While combination antiretroviral therapy maintains undetectable viremia in People Living With HIV (PLWH), a life-long treatment is necessary to prevent viremic rebound after therapy cessation. This rebound seemed mainly caused by long lived HIV-1 latently infected cells reversing to a viral productive status. Reversing latency and elimination of these cells by the so-called shock and kill strategy is one of the main investigated leads to achieve an HIV-1 cure. Small molecules referred as latency reversal agents (LRAs) proved to efficiently reactivate latent CD4
+
T cells. However, LRAs impact on
de novo
infection or HIV-1 production in productively infected macrophages remain elusive.
Nontoxic doses of bryostatin-1, JQ1 and romidepsin were investigated in human monocyte-derived macrophages (MDMs). Treatment with bryostatin-1 or romidepsin resulted in a downregulation of CD4 and CCR5 receptors respectively, accompanied by a reduction of R5 tropic virus infection. HIV-1 replication was mainly regulated by receptor modulation for bryostatin-1, while romidepsin effect rely on upregulation of SAMHD1 activity. LRA stimulation of chronically infected cells did not enhance neither HIV-1 production nor gene expression. Surprisingly, bryostatin-1 caused a major decrease in viral production. This effect was not viral strain specific but appears to occur only in myeloid cells. Bryostatin-1 treatment of infected MDMs led to decreased amounts of capsid and matrix mature proteins with little to no modulation of precursors.
Our observations revealed that bryostatin-1-treated myeloid and CD4
+
T cells are responding differently upon HIV-1 infection. Therefore, additional studies are warranted to more fully assess the efficiency of HIV-1 eradicating strategies.
Importance
HIV-1 persists in a cellular latent form despite therapy that quickly propagates infection upon treatment interruption. Reversing latency would contribute to eradicate these cells, closing a gap to a cure. Macrophages are an acknowledged HIV-1 reservoir during therapy and are suspected to harbor latency establishment
in vivo
. Yet, the impact of latency reversal agents (LRAs) on HIV-1 infection and viral production in human macrophages is poorly known but nonetheless crucial to probe the safety of this strategy. In this
in vitro
study, we discovered encouraging anti-replicative features of distinct LRAs in human macrophages. We also described a new viral production inhibition mechanism by protein kinase C agonists which is specific to myeloid cells. This study provides new insights on HIV-1 propagation restriction potentials by LRAs in human macrophages and underline the importance of assessing latency reversal strategy on all HIV-1 targeted cells.
Design and synthesis of new hybrid latency reversal agents for HIV treatment