HIV-1 replication in cell lines harboring INI1/hSNF5 mutations

Background: INI I/hSNF5 is a cellular protein that directly interacts with HIV-1 integrase (IN). It is specifically incorporated into HIV-1 virions. A dominant negative mutant derived from INI I inhibits HIV-1 replication. Recent studies indicate that INI I is associated with pre- integration and reverse transcription complexes that are formed upon viral entry into the target cells. INI I also is a tumor suppressor, biallelically deleted/ mutated in malignant rhabdoid tumors. We have utilized cell lines derived from the rhabdoid tumors, MON and STA-WTI, that harbor either null or truncating mutations of INI I respectively, to assess the effect of INI I on HIV-1 replication. Results: We found that while HIV-1 virions produced in 293T cells efficiently transduced MON and STA-WTI cells, HIV-1 particle production was severely reduced in both of these cells. Reintroduction of INI I into MON and STA-WTI significantly enhanced the particle production in both cell lines. HIV-1 particles produced in MON cells were reduced for infectivity, while those produced in STA-WTI were not. Further analysis indicated the presence of INI I in those virions produced from STA-WTI but not from those produced from MON cells. HIV-1 produced in MON cells were defective for synthesis of early and late reverse transcription products in the target cells. Furthermore, virions produced in MON cells were defective for exogenous reverse transcriptase activity carried out using exogenous template, primer and substrate. Conclusion: Our results suggest that INI I-deficient cells exhibit reduced particle production that can be partly enhanced by re-introduction of INI I. Infectivity of HIV-1 produced in some but not all INI I defective cells, is affected and this defect may correlate to the lack of INI I and/ or some other proteins in these virions. The block in early events of virion produced from MON cells appears to be at the stage of reverse transcription. These studies suggest that presence of INI I or some other host factor in virions and reverse transcription complexes may be important for early events of HIV-1 replication.