scholarly journals Simian-Human Immunodeficiency Virus SHIV89.6-Induced Protection against Intravaginal Challenge with Pathogenic SIVmac239 Is Independent of the Route of Immunization and Is Associated with a Combination of Cytotoxic T-Lymphocyte and Alpha Interferon Responses

2003 ◽  
Vol 77 (5) ◽  
pp. 3099-3118 ◽  
Author(s):  
Kristina Abel ◽  
Lara Compton ◽  
Tracy Rourke ◽  
David Montefiori ◽  
Ding Lu ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Immune Responses ◽  
Cytotoxic T Lymphocyte ◽  
Rhesus Macaques ◽  
Systemic Infection ◽  
Vaccine Virus ◽  
Mrna Levels ◽  
Peripheral Blood Mononuclear ◽  
Pronounced Increase ◽  
Immunodeficiency Virus

ABSTRACT Attenuated primate lentivirus vaccines provide the most consistent protection against challenge with pathogenic simian immunodeficiency virus (SIV). Thus, they provide an excellent model to examine the influence of the route of immunization on challenge outcome and to study vaccine-induced protective anti-SIV immune responses. In the present study, rhesus macaques were immunized with live nonpathogenic simian-human immunodeficiency virus (SHIV) 89.6 either intravenously or mucosally (intranasally or intravaginally) and then challenged intravaginally with pathogenic SIVmac239. The route of immunization did not affect mucosal challenge outcome after a prolonged period of systemic infection with the nonpathogenic vaccine virus. Further, protection from the SIV challenge was associated with the induction of multiple host immune effector mechanisms. A comparison of immune responses in vaccinated-protected and vaccinated-unprotected animals revealed that vaccinated-protected animals had higher frequencies of SIV Gag-specific cytotoxic T lymphocytes and gamma interferon (IFN-γ)-secreting cells during the acute phase postchallenge. Vaccinated-protected animals also had a more pronounced increase in peripheral blood mononuclear cell IFN-α mRNA levels than did the vaccinated-unprotected animals in the first few weeks after challenge. Thus, innate as well as cellular anti-SIV immune responses appeared to contribute to the SHIV89.6-induced protection against intravaginal challenge with pathogenic SIVmac239.

scholarly journals DNA Vaccination with the Human Immunodeficiency Virus Type 1 SF162ΔV2 Envelope Elicits Immune Responses That Offer Partial Protection from Simian/Human Immunodeficiency Virus Infection to CD8+ T-Cell-Depleted Rhesus Macaques

2001 ◽  
Vol 75 (3) ◽  
pp. 1547-1550 ◽  
Author(s):  
S. Cherpelis ◽  
I. Shrivastava ◽  
A. Gettie ◽  
X. Jin ◽  
D. D. Ho ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Cd8 T Cell ◽  
Dna Immunization ◽  
Plasma Virus ◽  
Partial Protection ◽  
Immunodeficiency Virus

ABSTRACT DNA immunization of macaques with the SF162ΔV2 envelope elicited lymphoproliferative responses and potent neutralizing antibodies. The animals were depleted of their CD8+ T lymphocytes and then challenged intravenously with SHIV162P4. Compared to unvaccinated animals, the vaccinated macaques had lower peak viremia levels, rapidly cleared plasma virus, and showed delayed seroconversion.

scholarly journals Rapid Definition of Five Novel HLA-A∗3002-Restricted Human Immunodeficiency Virus-Specific Cytotoxic T-Lymphocyte Epitopes by Elispot and Intracellular Cytokine Staining Assays

2001 ◽  
Vol 75 (3) ◽  
pp. 1339-1347 ◽  
Author(s):  
Philip J. R. Goulder ◽  
, Marylyn M. Addo ◽  
Marcus A. Altfeld ◽  
Eric S. Rosenberg ◽  
Yanhua Tang ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Mononuclear Cells ◽  
Cytotoxic T Lymphocyte ◽  
Intracellular Cytokine Staining ◽  
Initial Step ◽  
Peripheral Blood Mononuclear ◽  
Hla Restriction ◽  
Immunodeficiency Virus ◽  
Definition Of ◽  
Ctl Responses

ABSTRACT Human immunodeficiency virus (HIV)-specific cytotoxic T lymphocytes (CTL) play a major role in control of viral replication. To understand the contribution of this antiviral response, an initial step is to fully define the specific epitopes targeted by CTL. These studies focused on CTL responses restricted by HLA-A∗3002, one of the HLA-A molecules most prominent in African populations. To avoid the time-consuming effort and expense involved in culturing CTL prior to defining epitopes and restricting alleles, we developed a method combining Elispot assays with intracellular gamma interferon staining of peripheral blood mononuclear cells to first map the optimal epitopes targeted and then define the HLA restriction of novel epitopes. In two A∗3002-positive subjects whose CTL responses were characterized in detail, the strongest response in both cases was to an epitope in p17 Gag, RSLYNTVATLY (residues 76 to 86). Using this method, CTL epitopes for which there were no motif predictions were optimized and the HLA restriction was established within 48 to 72 h of receipt of blood. This simple and convenient approach should prove useful especially in the characterization of CTL responses specific to HIV and other viruses, particularly in localities where performing cytotoxicity assays would be problematic.

scholarly journals Gamma Interferon-Mediated Inflammation Is Associated with Lack of Protection from Intravaginal Simian Immunodeficiency Virus SIVmac239 Challenge in Simian-Human Immunodeficiency Virus 89.6-Immunized Rhesus Macaques

2004 ◽  
Vol 78 (2) ◽  
pp. 841-854 ◽  
Author(s):  
Kristina Abel ◽  
Lisa La Franco-Scheuch ◽  
Tracy Rourke ◽  
Zhong-Min Ma ◽  
Veronique de Silva ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Rhesus Macaques ◽  
T Cell Responses ◽  
Lymphoid Tissues ◽  
Mrna Levels ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Ifn Γ

ABSTRACT Although gamma interferon (IFN-γ) is a key mediator of antiviral defenses, it is also a mediator of inflammation. As inflammation can drive lentiviral replication, we sought to determine the relationship between IFN-γ-related host immune responses and challenge virus replication in lymphoid tissues of simian-human immunodeficiency virus 89.6 (SHIV89.6)-vaccinated and unvaccinated rhesus macaques 6 months after challenge with simian immunodeficiency virus SIVmac239. Vaccinated-protected monkeys had low tissue viral RNA (vRNA) levels, vaccinated-unprotected animals had moderate tissue vRNA levels, and unvaccinated animals had high tissue vRNA levels. The long-term challenge outcome in vaccinated monkeys was correlated with the relative balance between SIV-specific IFN-γ T-cell responses and nonspecific IFN-γ-driven inflammation. Vaccinated-protected monkeys had slightly increased tissue IFN-γ mRNA levels and a high frequency of IFN-γ-secreting T cells responding to in vitro SIVgag peptide stimulation; thus, it is likely that they could develop effective anti-SIV cytotoxic T lymphocytes in vivo. In contrast, both high tissue IFN-γ mRNA levels and strong in vitro SIV-specific IFN-γ T-cell responses were detected in lymphoid tissues of vaccinated-unprotected monkeys. Unvaccinated monkeys had increased tissue IFN-γ mRNA levels but weak in vitro anti-SIV IFN-γ T-cell responses. In addition, in lymphoid tissues of vaccinated-unprotected and unvaccinated monkeys, the increased IFN-γ mRNA levels were associated with increased Mig/CXCL9, IP-10/CXCL10, and CXCR3 mRNA levels, suggesting that increased Mig/CXCL9 and IP-10/CXCL10 expression resulted in recruitment of CXCR3+ activated T cells. Thus, IFN-γ-driven inflammation promotes SIV replication in vaccinated-unprotected and unvaccinated monkeys. Unlike all unvaccinated monkeys, most monkeys vaccinated with SHIV89.6 did not develop IFN-γ-driven inflammation, but they did develop effective antiviral CD8+-T-cell responses.

scholarly journals A Period of Transient Viremia and Occult Infection Precedes Persistent Viremia and Antiviral Immune Responses during Multiple Low-Dose Intravaginal Simian Immunodeficiency Virus Inoculations

2004 ◽  
Vol 78 (24) ◽  
pp. 14048-14052 ◽  
Author(s):  
Zhong-Min Ma ◽  
Kristina Abel ◽  
Tracy Rourke ◽  
Yichuan Wang ◽  
Christopher J. Miller
Keyword(s):  
Immune Responses ◽  
Simian Immunodeficiency Virus ◽  
Low Dose ◽  
Rhesus Macaques ◽  
Systemic Infection ◽  
Variable Number ◽  
Transmission Model ◽  
High Dose ◽  
Persistent Viremia ◽  
Immunodeficiency Virus

ABSTRACT In rhesus macaques, classic systemic infection, characterized by persistent viremia and seroconversion, occurred after multiple low-dose (103 50% tissue culture infective doses) intravaginal (IVAG) inoculations with simian immunodeficiency virus (SIV) strain SIVmac251. Monkeys developed classic SIV infections after a variable number of low-dose IVAG exposures to SIVmac251. Once established, the systemic infection was identical to SIV infection following high-dose IVAG SIV inoculation. However, occult systemic infection characterized by transient cell-associated or cell-free viremia consistently occurred early in the series of multiple vaginal SIV exposures. Further, antiviral cellular immune responses were present prior to the establishment of a classic systemic infection in the low-dose vaginal SIV transmission model.

scholarly journals Changes in Human Immunodeficiency Virus Type 1 Envelope Glycoproteins Responsible for the Pathogenicity of a Multiply Passaged Simian-Human Immunodeficiency Virus (SHIV-HXBc2)

1999 ◽  
Vol 73 (2) ◽  
pp. 976-984 ◽  
Author(s):  
Mark Cayabyab ◽  
Gunilla B. Karlsson ◽  
Bijan A. Etemad-Moghadam ◽  
Wolfgang Hofmann ◽  
Tavis Steenbeke ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Lymphocyte ◽  
Mononuclear Cells ◽  
Rhesus Macaques ◽  
Envelope Glycoproteins ◽  
Peripheral Blood Mononuclear ◽  
Lymphocyte Depletion ◽  
Immunodeficiency Virus

ABSTRACT In vivo passage of a poorly replicating, nonpathogenic simian-human immunodeficiency virus (SHIV-HXBc2) generated an efficiently replicating virus, KU-1, that caused rapid CD4+T-lymphocyte depletion and AIDS-like illness in monkeys (S. V. Joag, Z. Li, L. Foresman, E. B. Stephens, L.-J. Zhao, I. Adany, D. M. Pinson, H. M. McClure, and O. Narayan, J. Virol. 70:3189–3197, 1996). The env gene of the KU-1 virus was used to create a molecularly cloned virus, SHIV-HXBc2P 3.2, that differed from a nonpathogenic SHIV-HXBc2 virus in only 12 envelope glycoprotein residues. SHIV-HXBc2P 3.2 replicated efficiently and caused rapid and persistent CD4+ T-lymphocyte depletion in inoculated rhesus macaques. Compared with the envelope glycoproteins of the parental SHIV-HXBc2, the SHIV-HXBc2P 3.2 envelope glycoproteins supported more efficient infection of rhesus monkey peripheral blood mononuclear cells. Both the parental SHIV-HXBc2 and the pathogenic SHIV-HXBc2P 3.2 used CXCR4 but none of the other seven transmembrane segment receptors tested as a second receptor. Compared with the parental virus, viruses with the SHIV-HXBc2P 3.2 envelope glycoproteins were more resistant to neutralization by soluble CD4 and antibodies. Thus, changes in the envelope glycoproteins account for the ability of the passaged virus to deplete CD4+ T lymphocytes rapidly and specify increased replicative capacity and resistance to neutralization.

scholarly journals Levels of Human Immunodeficiency Virus Type 1-Specific Cytotoxic T-Lymphocyte Effector and Memory Responses Decline after Suppression of Viremia with Highly Active Antiretroviral Therapy

1999 ◽  
Vol 73 (8) ◽  
pp. 6721-6728 ◽  
Author(s):  
Spyros A. Kalams ◽  
Philip J. Goulder ◽  
Amy K. Shea ◽  
Norman G. Jones ◽  
Alicja K. Trocha ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Immune Responses ◽  
T Lymphocyte ◽  
Highly Active Antiretroviral Therapy ◽  
Cytotoxic T Lymphocyte ◽  
Highly Active ◽  
Immunodeficiency Virus ◽  
Hiv 1

ABSTRACT Therapeutic suppression of human immunodeficiency virus type 1 (HIV-1) replication may help elucidate interactions between the host cellular immune responses and HIV-1 infection. We performed a detailed longitudinal evaluation of two subjects before and after the start of highly active antiretroviral therapy (HAART). Both subjects had evidence of in vivo-activated and memory cytotoxic T-lymphocyte precursor (CTLp) activity against multiple HIV-1 gene products. After the start of therapy, both subjects had declines in the levels of in vivo-activated HIV-1-specific CTLs and had immediate increases in circulating HIV-1-specific CTL memory cells. With continued therapy, and continued suppression of viral load, levels of memory CTLps declined. HLA A*0201 peptide tetramer staining demonstrated that declining levels of in vivo-activated CTL activity were associated with a decrease in the expression of the CD38+ activation marker. Transient increases in viral load during continued therapy were associated with increases in the levels of virus-specific CTLps in both individuals. The results were confirmed by measuring CTL responses to discrete optimal epitopes. These studies illustrate the dynamic equilibrium between the host immune response and levels of viral antigen burden and suggest that efforts to augment HIV-1-specific immune responses in subjects on HAART may decrease the incidence of virologic relapse.

scholarly journals Mucosal Transmission and Induction of Simian AIDS by CCR5-Specific Simian/Human Immunodeficiency Virus SHIVSF162P3

2001 ◽  
Vol 75 (4) ◽  
pp. 1990-1995 ◽  
Author(s):  
Janet M. Harouse ◽  
Agegnehu Gettie ◽  
Tadesse Eshetu ◽  
Rei Chin How Tan ◽  
Rudolf Bohm ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Large Scale ◽  
Mononuclear Cells ◽  
Opportunistic Infections ◽  
Rhesus Macaques ◽  
Viral Transmission ◽  
Peripheral Blood Mononuclear ◽  
Mucosal Transmission ◽  
Macaque Model ◽  
Immunodeficiency Virus

ABSTRACT Nonhuman primate models are increasingly used in the screening of candidate AIDS vaccine and immunization strategies for advancement to large-scale human trials. The predictive value of such macaque studies is largely dependent upon the fidelity of the model system in mimicking human immunodeficiency virus (HIV) type 1 infection in terms of viral transmission, replication, and pathogenesis. Herein, we describe the efficient mucosal transmission of a CCR5-specific chimeric simian/human immunodeficiency virus, SHIVSF162P3. Female rhesus macaques were infected with SHIVSF162P3 after a single atraumatic application to the cervicovaginal mucosa. The disease course of SHIVSF162P3-infected monkeys is similar and as varied as natural HIV infection in terms of viral replication, gradual loss of CD4+ peripheral blood mononuclear cells, and the development of simian AIDS-defining opportunistic infections. The SHIVSF162P3/macaque model should facilitate direct preclinical assessment of HIV vaccine strategies in addition to antiviral compounds directed towards envelope target cell interactions. Furthermore, this controlled model provides the setting to investigate immunologic responses and putative host-specific susceptibility factors that alter viral transmission and subsequent disease progression.

scholarly journals Induction of Potent Immune Responses by Cationic Microparticles with Adsorbed Human Immunodeficiency Virus DNA Vaccines

2001 ◽  
Vol 75 (19) ◽  
pp. 9037-9043 ◽  
Author(s):  
Derek O'Hagan ◽  
Manmohan Singh ◽  
Mildred Ugozzoli ◽  
Carl Wild ◽  
Susan Barnett ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Immune Responses ◽  
Guinea Pigs ◽  
Dna Vaccines ◽  
Rhesus Macaques ◽  
Antibody Responses ◽  
Combination Vaccine ◽  
Enzyme Linked Immunosorbent Assay ◽  
Naked Dna ◽  
Immunodeficiency Virus

ABSTRACT The effectiveness of cationic microparticles with adsorbed DNA at inducing immune responses was investigated in mice, guinea pigs, and rhesus macaques. Plasmid DNA vaccines encoding human immunodeficiency virus (HIV) Gag and Env adsorbed onto the surface of cationic poly(lactide-coglycolide) (PLG) microparticles were shown to be substantially more potent than corresponding naked DNA vaccines. In mice immunized with HIV gag DNA, adsorption onto PLG increased CD8+ T-cell and antibody responses by ∼100- and ∼1,000-fold, respectively. In guinea pigs immunized with HIV env DNA adsorbed onto PLG, antibody responses showed a more rapid onset and achieved markedly higher enzyme-linked immunosorbent assay and neutralizing titers than in animals immunized with naked DNA. Further enhancement of antibody responses was observed in animals vaccinated with PLG/DNA microparticles formulated with aluminum phosphate. The magnitude of anti-Env antibody responses induced by PLG/DNA particles was equivalent to that induced by recombinant gp120 protein formulated with a strong adjuvant, MF-59. In guinea pigs immunized with a combination vaccine containing HIVenv and HIV gag DNA plasmids on PLG microparticles, substantially superior antibody responses were induced against both components, as measured by onset, duration, and titer. Furthermore, PLG formulation overcame an apparent hyporesponsiveness of the env DNA component in the combination vaccine. Finally, preliminary data in rhesus macaques demonstrated a substantial enhancement of immune responses afforded by PLG/DNA. Therefore, formulation of DNA vaccines by adsorption onto PLG microparticles is a powerful means of increasing vaccine potency.

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