The presence of latent human immunodeficiency virus (HIV) reservoirs is a major obstacle to a cure. The “shock and kill” therapy is based on the concept that latent reservoirs in HIV carriers with antiretroviral therapy are reactivated by latency-reversing agents (LRAs), followed by elimination due to HIV-associated cell death or killing by virus-specific cytotoxic T lymphocytes. Protein kinase C (PKC) activators are considered robust LRAs as they efficiently reactivate latently infected HIV. However, various adverse events hamper the intervention trial of PKC activators as LRAs. We found in this study that a novel PKC activator, 10-Methyl-aplog-1 (10MA-1), combined with an inhibitor of bromodomain and extra-terminal domain motifs, JQ1, strongly and synergistically reactivated latently infected HIV. Notably, higher concentrations of 10MA-1 alone induced the predominant side effect, i.e., global T cell activation as defined by CD25 expression and pro-inflammatory cytokine production in primary CD4+ T lymphocytes; however, JQ1 efficiently suppressed the 10MA-1-induced side effect in a dose-dependent manner. Considering the reasonable accessibility and availability of 10MA-1 since the chemical synthesis of 10MA-1 requires fewer processes than that of bryostatin 1 or prostratin, our results suggest that the combination of 10MA-1 with JQ1 may be a promising pair of LRAs for the clinical application of the “shock and kill” therapy.

S: Simian T-cell leukemia virus type-1 (STLV-1) is disseminated among various non-human primate species and is closely related to human T-cell leukemia virus type-1 (HTLV-1), the causative agent of adult T-cell leukemia and HTLV-1-associated myelopathy/tropical spastic paraparesis. Notably, the prevalence of STLV-1 infection in Japanese macaques (JMs) is estimated to be much greater than that in other non-human primates; however, the mechanism and mode of STLV-1 transmission remain unknown. We hypothesized that a substantial proportion of infected macaques may play a critical role as viral super-spreaders for efficient inter-individual transmission leading to the high prevalence of infection. To address this, we examined a cohort of 280 JMs reared in a free-range facility for levels of anti-STLV-1 antibody titers (ABTs) and STLV-1 proviral loads (PVLs). We found that the prevalence of STLV-1 in the cohort reached up to 65% (180/280), however, the ABTs and PVLs were normally distributed with mean values of 4076 and 0.62%, respectively, which were comparable to those of HTLV-1-infected humans. Contrary to our expectations, we did not observe the macaques with abnormally high PVLs and poor ABTs, and therefore, the possibility of viral super-spreaders was unlikely. Results from further analyses regarding age-dependent changes in STLV-1 prevalence and a longitudinal follow-up of STLV-1 seroconversion strongly suggest that frequent horizontal transmission is a major route of STLV-1 infection, probably due to the unique social ecology of JMs associated with environmental adaptation. Importance: We investigated the cause of the high prevalence of STLV-1 infection in the studied JMs cohort. Contrary to our expectations, the potential viral super-spreaders as shown by abnormally high PVLs and poor ABTs were not observed among the JMs. Rather, the ABTs and PVLs among the infected JMs were comparable to those of HTLV-1-infected humans although the prevalence of HTLV-1 in humans is much less than the macaques. Further analyses demonstrate that the prevalence drastically increased over one year of age and most of these animals over 6 years of age were infected with STLV-1, and that in the longitudinal follow-up study frequent seroconversion occurred in not only infants but also in juvenile and adult seronegative monkeys (around 20% per year). This is the first report showing that frequent horizontal transmission without viral super-spreaders may cause high prevalence of STLV-1 infection in JMs.