Human immunodeficiency virus type-1 (HIV-1), the etiologic agent of
acquired immune deficiency syndrome (
AIDS), is a global pandemic causing millions of deaths annually.
Highly active antiretroviral therapy (
HAART) greatly enhances lifespan but eventually causes debilitating side effects, in part, due to their chronic administration required to suppress HIV-1 replication. If treatment is discontinued, viral suppression is lost and dormant replication-competent monocytic cell reservoirs become reactivated, leading to viral recrudescence and progression to
AIDS. Therefore, novel strategies to circumvent obstacles to HIV-1
therapy are critically needed. We evaluated the potentially
therapeutic effects of
cycloviolacin O2 (CyO2) on cell viability (MTT assay), membrane disruption (
SYTOX Green uptake), p24 production [
enzyme-linked
immunosorbent assays (ELISA)], and proviral integration (PCR amplification) in U1 cells; a monocytic cell model of HIV-1 latency and reactivation. We demonstrate, for the first time, that CyO2 (0.5-5.0 μM) kills productively infected cells. Sub-toxic concentrations (<0.5 μM) of CyO2 disrupted plasma membranes in both latently-infected and productively-infected U1 cells and enhanced the
antiviral efficacy of
nelfinavir, a
HIV-1 protease inhibitor (HPI). Interestingly, CyO2 also decreased virus production by activated U1 cells; however, this effect was not due to suppression of integrated provirus in U1 cells. This suggested that, in addition to the known pore-forming ability of
cyclotides, a novel mode of
antiviral activity may exist for CyO2. Our data indicate that CyO2 may be a promising candidate for the targeting HIV-1 reservoirs in monocytes, and their inclusion in adjuvant
therapy approaches may augment the efficacy of HPIs and ultimately facilitate virus elimination.