Human immunodeficiency virus type 1 integrase (HIV-1 IN) is thought to have several putative roles at steps prior to integration, such as reverse transcription and nuclear transport of the preintegration complex (PIC).Here, we investigated new functional aspects of HIV-1 IN in the context of the viral replication cycle through point mutagenesis of Ser, Thr, Tyr, Lys, and Arg residues conserved in IN, some of which are located at possible phosphorylation sites. Our results showed that mutations of these Ser or Thr residues had no effect on reverse transcription and nuclear transport of PIC but had a slight effect on integration. Of note, mutations in the conserved KRK motif (amino acids 186 to 189), proposed previously as a putative nuclear localization signal Retroviruses establish a proviral state in which a doublestranded DNA copy of the viral genomic RNA is integrated into the host genome in a stable manner, through several steps following binding and entry into the target cell. These early events include uncoating, reverse transcription, nuclear transport of the viral genome, and integration. The viral enzyme integrase (IN) is encoded by the pol gene and the attachment (att) site located at the U3 and U5 termini of the viral DNA and is required for integration, which is the last event (6,14,43,47,53,56,57,61,66,74). The detailed mechanism of retroviral integration has been elucidated from in vitro studies using recombinant IN protein and a synthetic DNA substrate mimicking the viral att sites. These studies, using in vitro assays, have contributed much information toward the currently accepted mechanism of retroviral integration (reviewed in references 34, 42, and 75). Mutational and structural studies of human immunodeficiency virus type 1 (HIV-1) IN have identified three functional domains: a central catalytic core domain, an N-terminal zinc binding domain, and a C-terminal nonspecific DNA binding domain. The core domain contains the highly conserved D,D35E motif, which is directly involved in the catalytic activities of IN (7,23,46,48). The N-terminal domain contains a highly conserved HHCC motif, which binds to zinc. Through a tetrahedral attachment to the HHCC motif, zinc enhances both multimerization and enzymatic activities of 8,21,79). The C terminus, consisting of a structure that closely resembles Src homology 3 domains, possesses sequence-and metal ion-independent DNA binding activity (20,51). Each domain has been demonstrated to form a dimer or higher multimerization state of IN (8,19,20), which might be required for its full activity (13,21,22,66,70,73).Genetic analysis of HIV-1 IN has demonstrated multiple effects of mutations at steps distinct from integration. These steps include correct viral particle formation (24, 59), uncoating (54, 59), and reverse transcription (49,54). During the early events of the infection cycle, prior to integration, around 50-100 protomers of IN exist as one of the major components of the preintegration complex (PIC). This is composed of the viral genome, the matr...

Human immunodeficiency virus type 1 (HIV-1) utilizes the macromolecular machinery of the infected host cell to produce progeny virus. The discovery of cellular factors that participate in HIV-1 replication pathways has provided further insight into the molecular basis of virus-host cell interactions. Here, we report that the suppressor of cytokine signaling 1 (SOCS1) is an inducible host factor during HIV-1 infection and regulates the late stages of the HIV-1 replication pathway. SOCS1 can directly bind to the matrix and nucleocapsid regions of the HIV-1 p55 Gag polyprotein and enhance its stability and trafficking, resulting in the efficient production of HIV-1 particles via an IFN signaling-independent mechanism. The depletion of SOCS1 by siRNA reduces both the targeted trafficking and assembly of HIV-1 Gag, resulting in its accumulation as perinuclear solid aggregates that are eventually subjected to lysosomal degradation. These results together indicate that SOCS1 is a crucial host factor that regulates the intracellular dynamism of HIV-1 Gag and could therefore be a potential new therapeutic target for AIDS and its related disorders.AIDS ͉ pathogenesis ͉ drug target ͉ lysozyme

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