The Road Less Traveled: HIV's Use of Alternative Routes through Cellular Pathways

Abstract

Pathogens such as HIV-1, with their minimalist genomes, must navigate cellular networks and rely on hijacking and manipulating the host machinery for successful replication. Limited overlap of host factors identified as vital for pathogen replication may be explained by considering that pathogens target, rather than specific cellular factors, crucial cellular pathways by targeting different, functionally equivalent, protein-protein interactions within that pathway. The ability to utilize alternative routes through cellular pathways may be essential for pathogen survival when restricted and provide flexibility depending on the viral replication stage and the environment in the infected host. In this minireview, we evaluate evidence supporting this notion, discuss specific HIV-1 examples, and consider the molecular mechanisms which allow pathogens to flexibly exploit different routes.

MxB impedes the NUP358-mediated HIV-1 pre-integration complex nuclear import and viral replication cooperatively with CPSF6

“…After reverse transcription, HIV-1 PIC hijack the host cellular components and nuclear transport machinery for transportation to the nucleus [20,37]. MxB has been implicated in cellular functions to regulate cytoplasmicnuclear transport [1].…”

“…During the nuclear import of the viral genome, HIV-1 CA plays a critical part through a series of interactions with multiple host cell factors [21,41,42]. HIV-1 CA mutations, including N74D mutation, have been shown to change the requirement for specific nucleoporins (for example, NUP358, NUP98, NUP153 and NUP155) during HIV-1 nuclear import, and to alter the distribution of sites at which HIV-1 DNA integrates into host chromosomes [20,27,[34][35][36][37]43]. Moreover, MxB localizes to nuclear pores and inhibits the nuclear entry step of HIV-1 infection.…”

“…CPSF6 1-358 , a truncated version of CPSF6, impedes nuclear import of HIV-1 PIC, indicating that full length of CPSF6 is required for its role in helping PIC nuclear import [31,32]. Notably, relative to the wild-type HIV-1 (HIV-1 WT ), HIV-1 N74D , which bears the capsid mutation N74D, abolishes CA binding to CPSF6 [27,33], differs in host nuclear transport and dependence on nuclear pore proteins including NUP358, NUP98 and Transportin 3 (TNPO3), all of which have been shown to be important for HIV-1 WT infection [20,27,[34][35][36][37]. These observations highlight the diverse functions played by CPSF6, together with NUP358 during the nuclear import step of the HIV-1 replication cycle.…”

Structure of FIV capsid C-terminal domain demonstrates lentiviral evasion of genetic fragility by coevolved substitutions

“…Mutations can directly impair enzymatic activity or perturb interfaces central to intrinsic folding or extrinsic interactions essential for crafting protein assemblies of virus and viral-host complexes. Auxiliary mutations, which induce compensatory structural and functional changes, can stabilize a mutant protein facilitating its persistence in an evolved virus strain (reviewed in 1 ). Essentially, coevolved second-site compensatory mutations repair the protein fold and/or enzymatic activity, or fix protein interfaces vital for interactions with other proteins 2 3 .…”

Silencing of Unintegrated Retroviral DNAs

“…Indeed, it is even possible that it only poorly infects cells without passage through pores of intact nuclei [37]. There are likely more than one route of entry [38], largely determined by the viral capsid (CA) protein. The existence of these alternative pathways has been most clearly revealed by the distinctive requirements for host factors exhibited by different mutant CA proteins [39].…”