Patterns of HIV-1 Protein Interaction Identify Perturbed Host-Cellular Subsystems

Abstract

Human immunodeficiency virus type 1 (HIV-1) exploits a diverse array of host cell functions in order to replicate. This is mediated through a network of virus-host interactions. A variety of recent studies have catalogued this information. In particular the HIV-1, Human Protein Interaction Database (HHPID) has provided a unique depth of protein interaction detail. However, as a map of HIV-1 infection, the HHPID is problematic, as it contains curation error and redundancy; in addition, it is based on a heterogeneous set of experimental methods. Based on identifying shared patterns of HIV-host interaction, we have developed a novel methodology to delimit the core set of host-cellular functions and their associated perturbation from the HHPID. Initially, using biclustering, we identify 279 significant sets of host proteins that undergo the same types of interaction. The functional cohesiveness of these protein sets was validated using a human protein-protein interaction network, gene ontology annotation and sequence similarity. Next, using a distance measure, we group host protein sets and identify 37 distinct higher-level subsystems. We further demonstrate the biological significance of these subsystems by cross-referencing with global siRNA screens that have been used to detect host factors necessary for HIV-1 replication, and investigate the seemingly small intersect between these data sets. Our results highlight significant host-cell subsystems that are perturbed during the course of HIV-1 infection. Moreover, we characterise the patterns of interaction that contribute to these perturbations. Thus, our work disentangles the complex set of HIV-1-host protein interactions in the HHPID, reconciles these with siRNA screens and provides an accessible and interpretable map of infection.

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

“…Although HIV-targeted cellular factors identified by different largescale screens (5)(6)(7)(8)(9) revealed only a few overlaps of individual factors, many factors mapped to the same cellular pathways (4,(8)(9)(10)(11)(12)(13)(14)(15), implying HIV-host interaction conservation at the pathway rather than protein level (4,8) (Fig. 1).…”

“…Whereas the variability of the individual cellular factors identified was often accounted for by experimental factors, including the specific activation of particular PPI modules (depending on the cell types used [i.e., cell-specific factors] and the viral infection stage [e.g., the timing of sampling]) (2,10,(14)(15)(16)(17), the underlying message from these screening studies may be that specific interactions matter less than the targeted cellular pathways. In other words, disruption or manipulation of a particular pathway by whatever means may be the common and critical factor in HIV-1 replication (8).…”

“…All PPIs depend on specific physical interfaces between interacting proteins, and so mimicry of internal cellular PPI interfaces may be a mechanism by which pathogens modulate the biology of their hosts (10,40). Analysis of virus-host (external) and host-host (internal) PPIs revealed that ϳ50% of the virally targeted host cofactor interfaces participate in internal cellular PPIs (40).…”

“…For example, cellular proteins LEDGF/p75 and HRP-2 contain an IBD domain that interacts with HIV-1 integrase (IN) (20), and the structural similarity be-tween the C-terminal domains of Nup358 and Cyclophilin-A (CypA) facilitates HIV-1 CA recruitment of both proteins (56,57). Another example is the high (50% to 80%) sequence similarity between the various Importin-␣ subtypes (6 proteins) that can also explain their flexible targeting by HIV-1 proteins (10,18). Similarly, host proteins interacting with HIV-1 IN were found enriched with 14-3-3 domains, which generally bind phosphorylated regions of proteins, whereas proteins containing ␤-propellers have a higher propensity for binding to HIV-1 Vpr (9).…”

Role of TIM-4 in exosome-dependent entry of HIV-1 into human immune cells

“…Intriguingly, HIV-1 particles have been detected in cells that lack these receptors, suggesting the existence of a non-traditional pathway by which HIV-1 can gain cellular entry using unique molecules that enhance infection. [1][2][3][4] One important feature of HIV-1 is its envelope, which it acquires upon exiting the host cell. The envelope gives HIV-1 a barrier that shields the virus from the immune system due to lipids and proteins derived from the target cell's membrane with major roles in HIV-1's pathogenicity.…”