TNPO3, transportin-SR2 or Tnp3, a member of the karyopherin β superfamily of proteins, is important for the ability of human immunodeficiency virus (HIV-1) to achieve productive infection, as TNPO3 depletion in human cells leads to a dramatic reduction of infection. Here we describe and discuss recent findings suggesting that TNPO3 assists HIV-1 replication in the nucleus and in fact that TNPO3 may assist PIC maturation in the nucleus. In addition, the viral determinant for the requirement of TNPO3 in HIV-1 infection is discussed. This paper summarizes the most significant recent discoveries about this important host factor and its role in HIV-1 replication. 1. Introduction The influence of the physiological state of cells on retroviral replication has been known since Temin and Rubin demonstrated that stopping cell division by X-rays or UV light prevents Rous sarcoma virus replication [1]. Subsequent research established the relationship between cell cycle stage and retroviral infection, revealing that retroviruses do not all have the same requirements for productive infection [2, 3]. For example, -retroviruses such as murine leukemia virus (MLV) require the host cell to pass through mitosis for efficient infection [4, 5]. The MLV titer decreases at least 10-fold when infecting cells that are arrested in a non-dividing state. By contrast, lentiviruses such as HIV-1 show no difference in productive infection in dividing versus nondividing cells [6]. This evidence suggests that lentiviruses have developed specific mechanisms for the infection of non-dividing cells. The ability of HIV-1 to infect non-dividing cells has been attributed to its capacity to transport the preintegration complex (PIC) to the nucleus [7, 8]. Translocation of the HIV-1 PIC into the nucleus is not a simple process as the PIC is a large complex that contains integrase, matrix, capsid, Vpr, and the viral DNA [7, 9, 10]. Because of its large size, it is unlikely that the PIC enters the nucleus by passive diffusion [11]. On the contrary, HIV-1 PIC translocation into the nucleus must be an active process, possibly making use of nuclear localization signals [12]. Several viral components of the PIC such as matrix, Vpr, integrase, and the central DNA flap have been proposed to be directly involved in PIC transport into the nucleus. However, evidence in the literature both supports and refutes a role for these different components in nuclear translocation [13, 14]. Although only small amounts of capsid can be found in biochemically purified HIV-1 PICs [7, 12, 15, 16], evidence has shown
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