scholarly journals CD8+ Lymphocytes Do Not Mediate Protection against Acute Superinfection 20 Days after Vaccination with a Live Attenuated Simian Immunodeficiency Virus

2005 ◽  
Vol 79 (19) ◽  
pp. 12264-12272 ◽  
Author(s):  
Richard Stebbings ◽  
Neil Berry ◽  
Herman Waldmann ◽  
Pru Bird ◽  
Geoff Hale ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Lymphocytes ◽  
Simian Immunodeficiency Virus ◽  
Cytotoxic T Lymphocytes ◽  
T Lymphocyte ◽  
Lymphoid Tissue ◽  
Human Immunoglobulin ◽  
Wild Type ◽  
Lymphocyte Depletion ◽  
Immunodeficiency Virus

ABSTRACT In order to test the hypothesis that CD8+ cytotoxic T lymphocytes mediate protection against acute superinfection, we depleted >99% of CD8+ lymphocytes in live attenuated simian immunodeficiency virus macC8 (SIVmacC8) vaccinees from the onset of vaccination, maintained that depletion for 20 days, and then challenged with pathogenic, wild-type SIVmacJ5. Vaccinees received 5 mg per kg of humanized anti-CD8 monoclonal antibody (MAb) 1 h before inoculation, followed by the same dose again on days 3, 7, 10, 13, and 17. On day 13, peripheral CD8+ T lymphocytes were >99% depleted in three out of four anti-CD8 MAb-treated vaccinees. At this time attenuated SIVmacC8 viral RNA loads in anti-CD8 MAb-treated vaccinees were significantly higher than control vaccinees treated contemporaneously with nonspecific human immunoglobulin. Lymphoid tissue CD8+ T lymphocyte depletion was >99% in three out of four anti-CD8 MAb-treated vaccinees on the day of wild-type SIVmacJ5 challenge. All four control vaccinees and three out of four anti-CD8 MAb-treated vaccinees were protected against detectable superinfection with wild-type SIVmacJ5. Although superinfection with wild-type SIVmacJ5 was detected at postmortem in a single anti-CD8 MAb-treated vaccinee, this did not correlate with the degree of preceding CD8+ T lymphocyte depletion. Clearance of attenuated SIVmacC8 viremia coincided with recovery of normal CD8+ T lymphocyte counts between days 48 and 76. These results support the view that cytotoxic T lymphocytes are important for host-mediated control of SIV primary viremia but do not indicate a central role in protection against acute superinfection conferred by inoculation with live attenuated SIV.

scholarly journals Distinct Chemokine Triggers and In Vivo Migratory Paths of Fluorescein Dye-Labeled T Lymphocytes in Acutely Simian Immunodeficiency Virus SIVmac251-Infected and Uninfected Macaques

2005 ◽  
Vol 79 (21) ◽  
pp. 13759-13768 ◽  
Author(s):  
Candice C. Clay ◽  
Denise S. Rodrigues ◽  
Danielle J. Harvey ◽  
Christian M. Leutenegger ◽  
Ursula Esser
Keyword(s):  
Small Intestine ◽  
T Lymphocytes ◽  
Simian Immunodeficiency Virus ◽  
T Lymphocyte ◽  
Chemokine Receptors ◽  
Lymphocyte Trafficking ◽  
Lymphocyte Depletion ◽  
Immunodeficiency Virus ◽  
Siv Infection

ABSTRACT To define the possible impact of T-lymphocyte trafficking parameters on simian immunodeficiency virus (SIV) pathogenesis, we examined migratory profiles of carboxyfluorescein diacetate succinimidyl ester (CFSE)-labeled T lymphocytes in acutely SIVmac251-infected and uninfected macaques within 48 h after autologous transfer. Despite significant upregulation of homeostatic chemokine CCL19/macrophage inflammatory protein 3β and proinflammatory chemokine CXCL9/monokine induced by gamma interferon in secondary lymphoid tissue in SIV infection, no differences in CFSE+ T-lymphocyte frequencies or cell compartmentalization in lymph nodes were identified between animal groups. By contrast, a higher frequency of CFSE+ T lymphocytes in the small intestine was detected in acute SIV infection. This result correlated with increased numbers of gut CD4 T lymphocytes expressing chemokine receptors CCR9, CCR7, and CXCR3 and high levels of their respective chemokine ligands in the small intestine. The changes in trafficking parameters in SIV-infected macaques occurred concomitantly with acute gut CD4 T-lymphocyte depletion. Here, we present the first in vivo T-lymphocyte trafficking study in SIV infection and a novel approach to delineate T-lymphocyte recruitment into tissues in the nonhuman primate animal model for AIDS. Such studies are likely to provide unique insights into T-lymphocyte sequestration in distinct tissue compartments and possible mechanisms of CD4 T-lymphocyte depletion and immune dysfunction in simian AIDS.

scholarly journals Memory CD4+ T-Lymphocyte Loss and Dysfunction during Primary Simian Immunodeficiency Virus Infection

2007 ◽  
Vol 81 (15) ◽  
pp. 8009-8015 ◽  
Author(s):  
Yue Sun ◽  
Sallie R. Permar ◽  
Adam P. Buzby ◽  
Norman L. Letvin
Keyword(s):  
T Lymphocytes ◽  
Simian Immunodeficiency Virus ◽  
T Lymphocyte ◽  
Rhesus Monkeys ◽  
Cytokine Production ◽  
Immune Dysregulation ◽  
Staphylococcal Enterotoxin B ◽  
Immunodeficiency Virus ◽  
Selective Depletion ◽  
Siv Infection

ABSTRACT It has long been appreciated that CD4+ T lymphocytes are dysfunctional in human immunodeficiency virus (HIV)/simian immunodeficiency virus (SIV)-infected individuals, and it has recently been shown that HIV/SIV infections are associated with a dramatic early destruction of memory CD4+ T lymphocytes. However, the relative contributions of CD4+ T-lymphocyte dysfunction and loss to immune dysregulation during primary HIV/SIV infection have not been fully elucidated. In the current study, we evaluated CD4+ T lymphocytes and their functional repertoire during primary SIVmac251 infection in rhesus monkeys. We show that the extent of loss of memory CD4+ T lymphocytes and staphylococcal enterotoxin B-stimulated cytokine production by total CD4+ T lymphocytes during primary SIVmac251 infection is tightly linked in a cohort of six rhesus monkeys to set point plasma viral RNA levels, with greater loss and dysfunction being associated with higher steady-state viral replication. Moreover, in exploring the mechanism underlying this phenomenon, we demonstrate that the loss of functional CD4+ T lymphocytes during primary SIVmac251 infection is associated with both a selective depletion of memory CD4+ T cells and a loss of the functional capacity of the memory CD4+ T lymphocytes that escape viral destruction.

scholarly journals Distinct Recognition of Non-Clade B Human Immunodeficiency Virus Type 1 Epitopes by Cytotoxic T Lymphocytes Generated from Donors Infected in Africa

1999 ◽  
Vol 73 (2) ◽  
pp. 1708-1714 ◽  
Author(s):  
Lucy Dorrell ◽  
Tao Dong ◽  
Graham S. Ogg ◽  
Simon Lister ◽  
Steve McAdam ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocytes ◽  
Cytotoxic T Lymphocytes ◽  
Human Immunodeficiency Virus Type ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Clade B ◽  
Immunodeficiency Virus ◽  
Hiv Type 1

ABSTRACT We present detailed studies of human immunodeficiency virus (HIV)-specific cytotoxic T-lymphocyte (CTL) responses to clade A or C HIV type 1 in three donors infected in East Africa. We define several novel non-clade B CTL epitopes, including some restricted by HLA alleles common in Africans. Although cross-clade CTL recognition of these epitopes does occur, recognition can also be highly clade specific.

scholarly journals CD8+ T-Lymphocyte Response to Major Immunodominant Epitopes after Vaginal Exposure to Simian Immunodeficiency Virus: Too Late and Too Little

2005 ◽  
Vol 79 (14) ◽  
pp. 9228-9235 ◽  
Author(s):  
Matthew R. Reynolds ◽  
Eva Rakasz ◽  
Pamela J. Skinner ◽  
Cara White ◽  
Kristina Abel ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Simian Immunodeficiency Virus ◽  
T Lymphocyte ◽  
Virus Production ◽  
Acute Stage ◽  
Female Reproductive Tract ◽  
Lymphocyte Response ◽  
Route Of Transmission ◽  
Immunodeficiency Virus ◽  
Lymphocyte Responses

ABSTRACT In the acute stage of infection following sexual transmission of human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV), virus-specific CD8+ T-lymphocyte responses partially control but do not eradicate infection from the lymphatic tissues (LTs) or prevent the particularly massive depletion of CD4+ T lymphocytes in gut-associated lymphatic tissue (GALT). We explored hypothetical explanations for this failure to clear infection and prevent CD4+ T-lymphocyte loss in the SIV/rhesus macaque model of intravaginal transmission. We examined the relationship between the timing and magnitude of the CD8+ T-lymphocyte response to immunodominant SIV epitopes and viral replication, and we show first that the failure to contain infection is not because the female reproductive tract is a poor inductive site. We documented robust responses in cervicovaginal tissues and uterus, but only several days after the peak of virus production. Second, while we also documented a modest response in the draining genital and peripheral lymph nodes, the response at these sites also lagged behind peak virus production in these LT compartments. Third, we found that the response in GALT was surprisingly low or undetectable, possibly contributing to the severe and sustained depletion of CD4+ T lymphocytes in the GALT. Thus, the virus-specific CD8+ T-lymphocyte response is “too late and too little” to clear infection and prevent CD4+ T-lymphocyte loss. However, the robust response in female reproductive tissues may be an encouraging sign that vaccines that rapidly induce high-frequency CD8+ T-lymphocyte responses might be able to prevent acquisition of HIV-1 infection by the most common route of transmission.

scholarly journals Elicitation of Simian Immunodeficiency Virus-Specific Cytotoxic T Lymphocytes in Mucosal Compartments of Rhesus Monkeys by Systemic Vaccination

2002 ◽  
Vol 76 (22) ◽  
pp. 11484-11490 ◽  
Author(s):  
Jamal Baig ◽  
Daniel B. Levy ◽  
Paul F. McKay ◽  
Joern E. Schmitz ◽  
Sampa Santra ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
Cytotoxic T Lymphocytes ◽  
Rhesus Monkeys ◽  
Hiv Infections ◽  
Systemic Delivery ◽  
Mucosal Tissues ◽  
Immunodeficiency Virus ◽  
Ctl Responses

ABSTRACT Since most human immunodeficiency virus (HIV) infections are initiated following mucosal exposure to the virus, the anatomic containment or abortion of an HIV infection is likely to require vaccine-elicited cellular immune responses in those mucosal sites. Studying vaccine-elicited mucosal immune responses has been problematic because of the difficulties associated with sampling T lymphocytes from those anatomic compartments. In the present study, we demonstrate that mucosal cytotoxic T lymphocytes (CTL) specific for simian immunodeficiency virus (SIV) and simian HIV can be reproducibly sampled from intestinal mucosal tissue of rhesus monkeys obtained under endoscopic guidance. These lymphocytes recognize peptide-major histocompatibility complex class I complexes and express gamma interferon on exposure to peptide antigen. Interestingly, systemic immunization of monkeys with plasmid DNA immunogens followed by live recombinant attenuated poxviruses or adenoviruses with genes deleted elicits high-frequency SIV-specific CTL responses in these mucosal tissues. These studies therefore suggest that systemic delivery of potent HIV immunogens may suffice to elicit substantial mucosal CTL responses.

scholarly journals Mucosal Immunization of Cynomolgus Macaques with Two Serotypes of Live Poliovirus Vectors Expressing Simian Immunodeficiency Virus Antigens: Stimulation of Humoral, Mucosal, and Cellular Immunity

1999 ◽  
Vol 73 (11) ◽  
pp. 9485-9495 ◽  
Author(s):  
Shane Crotty ◽  
Barbara L. Lohman ◽  
Fabien X.-S. Lü ◽  
ShenBei Tang ◽  
Christopher J. Miller ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Simian Immunodeficiency Virus ◽  
Cytotoxic T Lymphocytes ◽  
Cytotoxic T Lymphocyte ◽  
Immunoglobulin A ◽  
Live Virus ◽  
Mucosal Antibody ◽  
Immunodeficiency Virus ◽  
Cynomolgus Macaques

ABSTRACT Poliovirus live virus vectors are a candidate recombinant vaccine system. Previous studies using this system showed that a live poliovirus vector expressing a foreign antigen between the structural and nonstructural proteins generates both antibody and cytotoxic T-lymphocyte responses in mice. Here we describe a novel in vitro method of cloning recombinant polioviruses involving a hybrid-PCR approach. We report the construction of recombinant vectors of two different serotypes of poliovirus-expressing simian immunodeficiency virus (SIV) antigens and the intranasal and intravenous inoculations of four adult cynomolgus macaques with these poliovirus vectors expressing the SIV proteins p17 gag and gp41 env . All macaques generated a mucosal anti-SIV immunoglobulin A (IgA) response in rectal secretions. Two of the four macaques generated mucosal antibody responses detectable in vaginal lavages. Strong serum IgG responses lasting for at least 1 year were detected in two of the four monkeys. SIV-specific T-cell lymphoproliferative responses were detected in three of the four monkeys. SIV-specific cytotoxic T lymphocytes were detected in two of the four monkeys. This is the first report of poliovirus-elicited vaginal IgA or cytotoxic T lymphocytes in any naturally infectable primate, including humans. These findings support the concept that a live poliovirus vector is a potentially useful delivery system that elicits humoral, mucosal, and cellular immune responses against exogenous antigens.

scholarly journals Decline of Simian Immunodeficiency Virus (SIV)–Specific Cytotoxic T Lymphocytes in the Peripheral Blood of Long‐Term Nonprogressing Macaques Infected with SIVmac32H‐J5

1999 ◽  
Vol 180 (4) ◽  
pp. 1133-1141 ◽  
Author(s):  
Anna‐Maria Geretti ◽  
Ellen G. J. Hulskotte ◽  
Marlinda E. M. Dings ◽  
Carel A. van Baalen ◽  
Geert van Amerongen ◽  
...  
Keyword(s):  
T Lymphocytes ◽  
Simian Immunodeficiency Virus ◽  
Cytotoxic T Lymphocytes ◽  
Peripheral Blood ◽  
Immunodeficiency Virus

scholarly journals The Envelope Glycoprotein Ectodomains Determine the Efficiency of CD4+ T Lymphocyte Depletion in Simian– Human Immunodeficiency Virus–Infected Macaques

1998 ◽  
Vol 188 (6) ◽  
pp. 1159-1171 ◽  
Author(s):  
Gunilla B. Karlsson ◽  
Matilda Halloran ◽  
Dominik Schenten ◽  
Juliette Lee ◽  
Paul Racz ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocytes ◽  
T Lymphocyte ◽  
Envelope Glycoprotein ◽  
Rhesus Macaques ◽  
Immune Deficiency Syndrome ◽  
Lymphocyte Depletion ◽  
Immunodeficiency Virus ◽  
Hiv 1

CD4+ T lymphocyte depletion in human immunodeficiency virus type 1 (HIV-1)–infected humans underlies the development of acquired immune deficiency syndrome. Using a model in which rhesus macaques were infected with chimeric simian–human immunodeficiency viruses (SHIVs), we show that both the level of viremia and the structure of the HIV-1 envelope glycoprotein ectodomains individually contributed to the efficiency with which CD4+ T lymphocytes were depleted. The envelope glycoproteins of recombinant SHIVs that efficiently caused loss of CD4+ T lymphocytes exhibited increased chemokine receptor binding and membrane-fusing capacity compared with those of less pathogenic viruses. These studies identify the HIV-1 envelope glycoprotein ectodomains as determinants of CD4+ T lymphocyte loss in vivo and provide a foundation for studying pathogenic mechanisms.

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