Simian Immunodeficiency Virus Infection in Neonatal Macaques

Veazey, Ronald S.; Lifson, Jeffrey D.; Pandrea, Ivona; Purcell, Jeanette E.; Piatak, Michael; Lackner, Andrew A.

doi:10.1128/jvi.77.16.8783-8792.2003

Cited by 35 publications

(47 citation statements)

References 48 publications

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“…11,12 The data in Figure 4A recapitulate this prior data and also show a reciprocal increase in CD8 ϩ T cells in the jejunum within 14 days of infection. To examine changes in proliferating subsets of CD4 ϩ and CD8 ϩ T cells in these tissues during primary infection of neonatal macaques, we compared percentages of BrdU ϩ T-cell subsets in neonates with age-matched uninfected controls.…”

Section: T Cells Occurs In Siv-infected Neonatessupporting

confidence: 70%

“…11,12 Furthermore, most intestinal CD4 ϩ T cells in the intestinal lamina propria of normal neonatal macaques already have an "activated, memory" phenotype, even on the day of birth, despite not having encountered environmental antigens outside the womb. 11 This suggests that neonates have ample target cells to support HIV infection and amplification, even prior to birth, and that these intestinal cells may be capable of mounting functional immune responses.…”

Section: Introductionmentioning

confidence: 99%

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Simian immunodeficiency virus selectively infects proliferating CD4+ T cells in neonatal rhesus macaques

Wang

Pahar

et al. 2010

Blood

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IntroductionRapid and profound loss of "activated" memory CD4 ϩ T cells, particularly in the intestine, is a hallmark of both HIV and simian immunodeficiency virus (SIV) infection. However, the mechanism by which CD4 ϩ T cells are eliminated in early infection remains obscure. Furthermore, infants usually have a more rapid and severe course of disease, with persistently higher viral loads than adults with HIV infection. [1][2][3][4][5] Because neonates are believed to be born with mostly "naive" T cells, why would HIV infection be more severe in infants, who have far fewer of the "activated" memory CD4 ϩ T cells required to fuel viral replication?It is well established that the intestinal tract is a major site of early HIV/SIV infection in adults 6-10 and prior studies in SIVinfected neonates showed that as in adults, intestinal CD4 ϩ T cells are also the major target for early pediatric SIV infection. 11,12 Furthermore, most intestinal CD4 ϩ T cells in the intestinal lamina propria of normal neonatal macaques already have an "activated, memory" phenotype, even on the day of birth, despite not having encountered environmental antigens outside the womb. 11 This suggests that neonates have ample target cells to support HIV infection and amplification, even prior to birth, and that these intestinal cells may be capable of mounting functional immune responses. However, absolute numbers and percentages of these target cells are far fewer in neonates than adults, so this alone cannot explain the higher viral loads in infected neonates. Because neonates are immediately exposed to a variety of new environmental antigens after birth, we hypothesized that increased activation, infection, and perhaps most importantly, a more sustained turnover of viral target cells in neonatal intestines could potentially explain why neonates have sustained viral loads and accelerated disease progression.To date, information on T-cell turnover rates is limited to peripheral blood, and few studies have examined proliferation and T-cell turnover in tissues, particularly the intestinal tract, the primary target for acute SIV and HIV infection. Furthermore, little data on mucosal immune responses to HIV or SIV infection of neonates have been published. To monitor proliferation of cell subsets in tissues, we administered bromodeoxyuridine (BrdU) to neonates 24 hours prior to tissue collection. Because BrdU is a thymidine analog incorporated only by cells synthesizing DNA, this method allows for detection of cells in the synthesis phase (S-phase) of cell division. Proliferation rates of T-cell subsets were compared in the blood, lymph nodes, spleen, and intestines of adult and pediatric macaques, as well as pediatric macaques infected with SIVmac251 and age-matched uninfected controls. Methods Animals, virus, and BrdU inoculationTissues from 23 infected and 20 age-matched uninfected neonatal rhesus macaques (Macaca mulatta) were obtained from the Tulane National Primate Research Center. All monkeys were housed and maintained in accordance with t...

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Section: T Cells Occurs In Siv-infected Neonatessupporting

confidence: 70%

Section: Introductionmentioning

confidence: 99%

Simian immunodeficiency virus selectively infects proliferating CD4+ T cells in neonatal rhesus macaques

Wang

Pahar

et al. 2010

Blood

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“…Higher expression of activation markers (HLA-DR, CD69 and CD25) has previously been reported on intestinal CD4 + T cells from neonatal and adult macaques [1,39]. Intestinal DP T cells also had higher expression of CCR5.…”

Section: Cytokine Expression By Dp Cd4 + Cd8 + Cells In Blood and Gutmentioning

confidence: 47%

Intestinal double‐positive CD4⁺CD8⁺ T cells are highly activated memory cells with an increased capacity to produce cytokines

2006

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Peripheral blood and intestinal CD4 + CD8 + double-positive (DP) T cells have been described in several species including humans, but their function and immunophenotypic characteristics are still not clearly understood. Here we demonstrate that DP T cells are abundant in the intestinal lamina propria of normal rhesus macaques (Macaca mulatta). Moreover, DP T cells have a memory phenotype and are capable of producing different and/or higher levels of cytokines and chemokines in response to mitogen stimulation compared to CD4 + single-positive T cells. Intestinal DP T cells are also highly activated and have higher expression of CCR5, which makes them preferred targets for simian immunodeficiency virus/HIV infection. Increased levels of CD69, CD25 and HLA-DR, and lower CD62L expression were found on intestinal DP T cells populations compared to CD4 + single-positive T cells. Collectively, these findings demonstrate that intestinal and peripheral blood DP T cells are effector cells and may be important in regulating immune responses, which distinguishes them from the immature DP cells found in the thymus. Finally, these intestinal DP T cells may be important target cells for HIV infection and replication due to their activation, memory phenotype and high expression of CCR5. IntroductionCD4 + CD8 + double positive (DP) T cells in the intestine have been shown to be a major early target in primary simian immunodeficiency virus (SIV) infection [1]. Rapid depletion of intestinal DP cells occurs faster and more profoundly than that of intestinal CD4 + singlepositive (SP) cells which we have previously correlated with increased levels of CCR5 expression on the former [1]. Although DP T cells have been described in the blood and intestine of humans, nonhuman primates, swine and rodents [2][3][4][5][6][7][8][9][10][11][12], little is known regarding their function or immunophenotypic (naive versus memory status etc.) characteristics. DP T cells are perhaps best known in the thymus, where they are T cell precursors in early states of T cell maturation. However, DP T cells in the peripheral blood have been shown to differ from those in the thymus [2].Several investigators have reported the presence of circulating blood DP T cells, in both healthy [13,14] and diseased individuals [15][16][17][18][19][20][21][22]. Existence of this unconventional and rare lymphocyte population in peripheral blood has been hypothesized to result from premature release of immature CD4 + CD8 + T cells from the thymus to the periphery, where their maturation into functionally competent SP cell continues [23]. However, in HIV and Epstein-Barr virus infections, the percentage of DP T cells can increase to 20% of circulating lymphocytes, suggesting they are effector cells responding to infection [14,15]. In humans and animals DP T cells have also been shown to have antiviral activity, further suggesting they are indeed antigen-specific effector cells rather than immature cells from the thymus [2, 4,24]. The intestine is the major target organ of HIV...

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“…Plasma was separated by centrifugation (583g for 10 minutes), and PBMCs were extracted as described. 32 Superficial LN (axillary and inguinal) biopsies were removed from animals using sterile surgical procedures on days Ϫ7, 0, 7, 10, 14, 28, 42, 120, 180, 240, 300, and 360 pi LN mononuclear cells were isolated as described. 32 Intestinal samples (proximal jejunum) consisting of approximately 10 to 15, 1-to 2-mm 2 pieces were obtained by endoscopic-guided biopsy on days Ϫ7, 0, 10, 14, 21, 28, 42, and 56 pi.…”

Section: Sampling Of Blood Lns and Intestinementioning

confidence: 99%

Limited ability of humoral immune responses in control of viremia during infection with SIVsmmD215 strain

Gaufin

Gautam

Kasheta³

et al. 2009

Blood

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We investigated the impact of rhesus macaque (RM) B-cell depletion before inoculation with the isolate SIVsmmD215. Seven RMs were treated every 3 weeks with 50 mg/kg of an anti-CD20 antibody (rituximab) starting 7 days before inoculation for 2 (n ‫؍‬ 4) and 5 (n ‫؍‬ 3) months. Four control animals received no antibody. Three animals were completely depleted of CD20 ؉ B cells, but 4 were only partially depleted of CD20 cells in the LNs and intestine. The decrease in antibody production was consistent with the efficacy of tissue CD20 depletion. Seroconversion and neutralizing antibody production was significantly delayed in animals showing complete tissue CD20 depletion and remained at low titers in all CD20-depleted RMs. Surprisingly, there was no significant difference in acute or chronic viral loads between CD20-depleted and control animal groups. There was a tendency for lower viral set points in CD20-depleted animals. At 6 weeks after inoculation, cellular immune responses were significantly stronger in CD20-depleted animals than in controls. There was no significant difference in survival between CD20-depleted and control animals. Our data suggest that a deficiency of Ab responses did not markedly affect viral replication or disease progression and that they may be compensated by more robust cellular responses. (Blood. 2009; 113:4250-4261)

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Simian Immunodeficiency Virus Infection in Neonatal Macaques

Cited by 35 publications

References 48 publications

Simian immunodeficiency virus selectively infects proliferating CD4+ T cells in neonatal rhesus macaques

Simian immunodeficiency virus selectively infects proliferating CD4+ T cells in neonatal rhesus macaques

Intestinal double‐positive CD4⁺CD8⁺ T cells are highly activated memory cells with an increased capacity to produce cytokines

Limited ability of humoral immune responses in control of viremia during infection with SIVsmmD215 strain

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Simian Immunodeficiency Virus Infection in Neonatal Macaques

Cited by 35 publications

References 48 publications

Simian immunodeficiency virus selectively infects proliferating CD4+ T cells in neonatal rhesus macaques

Simian immunodeficiency virus selectively infects proliferating CD4+ T cells in neonatal rhesus macaques

Intestinal double‐positive CD4+CD8+ T cells are highly activated memory cells with an increased capacity to produce cytokines

Limited ability of humoral immune responses in control of viremia during infection with SIVsmmD215 strain

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Intestinal double‐positive CD4⁺CD8⁺ T cells are highly activated memory cells with an increased capacity to produce cytokines