We have recently performed a vaccine trial using Mamu-B*17+ Indian rhesus macaques, which demonstrated remarkable control of chronic phase viral replication in five ?rapid controller? animals. Control correlated with the development of increased endpoint titers of vaccine-induced anti-gp140 binding antibodies (Abs) on day of challenge. These Abs did not neutralize the simian immunodeficiency virus mac239 (SIVmac239) clone. We have rarely seen this type of stringent control of SIVmac239 replication in more than 130 intrarectally (IR)-challenged macaques with the same dose of this stock of SIVmac239.
In Specific Aim I, we will investigate whether the vaccine-induced Env-binding Abs in the Mamu-B*17+ ?rapid controller? animals either had direct anti-viral effects or facilitated the development of efficacious T-cell responses. We will address this hypothesis by utilizing two different approaches involving transfer of serum IgG and monoclonal antibodies (mAbs) from the ?rapid controller? animals to vaccinated and nave animals. We will also investigate the nature of control in Mamu-B*08+ Indian rhesus macaques. More than 50% of nave (no vaccine or drug treatment) Mamu-B*08+ macaques become ?elite controllers? (ECs) after infection with SIVmac239.
In Specific Aim II, we will determine the genes involved in the control of the innate immune response that influence the development of elite control in macaques that express Mamu-B*08. It is becoming increasingly apparent that classical vaccine-induced CD8+ T-cells by themselves will not be sufficient to either prevent or control human immunodeficiency virus (HIV) or SIV infection. Recent studies have suggested that in conjunction with other effector molecules (Abs, innate immune responses) CD8+ T-cells can function effectively in the control of HIV/SIV replication in vaccinated individuals. Our studies plan to elucidate these mechanisms in two cohorts of macaques where unusual control of SIV replication has been observed.

Public Health Relevance

We will investigate control of antibodies information vaccine-induced antibody responses and innate immune responses associated with the If we are successful in defining the nature and the targets of these and the novel innate immune response pathways involved in viral control, incorporating this into vaccine design may facilitate the eventual development of an HIV v accine. SIVmac239 replication.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI052056-20
Application #
10065481
Study Section
HIV/AIDS Vaccines Study Section (VACC)
Program Officer
Lawrence, Diane M
Project Start
2003-04-01
Project End
2023-11-30
Budget Start
2020-12-01
Budget End
2021-11-30
Support Year
20
Fiscal Year
2021
Total Cost
Indirect Cost
Name
George Washington University
Department
Pathology
Type
Schools of Medicine
DUNS #
043990498
City
Washington
State
DC
Country
United States
Zip Code
20052
Abdelaal, Hadia M; Kim, Hyeon O; Wagstaff, Reece et al. (2015) Comparison of Vibratome and Compresstome sectioning of fresh primate lymphoid and genital tissues for in situ MHC-tetramer and immunofluorescence staining. Biol Proced Online 17:2
Maness, Nicholas J; Wilson, Nancy A; Reed, Jason S et al. (2010) Robust, vaccine-induced CD8(+) T lymphocyte response against an out-of-frame epitope. J Immunol 184:67-72
Giraldo-Vela, Juan P; Bean, Alex T; Rudersdorf, Richard et al. (2010) Simian immunodeficiency virus-specific CD4+ T cells from successful vaccinees target the SIV Gag capsid. Immunogenetics 62:701-7
Valentine, Laura E; Loffredo, John T; Bean, Alex T et al. (2009) Infection with ""escaped"" virus variants impairs control of simian immunodeficiency virus SIVmac239 replication in Mamu-B*08-positive macaques. J Virol 83:11514-27
Goulder, Philip J R; Watkins, David I (2008) Impact of MHC class I diversity on immune control of immunodeficiency virus replication. Nat Rev Immunol 8:619-30
Watkins, David I (2008) The hope for an HIV vaccine based on induction of CD8+ T lymphocytes--a review. Mem Inst Oswaldo Cruz 103:119-29
Loffredo, John T; Bean, Alex T; Beal, Dominic R et al. (2008) Patterns of CD8+ immunodominance may influence the ability of Mamu-B*08-positive macaques to naturally control simian immunodeficiency virus SIVmac239 replication. J Virol 82:1723-38
Maness, Nicholas J; Yant, Levi J; Chung, Chungwon et al. (2008) Comprehensive immunological evaluation reveals surprisingly few differences between elite controller and progressor Mamu-B*17-positive Simian immunodeficiency virus-infected rhesus macaques. J Virol 82:5245-54
Valentine, Laura E; Piaskowski, Shari M; Rakasz, Eva G et al. (2008) Recognition of escape variants in ELISPOT does not always predict CD8+ T-cell recognition of simian immunodeficiency virus-infected cells expressing the same variant sequences. J Virol 82:575-81
Reynolds, Matthew R; Weiler, Andrea M; Weisgrau, Kim L et al. (2008) Macaques vaccinated with live-attenuated SIV control replication of heterologous virus. J Exp Med 205:2537-50

Showing the most recent 10 out of 27 publications