Numerous strategies have been evaluated to address the issue of HIV cure. The most promising tactic to-date involves a “Shock and Kill” approach. This method utilizes a pharmacological agent to ‘shock’ inducible and infectious HIV in the reservoir into transcriptional activity, thereby enabling its detection and elimination by immune or therapeutic mechanisms. Research has demonstrated that most HIV proviruses become integrated within the introns of actively transcribed host genes, and that the main HIV latent reservoir is found within resting memory CD4 T cells. Therefore, CD4 T cells are often the targets for latency reversal agents (LRAs), seeking to purge latent virus. Until recently, the most promising LRAs were the non-specific Histone Deacetylase inhibitors (HDACi), due to their in vitro ability to promote histone acetylation of integrated proviral promoters [
5]. Prominent LRAs such as Vorinostat, Disulfiram, and Romidepsin have been tested in clinical studies as candidate LRAs to purge the HIV-1 reservoir [
6‐
10]. Unfortunately, none could significantly impact upon the size of the reservoir, regardless of the promising preclinical research using both primary cells and cell lines [
11]. More recently, in vitro latency reversal studies using two-drug regimens, incorporating HDACi and protein kinase C (PKC) agonists, have been shown to synergistically amplify latency reversal, providing support that an effective “shock” is achievable. Although HDACi were once highly promising, several alternative studies have reported minimal latent HIV-1 reactivation in primary CD4+ T cells ex vivo [
12]. Additionally, evidence suggests that certain HDACis may suppress immune responses through inhibited cytokine release, delayed killing of activated infected-CD4+ T cells, impaired CTL functioning, and unwanted apoptosis of NK cells [
13]. Furthermore, certain HDACis have immunomodulatory effects on B cells and inhibit primary germinal center responses [
14]. Finally, HDACi are non-specific T cell activators, which could theoretically cause the propagation of infected cells. New and improved LRAs are necessary to facilitate reservoir eradication and cure.
As disseminating HIV infection results in recruitment and activation of CD4 and CD8 T cells, it is thought that the anti-viral T cell response, although able to exert some level of viremic control, also fuels the HIV infection. Consequently, during acute infection, excluding any confounding STIs that may activate immune responses, it can be rationalized that anti-HIV CD4 T cell responses would be enriched more than T cell receptors (TCRs) with alternative antigen specificities, thus becoming candidate targets for latency establishment. Findings from our group and others suggest that most latently infected cells within the blood compartment of HIV-infected individuals appear to express TCRs specific for HIV peptides but not to control antigens, including PPD and Flu/Tetanus/CMV cocktails [
15‐
17]. Furthermore, non-specific TCR activators such as CD3/CD28 will result in de novo viral RNA production in HIV-infected CD4 T cells [
18,
19]. Collectively, these implicates T cell activation pathways as potentially important to achieving latency reversal. Furthermore, antigen presenting cells (APCs), such as dendritic cells (DCs), were shown to induce contact-dependent latency reversal [
20,
21]. Taken together, we hypothesized that if the largest pool of latently infected cells are HIV-specific resting memory T cells, they might be more efficiently activated and purged using a highly polyvalent vaccine preparation that is representative of the near-complete viral quasispecies. A highly representative vaccine is more likely to have its proteins processed and presented to latently infected T cells bearing HIV-specific TCRs. As proof of principle, we have conducted latency reversal studies in HIV-infected peripheral blood mononuclear cells (PBMCs) derived from infected volunteers that were treated during acute stage infection. We have constructed a polyvalent virus-like particle (VLP) formulation from HIV RNA isolated from infected individuals and for use as our latency reversing activating vector (ACT-VEC). Preliminary data suggests that ACT-VEC, when used to pulse DCs co-cultured with HIV-infected CD4 T cells, causes significant transcription of HIV RNA. Furthermore, ACT-VEC-induced latency reversal exceeds that of promising 1-drug and 2-drug LRA regimens presently in clinical trials. Ongoing studies evaluating ACT-VEC-mediated latency reversal in CD4 T cell cultures derived from chronic and pediatric volunteers will help characterize our formulation’s efficacy at different stages of disease and immune development. The pediatric cohort is particularly interesting as findings in the “Mississippi Child”, a perinatally HIV-infected child that was placed on ART shortly after birth, revealed a detectable decay in reservoir size following ART cessation. Logic suggests that underdeveloped immunological memory and immunoregulation are possible factors limiting reservoir size in this instance. Future studies on potential delivery and adjuvant strategies for ACT-VEC will enable us to understand whether ACT-VEC could function as an immunological priming strategy to facilitate the “Kill” component of the therapy [
22]. Of note, in the SIV-NHP model of infection, T cell vaccines delivering SIV proteins can elicit cellular immune responses, reduce viral loads, and preserve memory CD4 T cell numbers [
23‐
25]. As ACT-VEC represents the entire proteome and morphology of wildtype virus, it is plausible it could elicit similar humoral and cellular immune responses.