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Although the HIV-1 Nef protein (27 kDa) localizes primarily in cytoplasm, there is considerable evidence suggesting its occasional localization in the nucleus. Nef is known to play an important role in transcriptional events and viral replication, but the actual target of Nef in the nucleus remains to be identified.To examine the functional roles of Nef in the nucleus and its possible interactions with other unknown factors in the nucleus.High-density microarray analysis was used to screen directly the unique functions of Nef on host gene transcription. The nuclear localization of Nef and its effects on the expression of peroxisome proliferator-activated receptors (PPAR) was examined using PPAR promoter/reporter assay and immunoblotting. A long terminal repeat/reporter assay was used to investigated the effects of Nef and PPAR on viral transcription.Nef in the nucleus suppressed PPARγ expression and reduced fatty acid levels in human T and macrophage cell lines. Expression of Nef or PPAR suppressed viral replication; the effect of PPARγ or retinoid X receptor-α on viral replication were reduced by coexpression of Nef in MT(−)4 T cells.Nef may be involved in both viral replication and the wasting syndrome associated with AIDS.