Faculty Opinions recommendation of Immune Responses and Viral Persistence in Simian/Human Immunodeficiency Virus SHIV.C.CH848-Infected Rhesus Macaques.

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.

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

Journal of Virology ◽

10.1128/jvi.75.19.9037-9043.2001 ◽

2001 ◽

Vol 75 (19) ◽

pp. 9037-9043 ◽

Cited By ~ 141

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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Outcome of Simian-Human Immunodeficiency Virus Strain 89.6p Challenge following Vaccination of Rhesus Macaques with Human Immunodeficiency Virus Tat Protein

Journal of Virology ◽

10.1128/jvi.76.8.3800-3809.2002 ◽

2002 ◽

Vol 76 (8) ◽

pp. 3800-3809 ◽

Cited By ~ 45

Author(s):

Peter Silvera ◽

Max W. Richardson ◽

Jack Greenhouse ◽

Jake Yalley-Ogunro ◽

Nigel Shaw ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Immune Responses ◽

Vaccine Development ◽

Rhesus Macaques ◽

Biologically Active ◽

Cell Counts ◽

Human Immunodeficiency Virus Strain ◽

Immunodeficiency Virus ◽

Hiv 1

ABSTRACT The regulatory proteins Nef, Rev, and Tat of human immunodeficiency virus type 1 (HIV-1) are attractive targets for vaccine development, since induction of effective immune responses targeting these early proteins may best control virus replication. Here we investigated whether vaccination with biologically active Tat or inactive Tat toxoid derived from HIV-1IIIB and simian-human immunodeficiency virus (SHIV) strain 89.6p would induce protective immunity in rhesus macaques. Vaccination induced high titers of anti-Tat immunoglobulin G in all immunized animals by week 7, but titers were somewhat lower in the 89.6p Tat group. Dominant B-cell epitopes mapped to the amino terminus, the basic domain, and the carboxy-terminal region. Tat-specific T-helper responses were detected in 50% of immunized animals. T-cell epitopes appeared to map within amino acids (aa) 1 to 24 and aa 37 to 66. In addition, Tat-specific gamma interferon responses were detected in CD4+ and/or CD8+ T lymphocytes in 11 of 16 immunized animals on the day of challenge. However, all animals became infected upon intravenous challenge with 30 50% minimal infective doses of SHIV 89.6p, and there were no significant differences in viral loads or CD4+ T-cell counts between immunized and control animals. Thus, vaccination with HIV-1IIIB or SHIV 89.6p Tat or with Tat toxoid preparations failed to confer protection against SHIV 89.6p infection despite robust Tat-specific humoral and cellular immune responses in some animals. Given its apparent immunogenicity, Tat may be more effective as a component of a cocktail vaccine in combination with other regulatory and/or structural proteins of HIV-1.

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Vaccine protection from CD4+ T-cell loss caused by simian immunodeficiency virus (SIV) mac251 is afforded by sequential immunization with three unrelated vaccine vectors encoding multiple SIV antigens

Journal of General Virology ◽

10.1099/vir.0.80226-0 ◽

2004 ◽

Vol 85 (10) ◽

pp. 2915-2924 ◽

Cited By ~ 30

Author(s):

Gerrit Koopman ◽

Daniella Mortier ◽

Sam Hofman ◽

Henk Niphuis ◽

Zahra Fagrouch ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cell ◽

Immune Responses ◽

Simian Immunodeficiency Virus ◽

Cell Function ◽

Semliki Forest Virus ◽

Rhesus Macaques ◽

Cell Loss ◽

Inverse Association ◽

Immunodeficiency Virus

Candidate human immunodeficiency virus (HIV) vaccine strategies that induce strong cellular immune responses protect rhesus macaques that are infected with recombinant simian/human immunodeficiency virus SHIV89.6p from acute CD4+ T-cell loss and delay progression to AIDS. However, similar strategies have not proven as efficacious in the simian immunodeficiency virus (SIV)mac model of AIDS, an infection that causes a slow, steady loss of CD4+ T-cell function and numbers in rhesus macaques similar to that caused by HIV-1, the principal cause of AIDS in humans. Efforts to increase vaccine efficacy by repeated boosting with the same vector are quickly limited by rising anti-vector immune responses. Here, the sequential use of three different vectors (DNA, Semliki Forest virus and modified vaccinia virus Ankara) encoding the same SIVmac structural and regulatory antigens was investigated and demonstrated to prevent or slow the loss of CD4+ T-cells after mucosal challenge with the highly pathogenic SIVmac251 strain. Of particular interest was an inverse association between the extent of T-helper 2 cytokine responses and steady-state virus load. Although limited in the number of animals, this study provides important proof of the efficacy of the triple-vector vaccine strategy against chronic, progressive CD4+ T-cell loss in the rigorous SIVmac/rhesus macaque model of AIDS.

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Immune responses following simian/human immunodeficiency virus (SHIV) challenge of rhesus macaques after human immunodeficiency virus (HIV)-1 third variable domain (V3) loop-based genetic immunization

Journal of Medical Primatology ◽

10.1111/j.1600-0684.2000.290601.x ◽

2000 ◽

Vol 29 (6) ◽

pp. 371-386 ◽

Cited By ~ 2

Author(s):

Sylvie Le Borgne ◽

Roger Le Grand ◽

Marie-Louise Michel ◽

Bruno Vaslin ◽

Bertrand Boson ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Immune Responses ◽

Rhesus Macaques ◽

Variable Domain ◽

V3 Loop ◽

Genetic Immunization ◽

Immunodeficiency Virus ◽

Hiv 1

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Induction of Neutralizing Antibodies and Gag-Specific Cellular Immune Responses to an R5 Primary Isolate of Human Immunodeficiency Virus Type 1 in Rhesus Macaques

Journal of Virology ◽

10.1128/jvi.75.13.5879-5890.2001 ◽

2001 ◽

Vol 75 (13) ◽

pp. 5879-5890 ◽

Cited By ~ 52

Author(s):

David C. Montefiori ◽

Jeffrey T. Safrit ◽

Shari L. Lydy ◽

Ashley P. Barry ◽

Miroslawa Bilska ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Immune Responses ◽

Neutralizing Antibodies ◽

Rhesus Macaques ◽

Cellular Immune Responses ◽

Immunodeficiency Virus ◽

Ifn Γ ◽

Cellular Immune ◽

Hiv 1

ABSTRACT The ability to generate antibodies that cross-neutralize diverse primary isolates is an important goal for human immunodeficiency virus type 1 (HIV-1) vaccine development. Most of the candidate HIV-1 vaccines tested in humans and nonhuman primates have failed in this regard. Past efforts have focused almost entirely on the envelope glycoproteins of a small number of T-cell line-adapted strains of the virus as immunogens. Here we assessed the immunogenicity of noninfectious virus-like particles (VLP) consisting of Gag, Pro (protease), and Env from R5 primary isolate HIV-1Bx08. Immunogens were delivered to rhesus macaques in the form of either purified VLP, recombinant DNA and canarypox (ALVAC) vectors engineered to express VLP, or a combination of these products. Seroconversion to Gag and Pro was detected in all of the immunized animals. Antibodies that could neutralize HIV-1Bx08 were detected in animals that received (i) coinoculations with DNABx08 and VLPBx08, (ii) DNABx08 followed by ALVACBx08 boosting, and (iii) VLPBx08 alone. The neutralizing antibodies were highly strain specific despite the fact that they did not appear to be directed to linear epitopes in the V3 loop. Virus-specific cellular immune responses also were generated, as judged by the presence of Gag-specific gamma interferon (IFN-γ)-producing cells. These cellular immune responses required the inclusion of DNABx08 in the immunization modality, since few or no IFN-γ-producing cells were detected in animals that received either VLPBx08 or ALVACBx08 alone. The results demonstrate the feasibility of generating neutralizing antibodies and cellular immune responses that target an R5 primary HIV-1 isolate by vaccination in primates.

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Immune Responses and Viral Persistence in Simian/Human Immunodeficiency Virus SHIV.C.CH848-Infected Rhesus Macaques

Journal of Virology ◽

10.1128/jvi.02198-20 ◽

2021 ◽

Vol 95 (9) ◽

Author(s):

Widade Ziani ◽

Anya Bauer ◽

Hong Lu ◽

Xiaolei Wang ◽

Xueling Wu ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Cells ◽

Immune Responses ◽

Neutralizing Antibodies ◽

Rhesus Macaques ◽

Viral Rebound ◽

Viral Reservoirs ◽

Immunodeficiency Virus ◽

Hiv Research ◽

Hiv 1

ABSTRACT Chimeric simian/human immunodeficiency viruses (SHIVs) are widely used in nonhuman primate models to recapitulate human immunodeficiency virus (HIV) infection in humans, yet most SHIVs fail to establish persistent viral infection. We investigated immunological and virological events in rhesus macaques infected with the newly developed SHIV.C.CH848 (SHIVC) and treated with combined antiretroviral therapy (cART). Similar to HIV/simian immunodeficiency virus (SIV) infection, SHIV.C.CH848 infection established viral reservoirs in CD4+ T cells and myeloid cells, accompanied by productive infection and depletion of CD4+ T cells in systemic and lymphoid tissues throughout SHIV infection. Despite 6 months of cART-suppressed viral replication, integrated proviral DNA levels remained stable, especially in CD4+ T cells, and the viral rebound was also observed after ART interruption. Autologous neutralizing antibodies to the parental HIV-1 strain CH848 were detected, with limited viral evolution at 5 months postinfection. In comparison, heterogenous neutralizing antibodies in SHIV.C.CH848-infected macaques were not detected except for 1 (1 of 10) animal at 2 years postinfection. These findings suggest that SHIV.C.CH848, a novel class of transmitted/founder SHIVs, can establish sustained viremia and viral reservoirs in rhesus macaques with clinical immunodeficiency consequences, providing a valuable SHIV model for HIV research. IMPORTANCE SHIVs have been extensively used in a nonhuman primate (NHP) model for HIV research. In this study, we investigated viral reservoirs in tissues and immune responses in an NHP model inoculated with newly generated transmitted/founder HIV-1 clade C-based SHIV.C.CH848. The data show that transmitted founder (T/F) SHIVC infection of macaques more closely recapitulates the virological and clinical features of HIV infection, including persistent viremia and viral rebound once antiretroviral therapy is discontinued. These results suggest this CCR5-tropic, SHIVC strain is valuable for testing responses to HIV vaccines and therapeutics.

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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

Journal of Virology ◽

10.1128/jvi.77.5.3099-3118.2003 ◽

2003 ◽

Vol 77 (5) ◽

pp. 3099-3118 ◽

Cited By ~ 69

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.

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Simian-Human Immunodeficiency Virus SHIV.CH505-Infected Infant and Adult Rhesus Macaques Exhibit Similar Env-Specific Antibody Kinetics, despite Distinct T-Follicular Helper and Germinal Center B Cell Landscapes

Journal of Virology ◽

10.1128/jvi.00168-19 ◽

2019 ◽

Vol 93 (15) ◽

Cited By ~ 6

Author(s):

Ashley N. Nelson ◽

Ria Goswami ◽

Maria Dennis ◽

Joshua Tu ◽

Riley J. Mangan ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

Immune Responses ◽

Rhesus Macaques ◽

Intervention Strategies ◽

Infected Infant ◽

Humoral Immune ◽

Germinal Center B Cell ◽

Immunodeficiency Virus ◽

Shiv Infection ◽

Antibody Kinetics

ABSTRACTGlobal elimination of pediatric human immunodeficiency virus (HIV) infections will require the development of novel immune-based approaches, and understanding infant immunity to HIV is critical to guide the rational design of these intervention strategies. Despite their immunological immaturity, chronically HIV-infected children develop broadly neutralizing antibodies (bnAbs) more frequently and earlier than adults do. However, the ontogeny of humoral responses during acute HIV infection is poorly defined in infants and challenging to study in human cohorts due to the presence of maternal antibodies. To further our understanding of age-related differences in the development of HIV-specific immunity during acute infection, we evaluated the generation of virus-specific humoral immune responses in infant (n = 6) and adult (n = 12) rhesus macaques (RMs) infected with a transmitted/founder (T/F) simian-human immunodeficiency virus (SHIV) (SHIV.C.CH505 [CH505]). The plasma HIV envelope-specific IgG antibody kinetics were similar in SHIV-infected infant and adult RMs, with no significant differences in the magnitude or breadth of these responses. Interestingly, autologous tier 2 virus neutralization responses also developed with similar frequencies and kinetics in infant and adult RMs, despite infants exhibiting significantly higher follicular T helper cell (Tfh) and germinal center B cell frequencies than adults. Finally, we show that plasma viral load was the strongest predictor of the development of autologous virus neutralization in both age groups. Our results indicate that the humoral immune response to SHIV infection develops with similar kinetics among infant and adult RMs, suggesting that the early-life immune system is equipped to respond to HIV-1 and promote the production of neutralizing HIV antibodies.IMPORTANCEThere is a lack of understanding of how the maturation of the infant immune system influences immunity to HIV infection or how these responses differ from those of adults. Improving our knowledge of infant HIV immunity will help guide antiviral intervention strategies that take advantage of the unique infant immune environment to successfully elicit protective immune responses. We utilized a rhesus macaque model of SHIV infection as a tool to distinguish the differences in HIV humoral immunity in infants versus adults. Here, we demonstrate that the kinetics and quality of the infant humoral immune response to HIV are highly comparable to those of adults during the early phase of infection, despite distinct differences in their Tfh responses, indicating that slightly different mechanisms may drive infant and adult humoral immunity.

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