Role of HIV-1 Tat in AIDS pathogenesis: its effects on cytokine dysregulation and contributions to the pathogenesis of opportunistic infection

Introduction HIV is the primary etiological agent of AIDS. Effective treatment and prevention of HIV remain a top priority for governments and international health authorities worldwide. Nowadays, although the use of antiretroviral drugs remains an effective treatment to control AIDS progression, new strains of HIV subtypes continue to evolve. They are demonstrating drug resistance due to their effective and continuous mutations in vivo. Similarly, failure of HIV vaccine development is due to the unique mechanisms of HIV in evading the host immune response. Thus, it is imperative to further investigate the molecular basis of HIV pathogenesis and identify new targets for therapeutic intervention. HIV genome encodes nine proteins consisting of envelope, core, and polymerase and six others functioning as accessory proteins. One of the accessory proteins produced is trans-activator Tat, which is critical for virus replication. The HIV-1 Tat regulatory protein is synthesized at the early and also late stage of viral replication. Due to its efficient cell membrane transduction properties, Tat is released into the microenvironment and the circulation, and then taken up by the surrounding cells [1]. In clinical isolates, HIV Tat is present predominantly as a 101 amino acid form, which is encoded by two exons [2,3]. Another form of Tat that comprises of 86 amino acid is also found in some subtype B isolates and the laboratory stain HXB2. Most of the in vitro studies used this 86 amino acid form of Tat. There are five functional domains in Tat protein including N-terminal, cysteine-rich, core, basic, and C-terminal domains. In addition, there is a special region called protein transduction domain, which renders Tat to have the ability to cross cell membranes due to its rich lysine and arginine content [4]. Thus, HIV-1 Tat protein transduction domain has been used for the delivery of potential therapeutic agents including nanoparticles [5], proteins, and peptides into the cell [6]. HIV-1 Tat is first identified as the transactivating protein of HIV long terminal repeat (LTR) for the retroviral replication. In the presence of Tat for transactivation, the efficiency of HIV genomic transcription is a hundred-fold more than that of the non-Tat-activated ones [7]. To enhance the activation of LTR, HIV-1 Tat also interacts with other transcription factors including NF-κB [8], Sp-1 [9], and NF-IL-6 [10], thereby exerting its effects on cellular dysregulation. In subsequent studies, Tat has been shown to play a crucial role for AIDS pathogenesis. For example, previous reports demonstrated that Tat induces neurotoxicity in AIDS patients contributing to the development of HIV-associated dementia [11]. Additionally, HIV-1 Tat can cause damage to the host by dysregulation of cytokines expression in immune cells, induction of apoptosis in neuronal cells, and interaction with other cellular factors to favor its own survival. These processes may inadvertently develop a favorable environment for opportunistic infections [12]. Previous studies including ours showed that HIV-1 Tat induces different cytokines through various signaling cascades [12–14]. In recent studies, Tat proteins isolated from different HIV-1 clades including B and C exhibit differential effects on cytokine induction and other biological activities. For example, Tat expressed in HIV subtype C was shown to be a more potent inducer of anti-inflammatory cytokines, such as IL-4 and IL-10 in primary human blood monocytes, compared to the subtype B counterpart [15]. Also, clade C Tat protein is a stronger LTR activator compared to that of B subtypes [16]. Another report illustrated that a common cysteine to serine mutation found in residue 31 of clade C Tat protein could reduce the production of TNF-α, CCL2 and decrease the intracellular calcium influx [17]. In addition, this mutation may play a role in reducing the development of HIV-associated dementia due to the loss of chemotactic property of clade C Tat protein [18]. In contrast, clade B Tat was demonstrated to be a potent neuropathogenic agent compared to the clade C counterpart through upregulation of the rate-limiting enzyme of the kynurenine pathway, specifically indoleamine-2,3-dioxygenase, which produces a neurotoxic molecule known as kynurenine [19]. Another advantage of clade B Tat in HIV infection is that it could induce the CXCR4 expression on resting CD4 cells and enhance the infectivity of HIV by using CXCR4 as a coreceptor compared to that of the clade C Tat [20]. In this review, we will summarize the role of Tat in cytokine induction and its importance in HIV survival and replication, thereby leading to AIDS pathogenesis. Interleukin 6 IL-6 is a proinflammatory cytokine produced by many different cell types including T cells and monocytes/macrophages [21]. Initially, it was called B-cell differentiation factor because of its effect on B-cell growth and production of antibodies. Dysregulation of B-cell growth and overproduction of autoantibodies by IL-6 may lead to the development of autoimmune diseases such as systemic-onset juvenile idiopathic arthritis and systemic lupus erythematosis [22,23]. In addition to its role as a crucial mediator of inflammation, IL-6 induces the production of C-reactive protein and amyloid A, which are acute phase proteins associated with inflammation. IL-6 targets various cell types such as T cell, hematopoietic stem cells, and other lymphocytes for the regulation of hematopoiesis [24]. In HIV-1-infected patients, the serum level of IL-6 is elevated and can be correlated to the stages of disease progression [25]. The molecular mechanisms of IL-6 induction have been delineated with transcription factors NF-IL-6 and NF-κB being the most important factors in regulating the production of IL-6 [26]. The binding site of NF-IL-6 was first identified in the promoter region of IL-6 and later also found in different cytokine genes such as TNF-α and IL-8 [26]. As part of its adaptation for survival, a functional NF-IL-6 binding is found in the HIV 5′-LTR region [27]. Therefore, cellular processes such as IL-6 receptor binding resulting in NF-IL-6 induction also cause LTR activation leading to HIV replication. Other than NF-IL-6, HIV-1 Tat interacts with NF-κB p65 subunit to enhance HIV-LTR activity [10]. To investigate the mechanism of IL-6 overexpression in AIDS, we previously demonstrated that HIV-1 Tat could enhance the DNA-binding activity of NF-IL-6 to its cognate binding elements [13]. HIV-1 Tat can also bind to the IL-6 leader RNA and further interact with NF-IL-6 to upregulate the expression of IL-6 [28]. It also activates IκB degradation and nuclear translocation of NF-κB to promote IL-6 production [29]. Apart from the activation of transcription factors, HIV-1 Tat upregulates signaling kinases including MAP kinases, protein kinase R (PKR) and its substrate eIF-2α, protein kinase C (PKC), and cAMP-dependent protein kinase (PKA) to induce IL-6 expression [13,30] (Fig. 1). The activation of MAP kinases by HIV-1 Tat causes different biological responses including monocyte activation [31], apoptosis induction [31], cell cycle regulation [32], and neurodegeneration [33]. HIV-1 Tat also interacts with protein kinase PKR [34] and activates NF-κB [35], and further enhances the retroviral replication [36]. These data illustrate how HIV-1 Tat could activate different signaling kinases to cause a cascade of cellular events resulting in perturbation of cellular response.Fig. 1: Contribution of HIV-1 Tat-induced cytokine dysregulation to AIDS-associated diseases.In addition to the complicated Tat-induced effects, overproduction of IL-6 in AIDS patients may lead to the development of Kaposi's sarcoma. It is well described that γ-herpesvirus Kaposi's sarcoma herpesvirus/human herpesvirus-8 (KSNV/HHV8) plays a critical role in the pathogenesis of Kaposi's sarcoma. The viruses found in the Kaposi's sarcoma lesion are usually in their latent state. Reactivation of the viruses and further development of Kaposi's sarcoma occur in patients with immunodeficiency. In AIDS-Kaposi's sarcoma patients, the viral proteins, specifically Tat, produced by the reactivated viruses together with IL-6 prolong the process of inflammation and lead to the formation of Kaposi's sarcoma spindle cells and lesions [37]. In addition, HIV-1 Tat protects the Kaposi's sarcoma infected cells from apoptosis and further maintaining their Kaposi's sarcoma status. In brief, these results illustrated that HIV-1 Tat plays an important role in the development of AIDS-Kaposi's sarcoma. TNF-α TNF-α is a major mediator in inflammation, and it is mainly produced and secreted by activated macrophages. It can also induce apoptosis via activation of protein kinase PKR [38,39], resulting in inhibition of tumor growth and limitation of viral replication. Dysregulation of TNF-α causes inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, psoriasis, and refractory asthma. The lethal complications of septic shock are also due to uncontrolled overproduction of TNF-α induced by bacterial products including endotoxin. The molecular mechanisms for TNF-α production involve the activation of signaling kinases for initiation of transcription and stabilization of TNF-α mRNA. As TNF-α is an acute phase protein and first line of immune response to combat infections, it is rapidly deployed to counteract pathogens. In homeostatic situation, TNF-α mRNA is constantly produced in the resting macrophages. It has been shown that mRNA degradation involving the recognition of AU-rich element plays an important role in posttranscriptional regulation of gene expression. Because the 3′UTR of TNF-α contains such a sequence, the cytokine mRNA is easily degraded to avoid unnecessary synthesis. Once a pathogen such as Escherichia coli attacks, the unstable TNF-α mRNA will not be degraded, and instead it is translated to protein product. This process is usually achieved within the first hour of an infection. To amplify cellular response, the second component of TNF-α induction involves the activation of signaling molecules, including MAP kinases, PKC, and NF-κB. Previous studies demonstrated that HIV-1 Tat could activate the the and to induce efficient TNF-α production HIV-1 Tat also activates calcium signaling to TNF-α production previously identified that PKR is of the HIV-1 Tat-induced signaling kinases in regulating TNF-α production (Fig. 1). Apart from HIV-1 Tat interacts with to induce TNF-α, as part of the cascade for of cellular responses In the early stage of HIV there are viral proteins produced including Tat, and These viral proteins could not induce TNF-α expression also activate the TNF-α signaling important biological responses such as activation of upregulation of and induction of As HIV-1 Tat could with NF-κB to activate the HIV-LTR to more new for infection. For HIV effects on it has been shown that cells of Tat are to apoptosis This renders the infected cells to for the produced HIV the early phase of infection. 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