[Frontiers in Bioscience 2, d578-587, December 1, 1997]

	[Frontiers in Bioscience 2, d578-587, December 1, 1997] Reprints PubMed CAVEAT LECTOR
	HIV-1 NUCLEAR IMPORT: IN SEARCH OF A LEADER Michael I. Bukrinsky¹ and Omar K. Haffar² 1The Picower Institute for Medical Research, Manhasset, NY 11030, ²Cytokine Networks Inc., 101 Elliott Ave West, Suite 428, Seattle, WA 98119 Received 11/7/97 Accepted 11/14/97 2. INTRODUCTION Intense research into the fundamental processes of human immunodeficiency virus type 1 (HIV-1) replication has yielded knowledge that in many aspects equals or exceeds that of the oncogenic retroviruses. As a clearer picture of the pattern of HIV-1 replication evolves,it becomes apparent that HIV-1 biology is distinct from that of the prototypic oncogenic retroviruses in several key aspects, particularly with regard to host cell range and determinants of viral permissiveness. The most striking feature of HIV-1 biology is its ability to replicate in non-dividing cells (1-4). Non-dividing cells of the monocyte/macrophage lineage are supposed to be among the first targets of HIV infection (5,6) and are likely to contribute significantly to HIV-1 persistence (7,8) and the complications of AIDS (9). Early results (10) indicated that the process of nuclear import of the HIV-1 genome is ATP-dependent, thus implying an active, energy-dependent import mechanism, rather than passive diffusion. This is in contrast to oncogenic retroviruses which lack this mechanism and have to rely on the dissolution of the nuclear envelope during mitosis for delivery of their genome into the nucleus (3,11). Such an energy-dependent mechanism is characteristic for the nuclear import of cellular proteins and ribonucleoproteins (RNPs), thus suggesting that the virus is exploiting the cellular nuclear import machinery. An indirect confirmation of this hypothesis came from the demonstration that nuclear import of HIV-1 could be greatly impaired by mutations in a short stretch of basic amino acids within the viral matrix antigen (MA) with a high similarity to nuclear localization signals (NLSs) identified in many cellular nuclear proteins (4,12). Subsequent studies also added integrase (13) and viral protein R (Vpr) (2,12,14) to the list of viral karyophilic proteins. All these proteins have been shown to be components of the viral preintegration complex (PIC) (14,15), and the evolving hypothesis postulated that they function as adapters which connect the HIV-1 PIC to the nuclear import machinery. In this article, we review the mechanisms of interaction between the HIV-1 PIC and the cellular nuclear import machinery and discuss the role of HIV-1 karyophilic proteins in this interaction.

[Frontiers in Bioscience 2, d578-587, December 1, 1997]
Reprints
PubMed
CAVEAT LECTOR

HIV-1 NUCLEAR IMPORT: IN SEARCH OF A LEADER

Michael I. Bukrinsky¹ and Omar K. Haffar²

1The Picower Institute for Medical Research, Manhasset, NY 11030, ²Cytokine Networks Inc., 101 Elliott Ave West, Suite 428, Seattle, WA 98119

Received 11/7/97 Accepted 11/14/97

2. INTRODUCTION

Intense research into the fundamental processes of human immunodeficiency virus type 1 (HIV-1) replication has yielded knowledge that in many aspects equals or exceeds that of the oncogenic retroviruses. As a clearer picture of the pattern of HIV-1 replication evolves,it becomes apparent that HIV-1 biology is distinct from that of the prototypic oncogenic retroviruses in several key aspects, particularly with regard to host cell range and determinants of viral permissiveness. The most striking feature of HIV-1 biology is its ability to replicate in non-dividing cells (1-4). Non-dividing cells of the monocyte/macrophage lineage are supposed to be among the first targets of HIV infection (5,6) and are likely to contribute significantly to HIV-1 persistence (7,8) and the complications of AIDS (9). Early results (10) indicated that the process of nuclear import of the HIV-1 genome is ATP-dependent, thus implying an active, energy-dependent import mechanism, rather than passive diffusion. This is in contrast to oncogenic retroviruses which lack this mechanism and have to rely on the dissolution of the nuclear envelope during mitosis for delivery of their genome into the nucleus (3,11). Such an energy-dependent mechanism is characteristic for the nuclear import of cellular proteins and ribonucleoproteins (RNPs), thus suggesting that the virus is exploiting the cellular nuclear import machinery.

An indirect confirmation of this hypothesis came from the demonstration that nuclear import of HIV-1 could be greatly impaired by mutations in a short stretch of basic amino acids within the viral matrix antigen (MA) with a high similarity to nuclear localization signals (NLSs) identified in many cellular nuclear proteins (4,12). Subsequent studies also added integrase (13) and viral protein R (Vpr) (2,12,14) to the list of viral karyophilic proteins. All these proteins have been shown to be components of the viral preintegration complex (PIC) (14,15), and the evolving hypothesis postulated that they function as adapters which connect the HIV-1 PIC to the nuclear import machinery.

In this article, we review the mechanisms of interaction between the HIV-1 PIC and the cellular nuclear import machinery and discuss the role of HIV-1 karyophilic proteins in this interaction.