Development and evaluation of a heterogenous virus-like particle (VLP) formulation to achieve HIV-1 latency reversal and cure.

HIV-1 is the etiological agent behind acquired immune deficiency syndrome (AIDS) – a chronic, life-threatening condition that compromises host immune function. After nearly four decades and despite ongoing global efforts, HIV-1 persists in nearly 38 million individuals worldwide. Of this population, only 60% have access to life-saving combination antiretroviral therapy (cART), clearly emphasizing the need to realize a cure. Unfortunately, the establishment of replication-competent provirus in resting CD4+ T lymphocytes represents a significant barrier to HIV-1 curative research. The viral reservoir is highly stable and has a half-life of ~44 months. Therefore, it is unlikely that infection will naturally exhaust over the course of a human lifetime. Furthermore, infected cells are phenotypically indistinguishable from uninfected CD4+ T cells – thus making it difficult to selectively target these cells for eradication. Evidence suggests that HIV preferentially infects and establishes latency within HIV-specific CD4+ T cells and that HIV latency reversal can be achieved using HIV derived proteins. Therefore, a therapeutic vaccine that represents the entire proteome of HIV within a given individual, immediately prior to antiretroviral therapy, might activate the entire cellular reservoir and initiate proviral gene transcription. Herein, we investigate the ability of a highly diverse virus-like particle formulation to ‘shock’ HIV-infected cells into transcriptional activity, thus leading to their eradication via immune-mediated or viral cytopathic effects. This activation vector (ACT-VEC) represents the first targeted approach to HIV-1 latency reversal. Based on the detection of viral RNA in culture supernatants, we show that ACT-VEC significantly outperforms other clinically relevant latency reversing agents at both the acute and chronic stages of infection. Using a quantitative outgrowth assay, we determined that ACT-VEC was also capable of inducing replication competent provirus from HIV-infected CD4+ T cells. Furthermore, we provide preliminary evidence that a virus-like particle formulation can provide an immune-mediated ‘kill’ after transcriptional reactivation occurs. Our VLP construct is also minimally antigenic, suggesting that it will be well tolerated in vivo. All together, our research suggests that ACT-VEC is a highly efficacious transcriptional reactivator that merits further investigation in the context of curative therapeutic strategies