cells Review Host-HIV-1 Interactome: A Quest for Novel Therapeutic Intervention Ekta Shukla and Radha Chauhan * National Center for Cell Science, S.P Pune University, Pune-411007, Maharashtra, India; [email protected] * Correspondence: [email protected]; Tel.: +91-20-25708251 Received: 16 August 2019; Accepted: 9 September 2019; Published: 27 September 2019 Abstract: The complex nature and structure of the human immunodeficiency virus has rendered the cure for HIV infections elusive. The advances in antiretroviral treatment regimes and the development of highly advanced anti-retroviral therapy, which primarily targets the HIV enzymes, have dramatically changed the face of the HIV epidemic worldwide. Despite this remarkable progress, patients treated with these drugs often witness inadequate efficacy, compound toxicity and non-HIV complications. Considering the limited inventory of druggable HIV proteins and their susceptibility to develop drug resistance, recent attempts are focussed on targeting HIV-host interactomes that are essential for viral reproduction. Noticeably, unlike other viruses, HIV subverts the host nuclear pore complex to enter into and exit through the nucleus. Emerging evidence suggests a crucial role of interactions between HIV-1 proteins and host nucleoporins that underlie the import of the pre-integration complex into the nucleus and export of viral RNAs into the cytoplasm during viral replication. Nevertheless, the interaction of HIV-1 with nucleoporins has been poorly described and the role of nucleoporins during nucleocytoplasmic transport of HIV-1 still remains unclear. In this review, we highlight the advances and challenges in developing a more effective antiviral arsenal by exploring critical host-HIV interactions with a special focus on nuclear pore complex (NPC) and nucleoporins. Keywords: anti-retroviral therapy; drug resistance; protein-protein interactions; host factors; nuclear pore complex 1. Introduction HIV (Human Immunodeficiency Virus), a major killer worldwide was first recognised in the early 1980s in the United States as a strange retrovirus causing an entirely new disease called AIDS (Acquired Immunodeficiency Syndrome) [1]. To date, we do not have any cure for AIDS. The current anti-HIV treatment (Anti-Retroviral Therapy, or ART) has certainly resulted in a dramatic decrease in AIDS and AIDS-related complications in treated patients; however, the emergence of drug resistance and side effects posed by conventional medicines are currently restraining the clinical use of many of these antiviral compounds. In this review, we emphasize on the significance of host-viral interactions, particularly HIV-1 and human interactomes, which are now being revisited for exploring novel drug targets with higher efficacy. Furthermore, focus has been laid on the HIV-1 dependence on different host factors in the nuclear import and export of viral nucleic acids and proteins. While proper nuclear entry and exit is essential for viral replication, the nuclear pore complex can be a key target for virus subversion and may provide the basis for developing antiviral compounds for therapeutic intervention that not only target viral proteins alone but their interactions with nuclear membrane partners like nucleoporins. We also highlight the current challenges and further scope in the field. The lack of Cells 2019, 8, 1155; doi:10.3390/cells8101155 www.mdpi.com/journal/cells Cells 2019, 8, 1155 2 of 24 complete molecular understanding and structural knowledge of the host-viral protein complexes is the most significant limiting factor in the area. Global Burden and Geographic Distribution of HIV HIV arose through zoonotic transmissions of simian immunodeficiency viruses (SIV) during the past century in East and Central Africa [2,3]. Today, HIV-1, along with its less widespread cousin HIV-2, is responsible for a worldwide pandemic, infecting more than 36 million people. On the other hand, HIV-2 is relatively less prevalent and restricted to West Africa and some parts of Asia. Moreover, the infection with HIV-2 seems to be slowly progressing and less efficiently transmissible. These retroviruses are divided into different groups based on their genetic diversity. While HIV-2 has five groups and no subtypes/clades, three groups of HIV-1 have been identified, viz. M, N, and O, based on their genome differences. Most of the HIV-1 infections are caused by group M viruses which are further classified into nine clades (A–D, F–H, J and K) [4,5]. The DNA sequences of viruses belonging to distinct clades differ by 15–20%. Apparently, the extent of genetic divergence among the subtypes account for the different levels of their pathogenic efficiency and potential. Therefore, the evolutionary success of these viruses lies in their ‘deceptive simplicity’, i.e., even though these viruses possess a small genome and encodes few similar proteins, they are difficult to target due to their enormous genetic variations and capability of mutation. Despite encoding only 15 mature proteins (Table1), HIV-1 can persistently attack and compromise the innate and adaptive immune systems of an individual [6]. Furthermore, for a successful viral replication, it employs a series of well-planned steps which engage complex relationship between cellular and viral factors (Figure1). One of the surprising facets of the HIV/AIDS pandemic is the unequal distribution of HIV. In the year 2018, an estimated 37.9 million individuals were living with HIV worldwide with highest burden witnessed in southern and eastern Africa. In the same year, an estimated 1.7 million new HIV cases were reported [7]. Every year, the number of deaths occurring globally from HIV-related causes reaches 1.0 million. Even though no population or continent has been spared by HIV, some regions and populations have been affected far more than the others [8]. This indicates that a varied combination of biological and social factors governs the spread of HIV. Moreover, human susceptibility to HIV infection also differs. Vulnerability to infection depends on multiple aspects like genetic factors, innate resistance and psychosocial determinants of health, such as poverty, stigma, gender-based violence, mental health, etc. Table 1. HIV-encoded proteins and their functions. Class Protein Function builds a DNA copy of the viral RNA genome; reverse Reverse transcriptase (RT) transcription and RNAse H activity [9] Viral enzymes takes the DNA copy of the viral genome inside (encoded by pol) Integrase (IN) nucleus and inserts it into the infected cellular genome [10] essential for cleavage of polypeptides and maturation Protease (PR) of HIV particles [11] forms a coat on the inner surface of the viral Matrix (MA) membrane [12] forms a cone-shaped coat around the viral RNA, Structural proteins Capsid (CA) delivering it into the cell during infection [13] (encoded by gag and env) forms a stable complex with the viral RNA to protect Nucleocapsid (NC) it [14] Gp120 (SU envelope protein) bind to receptors on the surface of host cell and then penetrate the cell surface making way for fusion Gp41 (TM envelope protein) [15,16] Cells 2019, 8, x FOR PEER REVIEW 3 of 25 Gp120 (SU envelope protein) bind to receptors on the surface of host cell and then penetrate the cell surface making way for Gp41 (TM envelope fusion [15,16] protein) Cells 2019, 8, 1155 3 of 24 transactivator of transmembrane, enhances Tat transcription of viral mRNA [17] Table 1. Cont. Rev (regulator of regulates the splicing and nuclear export of viral Classvirion Proteinexpression) RNA Function [18] transactivator of transmembrane, enhances Tat Nef (negative inhibits host’stranscription defences; of viral pleiotropic mRNA [17] effects, can regulates the splicing and nuclear export of viral Rev (regulatorregulatory of virion factor) expression) increase or decrease virus replication [19] RNA [18] Accessory proteins incorporationinhibits host’s of defences; Vpr into pleiotropic new viruses; effects, can virion Nef (negative regulatory factor) P6 increase or decrease virus replication [19] Accessory proteins budding [20] incorporation of Vpr into new viruses; virion P6 Vif (viral infectivity increases virus infectivitybudding [20 by] inhibiting host’s increases virus infectivity by inhibiting host’s defence Vif (viralfactor) infectivity factor) defence proteins; helps in virion assembly [21] proteins; helps in virion assembly [21] VprVpr (viral (viral protein r) r) nuclear nuclear import import ofviral viral DNA DNA [22, 23[22,23]] Vpu (viral protein u) Helps in virus budding and release [24] Vpu (viral protein u) Helps in virus budding and release [24] FigureFigure 1. 1. SchematicSchematic overview of of the the HIV-1 HIV-1 replication replication cycle: cycle: (1) (1) The The HIV-1 HIV-1 particle particle attaches attaches and andfuses fusesitself itself to the to host the hostcell membrane cell membrane via its via surface its surface glycoproteins glycoproteins and enters and entersthe cell the cytoplasm; cell cytoplasm; (2) viral (2)genomic viral genomic RNA is RNA reverse is reverse transcribed transcribed into DNA, into DNA, accompanied accompanied by uncoating by uncoating of the of the viral viral capsid; capsid; (3) (3)nuclear nuclear entry entry of of pre-integration pre-integration complex complex occurs occurs with with the the help help ofof various various host host nuclear nuclear proteins; proteins; (4) (4)integration integration of of vDNA vDNA into into the the host host chromatin; chromatin; (5) (5)during during productive productive