Candidate: The objective of this K01 SERCA application is to provide the mentorship, support, and protected time necessary for Dr. Sarah Beck, DVM, PhD, DACVP to progress into a successful and productive career in independent translational research in the field of vaccine immunology. Dr. Beck is a veterinarian with extensive experience in viral immunology and nonhuman primate models of simian immunodeficiency virus (SIV). Her training at Johns Hopkins has provided her with expertise in a wide variety of animal models and comparative pathology, and she also is a Diplomate in the American College of Veterinary Pathologists (ACVP), making her a uniquely qualified candidate for translational research. Under the mentorship of a well-rounded and experienced scientific advisory committee and her co-mentors, Dr. Joel Blankson and Dr. Joseph Mankowski, the proposed training will allow her to expand her expertise into the field of vaccine immunology and the use of humanized mouse models of viral immunopathogenesis. Research Plan: Despite the fact that combined antiretroviral therapy is able to control viral replication and prolong the life of HIV infected individuals, HIV remains a pandemic without a cure. One of the largest blockades to achieving HIV cure is proving to be the presence of virus in resting CD4+ T cell reservoirs. Myriad studies have identified cell-mediated immunity (CMI) as an important mechanism for controlling viral replication. Although effective combined antiretroviral therapy (cART) prevents new rounds of HIV infection, it is incapable of eliminating pre-existing infected CD4+ cells, which are the most likely precursors to the majority of latently infected cells. In contrast, CD8+ T cells are capable of eliminating either productively infected or non-productively infected cells. This approach is supported by recent data using a CMV-based HIV vaccine, which showed that the presence of vaccine-induced CD8+ T cells in primary infection in SIV-infected rhesus were able to eliminate the viral reservoir entirely. The development of broad, persistent HIV Gag-specific CTL responses is believed to play a major role in control of viral replication and determination of clinical outcome. With this in mind, Dr. Beck plans to induce a robust, broad, HIV Gag-specific CD8+ T cell response using a novel virus like protein (VLP) platform with the goal of reducing or eliminating the viral reservoir by inducing effective CTL-mediated control of viral replication in primary HIV infection. This VLP vaccination strategy has several advantages over other vaccine strategies: 1) this VLP is a subunit type vaccine constructed on a bovine papillomavirus capsid, which is a foreign antigen to mice, monkeys, or humans, and therefore can be used across species easily, 2) it preferentially stimulates CTL response over humoral responses, and 3) it is able to induce a strong effector memory response. The overarching hypothesis of the proposed studies is that vaccination for HIV using the novel virus like protein (VLP) platform will stimulate broad HIV Gag-specific cytotoxic T cells, resulting in effective T cell-mediated killing of HIV-infected cells in primary infection, reducing the viral reservoir in HIV-infected BLT mice. She will test this hypothesis with the following specific aims:
Specific Aim #1 : Determine if VLPs can elicit broadly reactive HIV Gag-specific CTLs capable of controlling acute HIV replication in newly infected BLT mice Specific Aim #2: Determine if VLP elicited CTLs can prevent the accumulation of HIV escape mutations in newly infected BLT mice and decrease CD4+ T cell infection Specific Aim #3: Determine if VLP elicited CTLs can reduce the viral reservoir in HIV-infected mice on combination antiretroviral therapy (cART). This SERCA funding will allow Dr. Beck to receive the mentorship and skills needed to succeed as a independent scientist, and these studies will pave the way towards her future R01 funding to test VLP vaccination in larger macaque studies. Environment: The carefully crafted research plan developed by the applicant and her scientific mentor Joel Blankson is designed to give her interactive and multidisciplinary training in the highly collaborative environment at Johns Hopkins University. The Johns Hopkins University School of Medicine is a world- renowned leader in HIV research, encompassing programs in clinical and laboratory research, community outreach and HIV prevention, with the top experts in the field, providing the fertile ground for innovation and state of the art HIV research. This award will also allow Dr. Beck to attend yearly scientific meetings where she can further broaden her knowledge in viral and vaccine immunology, attend workshops, and network to gain recognition in the field. Her strong mentoring team, institutional support, and resource-rich environment will provide Dr. Beck with the scientific and career development needed to prepare her for a future as an independent researcher in an academic setting.
Despite the fact that combined antiretroviral therapy is able to control viral replication and prolong the life of HIV infected individuals, we have yet to find a cure for HIV or a therapy that can prevent the multitude of complications (ie. neurodegeneration, thromboses, cardiac complications) that result from chronic HIV infection. The cellular arm of host adaptive immunity has been identified as a major player in controlling early HIV-1 replication and it is highly likely that cell-mediated immunity also will play a crucial role in HIV cure strategies. A vaccine that can modulate the immune system in order to elicit CD8+ T cell-mediated natural control of HIV-1 in primary infection could successfully lower the viral load and decrease the number of infected CD4+ T cells, therefore reducing the resting CD4+ vaccine reservoir in later infection. These studies are a proof of principle that T cell vaccines can be used to lower viral load and reduce the viral reservoir. This will pave the way for future studies using T cell vaccination to target HIV-infected cells post-reactivation of latent HIV cellular reservoirs in a shock-and-kill strategy of HIV eradication, and hopefully allowing patients to discontinue combined antiretroviral therapy.
| Mangus, Lisa M; Beck, Sarah E; Queen, Suzanne E et al. (2018) Lymphocyte-Dominant Encephalitis and Meningitis in Simian Immunodeficiency Virus-Infected Macaques Receiving Antiretroviral Therapy. Am J Pathol 188:125-134 |
| Beck, Sarah E; Queen, Suzanne E; Metcalf Pate, Kelly A et al. (2018) An SIV/macaque model targeted to study HIV-associated neurocognitive disorders. J Neurovirol 24:204-212 |
| Rao, Avani D; Shin, Eun Ji; Beck, Sarah E et al. (2018) Demonstration of Safety and Feasibility of Hydrogel Marking of the Pancreas-Duodenum Interface for Image Guided Radiation Therapy (IGRT) in a Porcine Model: Implications in IGRT for Pancreatic Cancer Patients. Int J Radiat Oncol Biol Phys 101:640-645 |
| Pohlmeyer, Christopher W; Laskey, Sarah B; Beck, Sarah E et al. (2018) Cross-reactive microbial peptides can modulate HIV-specific CD8+ T cell responses. PLoS One 13:e0192098 |
