A heterogeneous human immunodeficiency virus-like particle (VLP) formulation produced by a novel vector system

Abstract

First identified as the etiological agent behind Acquired Immunodeficiency Syndrome (AIDS) in the early 1980s, HIV-1 has continued to spread into a global pandemic and major public health concern. Despite the success of antiretroviral therapy at reducing HIV-1 viremia and preventing the dramatic CD4+ T-cell collapse, infected individuals remain HIV positive for life. Unfortunately, it is increasingly clear that natural immunity is not, and may never be, protective against this pathogen. Therefore, efficacious vaccine interventions, which can either prevent infection or eradicate the latent viral reservoir and effect cure, are a major medical priority. Here we describe the development of a safe vaccine platform, currently being utilized in on-going prophylactic and therapeutic preclinical studies and consisting of highly heterogeneous virus-like particle formulations that represent the virus diversity within infected individuals. These VLPs contain no 5′LTR, no functional integrase, and have a severely mutated stem loop 1—thereby preventing any potential reverse transcription, integration, and RNA packaging. Furthermore, we demonstrate that these VLPs are morphologically identical to wild-type virus with polyvalent Env in a functional form. Finally, we show that the VLPs are antigenic and capable of generating strong immune recall responses.

Virus-Like Particle, Liposome, and Polymeric Particle-Based Vaccines against HIV-1

“…A preventative vaccine must be protective against HIV strains/subtypes circulating in multiple geographic regions. Polyvalent Env vaccines are one such approach to overcome the viral diversity and involve the use of heterogeneous Env mixtures to expose developing immune responses to a multitude of Env conformations ( 47 ). This is thought to help promote immuno-focusing of B cell responses onto more conserved regions of vulnerability such as the Env CD4-binding site and MPER while also promoting antibody breadth.…”

“…This is thought to help promote immuno-focusing of B cell responses onto more conserved regions of vulnerability such as the Env CD4-binding site and MPER while also promoting antibody breadth. To address this issue, Pankrac et al developed a chimeric HIV-1 VLP formulation capable of accommodating near full length (NFL) genomes of HIV-1 that captures the viral diversity within infected individuals ( 47 ). To do this, the authors took the plasma of five pre-cART HIV positive volunteers and engineered the isolated virus into a mixed VLP formulation.…”

“…They also deleted the 5′LTR so that the probability of reverse transcription was eliminated. Collectively, these “dead” viral particles were shown to have similar morphology to wild-type virus, contained p24 and p17, as well as expressed functional Env, Tat and Rev ( 47 , 48 ). Upon exposure of HIV-1 infected CD4 T cells to dendritic cells (DCs) pulsed with the heterologous VLPs, a strong IFN-g response was detected, indicating the ability to generate antigen-specific CD4 T cell recall responses.…”

“…Upon exposure of HIV-1 infected CD4 T cells to dendritic cells (DCs) pulsed with the heterologous VLPs, a strong IFN-g response was detected, indicating the ability to generate antigen-specific CD4 T cell recall responses. In addition, when the VLPs were used to pulse PBMC cultures, the authors demonstrated Granzyme B production, a biological marker for cytotoxicity ( 47 ). Finally, the VLPs were also shown to be able to prime and boost a CD4 adaptive immune response in vitro using healthy donor CD4 T cell-DC co-cultures ( 47 ).…”

“…In addition, when the VLPs were used to pulse PBMC cultures, the authors demonstrated Granzyme B production, a biological marker for cytotoxicity ( 47 ). Finally, the VLPs were also shown to be able to prime and boost a CD4 adaptive immune response in vitro using healthy donor CD4 T cell-DC co-cultures ( 47 ). This polyvalent VLP vaccine formulation is called ACT-VEC and is now being evaluated in non-human primates (NHPs) for its immunogenicity.…”