing of bystander CD4+ T cells, which does not require productive infection of these cells but depends on the presence of neighboring dying cells. X4-tropic HIV1 strains, which use CD4 and CXCR4 as receptors for cell entry, caused death of unstimulated noncycling primary CD4+ T cells only if the viruses were produced by dying, productively infected T cells, but not by living, chronically infected T cells or by living HIV1-transfected HeLa cells. Inducing cell death in HIV1-transfected HeLa cells was sufficient to obtain viruses that caused CD4+ T-cell death. The addition of supernatants from dying control cells, including primary T cells, allowed viruses produced by living HIV1-transfected cells to cause CD4+ T-cell death. CD4+ T-cell killing required HIV1 fusion and/or entry into these cells, but neither HIV1 envelope-mediated CD4 or CXCR4 signaling nor the presence of the HIV1 Nef protein in the viral particles. Supernatants from dying control cells contained CD95 ligand (CD95L), and antibody-mediated neutralization of CD95L prevented these supernatants from complementing HIV1 in inducing CD4+ T-cell death. Our in vitro findings suggest that the very extent of cell death induced in vivo during HIV1 infection by either virus cytopathic effects or immune activation may by itself provide an amplification loop in AIDS pathogenesis. More generally, they provide a paradigm for pathogen-mediated killing processes in which the extent of cell death occurring in the microenvironment might drive the capacity of the pathogen to induce further cell death.

Arnoult D, Petit F, Lelièvre JD, Lelièvie JD, Lecossier D, Hance A, Monceaux V, Hurtrel B, Huntrel B, Ho Tsong Fang R, Ameisen JC, Estaquier J. · INSERM EMI-U 9922, Faculté Bichat-Claude Bernard, Paris, France. · Cell Death Differ. · Pubmed #14576776 links to  free full text

Abstract: Studies of human immunodeficiency virus (HIV) and nonhuman primate models of pathogenic and nonpathogenic simian immunodeficiency virus (SIV) infections have suggested that enhanced ex vivo CD4 T-cell death is a feature of pathogenic infection in vivo. However, the relative contributions of the extrinsic and intrinsic pathways to programmed T-cell death in SIV infection have not been studied. We report here that the spontaneous death rate of CD4+ T cells from pathogenic SIVmac251-infected rhesus macaques ex vivo is correlated with CD4 T-cell depletion and plasma viral load in vivo. CD4+ T cells from SIVmac251-infected macaques showed upregulation of the death ligand (CD95L) and of the proapoptotic proteins Bim and Bak, but not of Bax. Both CD4+ and CD8+ T cells from SIVmac251-infected macaques underwent caspase-dependent death following CD95 ligation. The spontaneous death of CD4+ and CD8+ T cells was not prevented by a decoy CD95 receptor or by a broad-spectrum caspase inhibitor (zVAD-fmk), suggesting that this form of cell death is independent of CD95/CD95L interaction and caspase activation. IL-2 and IL-15 prevented the spontaneous death of CD4+ and CD8+ T cells, whereas IL-10 prevented only CD8 T-cell death and IL-7 had no effect on T-cell death. Our results indicate that caspase-dependent and caspase-independent pathways are involved in the death of T cells in pathogenic SIVmac251-infected primates.

Monceaux V, Ho Tsong Fang R, Cumont MC, Hurtrel B, Estaquier J. · Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, 28 rue du Docteur Roux, 75724 Paris, France. · J Virol. · Pubmed #12941915 links to  free full text

Abstract: Elevated CD4 T-cell turnover may lead to the exhaustion of the immune system during human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV) infections. However, this hypothesis remains controversial. Most studies of this subject have concerned the blood, and information about the lymph nodes is rare and controversial. We used Ki67 expression to measure cycling T cells in the blood and lymph nodes of uninfected macaques and of macaques infected with a pathogenic SIVmac251 strain or with a nonpathogenic SIVmac251Deltanef clone. During the asymptomatic phase of infection, the number of cycling CD8(+) T cells progressively increased (two- to eightfold) both in the blood and in the lymph nodes of macaques infected with SIVmac251. This increase was correlated with viral replication and the progression to AIDS. In contrast, no increases in the numbers of cycling CD4(+) T cells were found in the blood or lymph nodes of macaques infected with the pathogenic SIVmac251 strain in comparison with SIVmac251Deltanef-infected or healthy macaques during this chronic phase. However, the lymph nodes of pre-AIDS stage SIVmac251-infected macaques contained more cycling CD4(+) T cells (low baseline CD4(+)-T-cell counts in the blood). Taken together, these results show that the profiles of CD4(+)- and CD8(+)-T-cell dynamics are distinct both in the lymph nodes and blood and suggest that higher CD4(+)-T-cell proliferation at the onset of AIDS may lead to the exhaustion of the immune system.

Monceaux V, Estaquier J, Février M, Cumont MC, Rivière Y, Aubertin AM, Ameisen JC, Hurtrel B. · Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, CNRS URA 1930, 28 rue du Docteur Roux, 75724 Paris, France. · AIDS. · Pubmed #12853740 No free full text.

Abstract: OBJECTIVE: The acute phase of HIV and SIV infections leads to a host/virus equilibrium, and accumulating evidence suggests that this early phase dictates further progression towards AIDS. To gain insight into the early events that determine rapid disease progression, we performed a longitudinal study in the SIV rhesus macaque model, allowing an in-depth analysis of the primary stage of infection. METHODS: We assessed viral replication (quantification of replicating and infected cells in lymph nodes, plasma viral load), immune response (cytotoxic T lymphocyte, antibody, proliferative responses), apoptosis and cycling cells (Ki-67 labelling) on lymph nodes and blood in nine rhesus macaques infected with the pathogenic SIVmac251 isolate. RESULTS: Six primates remained asymptomatic during the one year follow-up period of the study, whereas three developed AIDS within 5-6 months. During the first 2 weeks of infection, peak numbers of apoptotic cells in the lymph node T-cell areas were significantly higher in the three future rapid progressors than in the six future slow progressors, and were correlated with subsequent viraemia levels measured 6 months after infection. The numbers of infected or cycling cells in the same lymph node T-cell areas, however, only became significantly different in future rapid and slow progressors 8 weeks after infection, at the end of the primary phase. CONCLUSION: Our findings identified extensive apoptosis induction in peripheral lymphoid organs as an early and predictive event that may play a crucial role in impairing the capacity of the immune system to control viral replication and progression towards disease.

Khatissian E, Monceaux V, Cumont MC, Ho Tsong Fang R, Estaquier J, Hurtrel B. · Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, 75724 Paris Cedex 15, France. · AIDS Res Hum Retroviruses. · Pubmed #12804002 No free full text.

Abstract: We assessed the possible role in vivo CD4(+) CD8(+) T cells as a viral reservoir for simian immunodeficiency virus (SIV), in a macaque with 50% CD4(+) CD8(+) T cells in peripheral blood. During primary infection (day 14) of this rhesus macaque with the pathogenic SIVmac251 strain, proviruses were detected at similar frequencies in CD4(+) CD8(+) T cells (1/10) and CD4(+) T cells (1/10) and at a lower frequency in CD8(+) T cells (1/800). On day 235, no viral DNA was detected in CD8(+) cells, despite the persistent high viral load, indicating that CD8(+) cells do not constitute a reservoir during the chronic phase of SIV infection. Infection induced early lymphopenia of CD4(+), CD4(+) CD8(+), and CD8(+) cells; only the CD8(+) cell population returned to initial levels and expanded further. We found that CD4(+) CD8(+) T cells expressed the costimulatory CD28 molecule less and were more prone to die in vitro after phytohemagglutinin/interleukin 2 stimulation than were CD4(+) T cells. Taken together, massive death of CD4(+) CD8(+) T cells during acute stages of SIV infection may explain why CD8(+) T cells did not represent a major reservoir for SIV at the onset of infection.

Onanga R, Kornfeld C, Pandrea I, Estaquier J, Souquière S, Rouquet P, Mavoungou VP, Bourry O, M'Boup S, Barré-Sinoussi F, Simon F, Apetrei C, Roques P, Müller-Trutwin MC. · Département de Virologie, Centre de Primatologie, Centre International de Recherches Médicales, Franceville BP 769, Gabon. · J Virol. · Pubmed #12239301 links to  free full text

Abstract: Early events during human immunodeficiency virus infections are considered to reflect the capacity of the host to control infection. We have studied early virus and host parameters during the early phase of simian immunodeficiency virus SIVmnd-1 nonpathogenic infection in its natural host, Mandrillus sphinx. Four mandrills were experimentally infected with a primary SIVmnd-1 strain derived from a naturally infected mandrill. Two noninfected control animals were monitored in parallel. Blood and lymph nodes were collected at three time points before infection, twice a week during the first month, and at days 60, 180, and 360 postinfection (p.i.). Anti-SIVmnd-1 antibodies were detected starting from days 28 to 32 p.i. Neither elevated temperature nor increased lymph node size were observed. The viral load in plasma peaked between days 7 to 10 p.i. (2 x 10(6) to 2 x 10(8) RNA equivalents/ml). Viremia then decreased 10- to 1,000-fold, reaching the viral set point between days 30 to 60 p.i. The levels during the chronic phase of infection were similar to that in the naturally infected donor mandrill (2 x 10(5) RNA equivalents/ml). The CD4(+) cell numbers and percentages in blood and lymph nodes decreased slightly (<10%) during primary infection, and CD8(+) cell numbers increased transiently. All values returned to preinfection infection levels by day 30 p.i. CD8(+) cell numbers or percentages, in peripheral blood and lymph nodes, did not increase during the 1 year of follow-up. In conclusion, SIVmnd-1 has the capacity for rapid and extensive replication in mandrills. Despite high levels of viremia, CD4(+) and CD8(+) cell numbers remained stable in the post-acute phase of infection, raising questions regarding the susceptibility of mandrill T cells to activation and/or cell death in response to SIVmnd-1 infection in vivo.

Petit F, Corbeil J, Lelièvre JD, Moutouh-de Parseval L, Pinon G, Green DR, Ameisen JC, Estaquier J. · EMI-U 9922, INSERM/Université Paris 7, CHU Bichat-Claude Bernard, Paris, France. · Eur J Immunol. · Pubmed #11745371 No free full text.

Abstract: CD95 plays a critical role in the homeostasis of the immune system, and has been reported to participate in T cell death during HIV infection. Here we report that the response to CD3-TCR stimulation of CD4(+) T cells from HIV-infected individuals and CD4(+) T cells from healthy donors incubated in vitro with HIV-1(Lai) depends on the manner the CD3-TCR complex is engaged. While stimulation by anti-CD3 antibodies in solution induced CD4 T cell apoptosis both in the absence or presence of anti-CD95 antibodies, stimulation by immobilized anti-CD3 antibodies rendered CD4(+) T cells resistant to CD95-mediated death and led to increased CD4 T cell proliferation in response to CD95 ligation. CD95 ligation of CD4(+) T cells led to the activation of caspases, while costimulation induced by anti-CD3 and anti-CD95 mAb prevented the full processing of caspase-3 and caspase-8. Proliferation of CD4(+) T cells induced by CD3-TCR and CD95 costimulation was decreased by treatments with a caspase-1 inhibitor or with neutralizing antibodies to IL-1ss, indicating a requirement for caspase-1-mediated IL-1beta processing and secretion. Our findings suggest a novel mechanism whereby in addition to its role in inducing T cell apoptosis, CD95 signaling during HIV infection may also provide a costimulatory signal leading to an enhancement of CD4 T cell proliferation in response to CD3-TCR complex engagement.

Estaquier J, Monceaux V, Cumont MC, Aubertin AM, Hurtrel B, Ameisen JC. · INSERM EMI 9922, Hôpital Bichat-Claude Bernard, Université Paris VII, France. · J Med Primatol. · Pubmed #11085574 No free full text.

Abstract: Primary infection of rhesus macaques with pathogenic strains of simian immunodeficiency virus (SIV) leads to rapid and dynamic changes in both viral load and T cell counts in the peripheral blood. We have performed a sequential analysis of peripheral blood CD4 and CD8 T cells in five macaques during the 8 weeks following SIVmac251 infection. We observed a transient lymphopenia of both CD4 and CD8 T cells during the first 2 weeks, followed by a rebound. The primary phase of infection was associated with changes in the T cells expressing CD25, CD69, or HLA-DR and with a priming of the peripheral blood CD4 and CD8 T cells for a process of apoptosis in vitro that was enhanced by CD95 (Fas) ligation, and was detected in two macaques as early as 7 days after infection. Despite the small numbers of animals studied, the importance of the early transient CD4 and CD8 T lymphopenia was positively correlated with the viral load. No correlation was found, however, between the level of activation markers expressed or of priming for apoptosis in peripheral blood T cells and the viral load. Our findings suggest the possibility that the early activation and priming for apoptosis of CD4 and CD8 T cells may involve indirect, host-related, mechanisms, or alternatively, that the T cells that remain in the peripheral blood during primary infection do not adequately reflect the viral-mediated changes in T cell activation and death that may occur in the lymphoid organs throughout the body.