Latent infection is a major barrier for cure of HIV-1/AIDS. HIV-1 is capable of establishing latency and the components of the apoptotic pathways may affect viral latency. However, it is not well-known how anti/pro-apoptotic components modulate HIV-1 replication and latency. Using the susceptible A3.01 cell line, we investigated some long-term effects of caspase-3 activities on HIV-1 DNA levels using a sensitive real-time PCR assay. Here we report that viral DNA levels increased upon treatment with caspase-3 inhibitor, Z-DEVD and decreased with caspase-3 activator, PAC1. We also simultaneously measured viral RNA from supernatants of these cell cultures and found that the degree of HIV-1 latency is inversely proportional to levels of viral replication. Furthermore, we demonstrated that inhibition of caspase-3 activities promoted viral latency and inhibited viral replication in several ways, which may include: 1) inhibition of viral RNA un coating with increased Trim5a expression; 2) deleterious mutations in the viral genome with increased APOBEC3G; 3) transcriptional interference with decreased levels of the host factors, NF-κB p65, Ap-1, Sp-1, NFAT, STAT1/3/5, IRF3/7, inactivated YB-1 and MAPK, Erk1/2 and p38, and inhibition of full-length of HIV-1 mRNA and P-TEF b signaling; 4) epigenetic silencing with decreased PCAF; 5) blocking trafficking of the components of viral particle and budding with decreased Tag101 and Alix. These data suggest that HIV-1 infection can employ or even manipulate the cellular apoptotic status to favor viral survival and escape monitoring and destruction by the host immune system.