A vaccine against HIV is urgently needed. The development of such vaccine represents an unprecedented challenge. The tremendous genetic diversity of HIV, for example, imposes a major obstacle for vaccine development. Furthermore, HIV infects activated CD4 T cells that are generated following vaccination or infection, suggesting that HIV feeds from the immune response that it elicits. Therefore, we propose that a viable vaccine strategy should minimize the induction of immune responses that fuel HIV and maximize immune responses that control HIV. We first would like to assess a possible detrimental role for virus-specific CD4 T cell responses and determine whether the immune dysregulation that is observed in AIDS patients has mechanistic overlaps with that observed in our model of LCMV infection in mice. We would also like to develop novel vaccine regimens that abrogate the activation of CD4 T cell responses and generate high antibody and CD8 T cell responses at sites where HIV replicates.
The Aims of this application are:
Aim 1. To compare the transcriptional signature of helper versus detrimental CD4 T cells following chronic LCMV infection, and compare these signatures to those of HIV infected patients.
Aim 2. To ascertain the role of memory CD4 T cells following HIV infection, and assess whether a vaccine that does not induce CD4 T cell responses can provide immune protection in the humanized mouse model of HIV infection.
Aim 3. To evaluate the immunogenicity of novel rLCMV vectors in mice, and develop regimens to maximize cytotoxic CD8 T cell responses in lymph nodes and gut in the complete absence of CD4 T cell priming. The findings from this K22 Career Development Award will be crucial for rational vaccine design, and may help to develop the first generation of tailored CD4-less vaccines against HIV.
HIV/AIDS affects millions of people worldwide, and as of now, candidate vaccines have failed to provide immune protection against this devastating disease. Since HIV is an infection of the immune system, mainly activated CD4 T cells, the new generation of candidate HIV vaccines should minimize the induction of activated CD4 T cell responses that could fuel HIV infection while maximizing protective immune responses that are not targeted by the virus.
|Bhattacharyya, Mitra; Penaloza-MacMaster, Pablo (2018) Dynamics of Lymphocyte Reconstitution After Hematopoietic Transplantation During Chronic Lymphocytic Choriomeningitis Virus Infection. AIDS Res Hum Retroviruses 34:430-438|
|Badamchi-Zadeh, Alexander; Moynihan, Kelly D; Larocca, Rafael A et al. (2018) Combined HDAC and BET Inhibition Enhances Melanoma Vaccine Immunogenicity and Efficacy. J Immunol 201:2744-2752|
|Bhattacharyya, Mitra; Whitney, James B; Seaman, Michael et al. (2018) T-cell subset differentiation and antibody responses following antiretroviral therapy during simian immunodeficiency virus infection. Immunology 155:458-466|
|Xu, Dan; Robinson, Andrew P; Ishii, Toshiyuki et al. (2018) Peripherally derived T regulatory and ?? T cells have opposing roles in the pathogenesis of intractable pediatric epilepsy. J Exp Med 215:1169-1186|
|Blass, Eryn; Aid, Malika; Martinot, Amanda J et al. (2018) Adenovirus Vector Vaccination Impacts NK Cell Rheostat Function following Lymphocytic Choriomeningitis Virus Infection. J Virol 92:|
|Bhattacharyya, Mitra; Madden, Patrick; Henning, Nathan et al. (2017) Regulation of CD4 T cells and their effects on immunopathological inflammation following viral infection. Immunology 152:328-343|
|Alayo, Quazim A; Provine, Nicholas M; Penaloza-MacMaster, Pablo (2017) Novel Concepts for HIV Vaccine Vector Design. mSphere 2:|
|Bhattacharyya, Mitra; Penaloza-MacMaster, Pablo (2017) T regulatory cells are critical for the maintenance, anamnestic expansion and protection elicited by vaccine-induced CD8 T cells. Immunology 151:340-348|
|Penaloza-MacMaster, Pablo (2017) CD8 T-cell regulation by T regulatory cells and the programmed cell death protein 1 pathway. Immunology 151:146-153|