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Cafaro, A.; Schietroma, I.; Sernicola, L.; Belli, R.; Campagna, M.; Mancini, F.; Farcomeni, S.; Pavone-Cossut, M.R.; Borsetti, A.; Monini, P.; et al. Role of extracellular Tat in HIV Pathogenesis. Encyclopedia. Available online: (accessed on 15 April 2024).
Cafaro A, Schietroma I, Sernicola L, Belli R, Campagna M, Mancini F, et al. Role of extracellular Tat in HIV Pathogenesis. Encyclopedia. Available at: Accessed April 15, 2024.
Cafaro, Aurelio, Ivan Schietroma, Leonardo Sernicola, Roberto Belli, Massimo Campagna, Flavia Mancini, Stefania Farcomeni, Maria Rosaria Pavone-Cossut, Alessandra Borsetti, Paolo Monini, et al. "Role of extracellular Tat in HIV Pathogenesis" Encyclopedia, (accessed April 15, 2024).
Cafaro, A., Schietroma, I., Sernicola, L., Belli, R., Campagna, M., Mancini, F., Farcomeni, S., Pavone-Cossut, M.R., Borsetti, A., Monini, P., & Ensoli, B. (2024, February 16). Role of extracellular Tat in HIV Pathogenesis. In Encyclopedia.
Cafaro, Aurelio, et al. "Role of extracellular Tat in HIV Pathogenesis." Encyclopedia. Web. 16 February, 2024.
Role of extracellular Tat in HIV Pathogenesis

Each time the virus starts a new round of expression/replication, even under effective antiretroviral therapy (ART), the transactivator of viral transcription Tat is one of the first HIV-1 protein to be produced, as it is strictly required for HIV replication and spreading. At this stage, most of the Tat protein exits infected cells, accumulates in the extracellular matrix and exerts profound effects on both the virus and neighbor cells, mostly of the innate and adaptive immune systems. Through these effects, extracellular Tat contributes to the acquisition of infection, spreading and progression to AIDS in untreated patients, or to non-AIDS co-morbidities in ART-treated individuals, who experience inflammation and immune activation despite virus suppression.

HIV-1 Tat protein extracellular Tat protein HIV-1 infection HIV-1 pathogenesis

1. Introduction

The introduction in the late 1990s of the combination antiretroviral therapy (cART) has dramatically changed the course of the infection, as virtually all successfully treated individuals do not progress to AIDS (acquired immune deficiency syndrome) [1] nor transmit infection [2]. However, cART suppresses virus replication and spreading but it does not eliminate latently infected cells, and residual HIV protein expression and virus production are still detected upon sporadic virus reactivation [3][4], particularly in the gut and central nervous system [5][6].
Of note, HIV-1 replication requires Tat, the trans-activator of transcription, whose main role in the HIV-1 life cycle is to promote gene expression and virus production [7]. In fact, in the absence of Tat, virtually no productive infection occurs. Interestingly, in acute infection about two-thirds of the Tat protein is released extracellularly [8][9][10][11][12] and exerts effects on both the virus and many cell types key to HIV acquisition, spreading, pathogenesis and progression to disease.
Thus, targeting Tat it is important in several respects: to prevent the establishment of infection and, in people living with HIV (PLWH), to reduce the burden of the residual disease (chronic inflammation and immune activation, early aging) commonly observed in individuals on suppressive cART [13] and responsible for the reduced quality of life and life expectancy [1]. Finally, targeting Tat may be critical to eradicating HIV.

2. The HIV-1 Tat Protein

Tat is a 14–16 kD HIV regulatory protein whose main role in the HIV life cycle is to promote virus transcription, and primarily transcript elongation. In fact, Tat is prominently known for its role in relieving RNA polymerase II from pause, thus promoting elongation, a key step leading to the completion of HIV gene transcription [14]. However, Tat is also required to initiate reverse transcription (RT) [7], to increase the rate of transcription [7] and to contribute to splicing regulation [15][16].
Tat is generated in two forms through alternative splicing. The first form is encoded by the multiply spliced two-exon transcript and varies in length between 86 and 101 amino acids, depending on the viral isolate, whereas the other form is encoded by a singly spliced one-exon transcript and is 72 amino acids long. Both Tat variants transactivate the LTR efficiently, but the two-exon Tat appears to exert additional effects on the infected cell, such as altering cytoskeleton structure and function [17], delaying Fas-mediated apoptosis [18], and reducing the triggering of innate and adaptive immune responses by downregulating expression of interferon-stimulated genes and MHC class-I and II molecules in antigen-presenting cells [19][20][21]. Here, unless differently stated, Tat refers to the 86 amino acids (aa)-long two-exon Tat protein, which is the most commonly used form of Tat [22].
The Tat protein is largely unstructured and contains six functional domains (Figure 1). These features make Tat capable of interacting with many molecules, as it can easily adapt to a molecule displaying one or more complementary domains or motifs.
Figure 1. HIV-1 Tat sequence (HXBc2 strain) and functional domains. See text for Tat domains’ detailed description.
The first domain (1–21 aa) at the N-terminus is an acidic proline-rich region and has a conserved Trp 11 that is critical to stabilize Tat binding to the inner leaf of the cell membrane [12]; the second domain (residues 22–37) has seven cysteines that are rather well conserved at positions 22, 25, 27, 30, 31, 34 and 37; six of them may establish intramolecular bonds, while the seventh cysteine is believed to mediate intermolecular bridging; the third domain (core, residues 38–48) contains two residues of a conserved four-amino-acid subdomain (36–39) reported to bind tubulin/microtubules through a microtubule-associated protein, LIS1 [23], leading to the alteration of microtubule dynamics and activation of a mitochondria-dependent apoptotic pathway [24][25]. Overall, the N-terminal half (1–48 aa, region I–III) of Tat is highly conserved, consistent with the critical role for activating the transcription of HIV genomic DNA due to the cysteine-rich motif (region II), required for dimerization, protein structure stabilization and metal binding, and the hydrophobic core motif (region III) required for binding to the CDK9-associated C-type cyclin [26] and to the transactivation response RNA element (TAR) of the newly transcribed HIV genomic RNA [27][28].
The C-terminal half (49–72 aa) of Tat contains two more regions: region IV (residues 49–55) is a conserved basic domain important for localizing Tat to the nucleus, binding of Tat to TAR and the internalization of the Tat protein into bystander cells by its interaction with surface proteins such as heparan sulfate proteoglycans (HSPG) [29][30]. Of note, a peptide corresponding to the basic region is currently exploited as a penetratin or transducing molecule to intracellularly deliver numerous cargos (proteins, DNA, RNA), underscoring its ability to cross membranes [31]. Residues 59–72 encompass the glutamine-rich domain (region V), which is less conserved and participates in the interaction of Tat with TAR and in Tat-mediated apoptosis [32].
Although more variable than Exon 1, most Exon 2 sequences (region VI) contain an arginine-glycine-aspartic acid (RGD) motif (78–80 aa) which is important for the Tat interaction with the RGD-binding integrins αvβ1, αvβ3, α5β1 [33][34]. Whether and to what extent Tat binds the other 5 RGD binding integrins remains to be investigated. Although not required, the second exon of Tat contributes to optimal virus replication in T cells and macrophages [35][36]. In T cells, Tat101 delayed FasL-mediated apoptosis, prolonging HIV-1 replication [18], and altered the function and distribution of mitochondria [37]. In myeloid cells, the two-exon protein has been reported to reduce the innate immunity activation observed with one-exon Tat [19].
Tat is expressed very early upon infection, even before virus integration [38]. Indeed, accumulating evidence indicates that Tat is incorporated into HIV-1 virions [39][40], thus priming both intra-virion and post-entry reverse transcription [41] and activating virus gene expression even prior to HIV gene expression [40].

3. Mechanism and Kinetics of the Extracellular Release of Tat (eTat)

The majority (about 65%) of the Tat protein produced by the infected cell is released extracellularly in the absence of cell death or cell permeability changes mainly by a leaderless secretory pathway similar to that used by basic fibroblast growth factor (FGF)2 to exit cells [8][10][11][12][42]. However, none of the unconventional secretory pathways used by FGF or interleukin (IL)-1 β are involved, as Tat appears to traffic to the plasma membrane without the contribution of intracellular intermediates [12]. In particular, the conserved Arg49, Lys50 and Lys51 (RKK motif) of Tat appears to bind the fraction of phosphatidylinositol-(4,5)-bisphosphate [PI(4,5)P2] located at the plasma membrane [12]. This binding is strengthened by the insertion of Tat Trp11 into a hydrophobic cleft of the inner membrane [12]. An additional interaction between the basic region (RRQRRR) of Tat and phosphatidylserine has also been reported very recently [43]. These interactions may affect several biological processes in which PI(4,5)P2 is involved, such as clathrin-mediated endocytosis [44], phagocytosis [45][46] or exocytosis [47]. Plasma-membrane-bound Tat is then released extracellularly by exocytosis [11], with still incompletely understood mechanism(s) (reviewed in [42]). Recent evidence indicates that Tat is also released extracellularly within exosomes, which appear to be enriched with small noncoding RNAs containing TAR and their derivative TAR miRNA [48], which, in turn, have been reported to promote, respectively, inflammation and tumorigenesis, two hallmarks of the residual disease observed in subjects on long-term suppressive cART [49][50][51]. Of note, extracellular Tat (eTat) crosses the blood–brain barrier and promotes the central nervous system (CNS) inflammation and T-cell activation [52], which persist despite treatment intensification with CNS-penetrating ART [53].
Upon release, eTat binds heparan sulphate proteoglycans (HSPG) of the extracellular matrix (ECM) and is detected in the tissues of infected individuals [8][9][11][52][54][55][56][57]. eTat is biologically active and exerts activities key for the acquisition of infection, virus reactivation and HIV disease maintenance in cART-treated individuals [9][10][11][12][38][55][56][57][58][59][60][61][62][63][64][65][66][67][68].
Up to 40 ng/mL (4 nM) of eTat has been detected in biological fluids, but these amounts are probably underestimated, as eTat accumulates in tissues, bound to the HSPG of the extracellular matrix (ECM) in a biologically active form [8][52][54][55][56][57]. eTat is also known to be taken up by uninfected cells, including T lymphocytes, macrophages and neurosecretory cells and to accumulate at the plasma membrane, where it stably binds to phosphatidylinositol (4,5) bisphosphate (PI(4,5)P2), thus interfering with the (PI(4,5)P2)-mediated functions, such as neurosecretion, phagocytosis and cardiac muscle repolarization [69]. For stable binding to (PI(4,5)P2), interaction of the Tatcys31 with cyclophilin A (CypA) and Tat palmitoylation by HHD20 are required [69]. Intriguingly, the Indian clade C Tat displays a naturally occurring cysteine 31 substitution that abolishes (PI(4,5)P2) sequestration by Tat, possibly contributing to the apparent lower pathogenicity of clade C Tat as compared to clade B [69]. In sharp contrast, Tat is efficiently released in productively infected cells. CypA binds the newly produced HIV-1 Gag protein, it is incorporated into the capsid and it is released from the cell within the budding virus [40]. As a result, intracellular CypA is depleted and Tat palmitoylation cannot occur [69].

4. Role of eTat in HIV Acquisition, Dissemination and Reservoir Formation

4.1. HIV Acquisition

HIV is mostly acquired through sexual intercourse, with the rate of acquisition being extremely low, which varies according to the type of unprotected sex (vaginal/anal/oral; insertive/receptive [70][71][72][73], and it is strongly favored by pre-existing genital infections [74] and viral load [75][76][77][78]. Thus, mucosae represent a strong barrier to the acquisition of HIV (reviewed in [79]), which must undergo a major selection to overcome the mucosal barrier [80], resulting in the systemic spreading of founder viruses characterized by Env with a “short” V1/V2 loop [81].
In this context, the data indicate that Tat binds native trimeric Env on HIV-1 virions to form a novel cell entry complex (the Tat/Env complex), enabling the virus to enter dendritic cells (DCs) through an integrin-mediated endocytic pathway alternative to the canonical endocytic pathway mediated by C-type lectin receptors [82]. Tat-mediated entry in DCs leads to the enhancement of HIV infection in these cells [82], which are key for HIV acquisition at the mucosal portal of entry. The Env V3 loop is a main Tat binding determinant, as a cyclic (but not linear) peptide encompassing the V3 loop was shown to bind recombinant Tat, and V3 loop deletion abrogates the capability of Tat to direct Env on the integrin receptors [82]. In this regard, the Env V1/V2 loop is known to engage and occlude the V3 loop at the Env trimer apex [83], and studies indicate that V1/V2 loop shortening dramatically increases the stability of the Tat/Env complex [82]. These data might explain why V1/V2 shortening is a common feature of the founder viruses emerging at the mucosal portal of entry.
Since the Tat/Env complex drives HIV to the DCs integrin receptors, anti-Env Abs blocking the Env interaction with C-type lectin receptors become ineffective at preventing HIV-1 entry in these cells [82]. However, entry is blocked by the addition of anti-Tat Abs [82]. Indeed, the immunization of monkeys with the Tat/Env complex led to infection containment upon intrarectal challenge with a pathogenic simian-HIV chimeric virus (SHIV), preventing virus spreading beyond the rectum [82]. Taken together, these data suggest that eTat plays a key role also in HIV-1 acquisition, providing the rationale to also include it in preventative vaccine approaches in association with Env.

4.2. HIV Dissemination

As Tat is required for HIV gene expression, it is apparent it plays a critical role in promoting virus replication and, ultimately, dissemination. Indeed, seroreversion of the antibody response to HIV, a bona fide proxy of virus remission or eradication, was reported in a small cohort of 23 women from Gabon infected with a Tat in which the cysteine in position 22 was replaced by a serine (Tat Oyi) making its transactivation silent [84]. Similarly, in the cART era, progressive accumulation over time of proviruses defective for replication [85] and/or for gene expression (i.e., containing solo LTRs) [86] was found. This is probably the result of the combined pressure exerted by cART and by a sufficiently restored immune response against HIV. In this scenario, only silent proviruses lacking Tat, as solo LTRs, are destined to persist.

4.3. Establishment and Maintenance of Latent Virus Reservoirs

Despite cART effectiveness, a low-level intermittent residual plasma viremia (<50 copies per mL), as well as viral “blips” (50–1000 copies/mL), persist, predict virus rebound and are believed to be at the origin of persistent immune activation, residual disease and the onset of comorbidities in treated patients (reviewed in [13]). In fact, HIV gene expression and viral production are sporadically resumed in HIV latently infected cells constituting the HIV reservoirs [3][4].
Furthermore, HIV gene expression it is not halted by cART, whereas residual virus replication, driven by low drug penetration in lymphoid tissue compartments [87][88] and drug-resistant cell-to-cell transmission modalities [89], may occur [90]. Of importance, while Tat mRNA accumulates in the nuclei of resting CD4 T cells from peripheral blood and cannot support HIV protein expression [91], resting CD4 T cells from lymphoid tissues do express positive transcription elongation factor (PTEF)b1 and support HIV-1 gene expression and replication, allowing HIV acquisition at the portal of entry [92] and likely contributing to residual virus replication and reservoir replenishment.
Intracellular HIV-1 Tat plays a key role in virus reservoir establishment and maintenance. In fact, Tat expression enhances stochastic fluctuations of the basal HIV transcriptional machinery driven by host transcriptional factors [54][93][94]. This, in turn, drives Tat expression itself into stochastic oscillations around the threshold of virus transcriptional extinction. Consequently, the Tat positive transcriptional feedback loop is pivotal for fate decision-making between HIV productive and latent infection [54][93][94]. The stochastic features of the Tat circuitry may in part explain the failure of “shock and kill” strategies to eradicate HIV based on the deterministic reversion of HIV latency through latency-reversing agents [95]. In contrast, agents inhibiting the Tat transcriptional loop effectively block the reactivation of latent HIV, which has led to the “block and lock” strategy for a permanent shut-off of HIV reservoirs [96].
Not surprisingly, Tat is produced and released in treated patients [52][97][98], pointing to a role for eTat in HIV reservoir dynamics. As already mentioned, eTat crosses the blood–brain barrier and chemoattracts monocytes/macrophages and T cells, promoting inflammation, the permissivity of resting T cells and T-cell activation, [52]. Thus, eTat promotes the establishment and maintenance of an HIV reservoir in the CNS, which is relatively insensitive to immune control and ART [53]. In this context, several lines of evidence also suggest that eTat plays a key role in the establishment and maintenance of the memory CD4 T cell reservoir. In fact, eTat promotes the activation and differentiation of naïve CD4 T cells towards the effector-memory phenotype [99], thus increasing the frequency of cells transitioning from the activated to the resting state, which, in turn, is associated with HIV latent infection [100]. Further, it upregulates anti-apoptotic genes, particularly Bcl-2, in CD4 T cells, promoting their survival [101]. Taken together, it is apparent that eTat is pivotal not only in HIV acquisition and spreading, but also in the establishment and maintenance of reservoirs.
Extensive evidence of the role of intracellular Tat in HIV reservoirs has been reviewed elsewhere [102].


  1. Trickey, A.; Sabin, C.A.; Burkholder, G.; Crane, H.; Monforte, A.D.; Egger, M.; Gill, M.J.; Grabar, S.; Guest, J.L.; Jarrin, I.; et al. Life expectancy after 2015 of adults with HIV on long-term antiretroviral therapy in Europe and North America: A collaborative analysis of cohort studies. Lancet HIV 2023, 10, e295–e307.
  2. Broyles, L.N.; Luo, R.; Boeras, D.; Vojnov, L. The risk of sexual transmission of HIV in individuals with low-level HIV viraemia: A systematic review. Lancet 2023, 402, 464–471.
  3. Aamer, H.A.; McClure, J.; Ko, D.; Maenza, J.; Collier, A.C.; Coombs, R.W.; Mullins, J.I.; Frenkel, L.M. Cells producing residual viremia during antiretroviral treatment appear to contribute to rebound viremia following interruption of treatment. PLoS Pathog. 2020, 16, e1008791.
  4. Veenhuis, R.T.; Abreu, C.M.; Costa, P.A.G.; Ferreira, E.A.; Ratliff, J.; Pohlenz, L.; Shirk, E.N.; Rubin, L.H.; Blankson, J.N.; Gama, L.; et al. Monocyte-derived macrophages contain persistent latent HIV reservoirs. Nat. Microbiol. 2023, 8, 833–844.
  5. Farhadian, S.F.; Lindenbaum, O.; Zhao, J.; Corley, M.J.; Im, Y.; Walsh, H.; Vecchio, A.; Garcia-Milian, R.; Chiarella, J.; Chintanaphol, M.; et al. HIV viral transcription and immune perturbations in the CNS of people with HIV despite ART. JCI Insight 2022, 7, e160267.
  6. Asowata, O.E.; Singh, A.; Ngoepe, A.; Herbert, N.; Fardoos, R.; Reddy, K.; Zungu, Y.; Nene, F.; Mthabela, N.; Ramjit, D.; et al. Irreversible depletion of intestinal CD4+ T cells is associated with T cell activation during chronic HIV infection. JCI Insight 2021, 6, e146162.
  7. Laspia, M.F.; Rice, A.P.; Mathews, M.B. HIV-1 Tat protein increases transcriptional initiation and stabilizes elongation. Cell 1989, 59, 283–292.
  8. Ensoli, B.; Barillari, G.; Salahuddin, S.Z.; Gallo, R.C.; Wong-Staal, F. Tat protein of HIV-1 stimulates growth of cells derived from Kaposi’s sarcoma lesions of AIDS patients. Nature 1990, 345, 84–86.
  9. Ensoli, B.; Gendelman, R.; Markham, P.; Fiorelli, V.; Colombini, S.; Raffeld, M.; Cafaro, A.; Chang, H.K.; Brady, J.N.; Gallo, R.C. Synergy between basic fibroblast growth factor and HIV-1 Tat protein in induction of Kaposi’s sarcoma. Nature 1994, 371, 674–680.
  10. Ensoli, B.; Buonaguro, L.; Barillari, G.; Fiorelli, V.; Gendelman, R.; Morgan, R.A.; Wingfield, P.; Gallo, R.C. Release, uptake, and effects of extracellular HIV-1 Tat protein on cell growth and viral transactivation. J. Virol. 1993, 67, 277–287.
  11. Chang, H.C.; Samaniego, F.; Nair, B.C.; Buonaguro, L.; Ensoli, B. HIV-1 Tat protein exits from cells via a leaderless secretory pathway and binds to extracellular matrix-associated heparan sulfate proteoglycans through its basic region. AIDS 1997, 11, 1421–1431.
  12. Rayne, F.; Debaisieux, S.; Yezid, H.; Lin, Y.-L.; Mettling, C.; Konate, K.; Chazal, N.; Arold, S.T.; Pugnière, M.; Sanchez, F.; et al. Phosphatidylinositol-(4,5)-bisphosphate enables efficient secretion of HIV-1 Tat by infected T-cells. EMBO J. 2010, 29, 1348–1362.
  13. Deeks, S.G.; Tracy, R.; Douek, D.C. Systemic effects of inflammation on health during chronic HIV infection. Immunity 2013, 39, 633–645.
  14. Feinberg, M.B.; Baltimore, D.; Frankel, A.D. The role of Tat in the human immunodeficiency virus life cycle indicates a primary effect on transcriptional elongation. Proc. Natl. Acad. Sci. USA 1991, 88, 4045–4049.
  15. Mueller, N.; Pasternak, A.O.; Klaver, B.; Cornelissen, M.; Berkhout, B.; Das, A.T. The HIV-1 Tat Protein Enhances Splicing at the Major Splice Donor Site. J. Virol. 2018, 92, e01855-17.
  16. D’Orso, I.; Frankel, A.D. RNA-mediated displacement of an inhibitory snRNP complex activates transcription elongation. Nat. Struct. Mol. Biol. 2010, 17, 815–821.
  17. López-Huertas, M.R.; Callejas, S.; Abia, D.; Mateos, E.; Dopazo, A.; Alcami, J.; Coiras, M. Modifications in host cell cytoskeleton structure and function mediated by intracellular HIV-1 Tat protein are greatly dependent on the second coding exon. Nucleic Acids Res. 2010, 38, 3287–3307.
  18. López-Huertas, M.R.; Mateos, E.; del Cojo, M.S.; Gómez-Esquer, F.; Díaz-Gil, G.; Rodríguez-Mora, S.; López, J.A.; Calvo, E.; López-Campos, G.; Alcamí, J.; et al. The presence of HIV-1 Tat protein second exon delays fas protein-mediated apoptosis in CD4+ T lymphocytes: A potential mechanism for persistent viral production. J. Biol. Chem. 2013, 288, 7626–7644.
  19. Kukkonen, S.; Martinez-Viedma, M.D.P.; Kim, N.; Manrique, M.; Aldovini, A. HIV-1 Tat second exon limits the extent of Tat-mediated modulation of interferon-stimulated genes in antigen presenting cells. Retrovirology 2014, 11, 30.
  20. Howcroft, T.K.; Strebel, K.; Martin, M.A.; Singer, D.S. Repression of MHC class I gene promoter activity by two-exon Tat of HIV. Science 1993, 260, 1320–1322.
  21. Kanazawa, S.; Okamoto, T.; Peterlin, B. Tat competes with CIITA for the binding to P-TEFb and blocks the expression of MHC class II genes in HIV infection. Immunity 2000, 12, 61–70.
  22. Mele, A.R.; Marino, J.; Dampier, W.; Wigdahl, B.; Nonnemacher, M.R. HIV-1 Tat Length: Comparative and Functional Considerations. Front. Microbiol. 2020, 11, 444.
  23. Epie, N.; Ammosova, T.; Sapir, T.; Voloshin, Y.; Lane, W.S.; Turner, W.; Reiner, O.; Nekhai, S. HIV-1 Tat interacts with LIS1 protein. Retrovirology 2005, 2, 6.
  24. Chen, D.; Wang, M.; Zhou, S.; Zhou, Q. HIV-1 Tat targets microtubules to induce apoptosis, a process promoted by the pro-apoptotic Bcl-2 relative Bim. EMBO J. 2002, 21, 6801–6810.
  25. Huo, L.; Li, D.; Sun, L.; Liu, M.; Shi, X.; Sun, X.; Li, J.; Dong, B.; Dong, X.; Zhou, J. Tat acetylation regulates its actions on microtubule dynamics and apoptosis in T lymphocytes. J. Pathol. 2010, 223, 28–36.
  26. Wei, P.; Garber, M.E.; Fang, S.-M.; Fischer, W.H.; Jones, K.A. A novel CDK9-associated C-type cyclin interacts directly with HIV-1 Tat and mediates its high-affinity, loop-specific binding to TAR RNA. Cell 1998, 92, 451–462.
  27. Berkhout, B.; Silverman, R.H.; Jeang, K.-T. Tat trans-activates the human immunodeficiency virus through a nascent RNA target. Cell 1989, 59, 273–282.
  28. Gotora, P.T.; van der Sluis, R.; Williams, M.E. HIV-1 Tat amino acid residues that influence Tat-TAR binding affinity: A scoping review. BMC Infect. Dis. 2023, 23, 164.
  29. Tyagi, M.; Rusnati, M.; Presta, M.; Giacca, M. Internalization of HIV-1 tat requires cell surface heparan sulfate proteoglycans. J. Biol. Chem. 2001, 276, 3254–3261.
  30. Ruiz, A.P.; Ajasin, D.O.; Ramasamy, S.; DesMarais, V.; Eugenin, E.A.; Prasad, V.R. A Naturally Occurring Polymorphism in the HIV-1 Tat Basic Domain Inhibits Uptake by Bystander Cells and Leads to Reduced Neuroinflammation. Sci. Rep. 2019, 9, 3308.
  31. Gump, J.M.; June, R.K.; Dowdy, S.F. Revised role of glycosaminoglycans in TAT protein transduction domain-mediated cellular transduction. J. Biol. Chem. 2010, 285, 1500–1507.
  32. King, J.; Eugenin, E.; Buckner, C.; Berman, J. HIV tat and neurotoxicity. Microbes Infect. 2006, 8, 1347–1357.
  33. Brake, D.A.; Debouck, C.; Biesecker, G. Identification of an Arg-Gly-Asp (RGD) cell adhesion site in human immunodeficiency virus type 1 transactivation protein, tat. J. Cell Biol. 1990, 111, 1275–1281.
  34. Barillari, G.; Gendelman, R.; Gallo, R.C.; Ensoli, B. The Tat protein of human immunodeficiency virus type 1, a growth factor for AIDS Kaposi sarcoma and cytokine-activated vascular cells, induces adhesion of the same cell types by using integrin receptors recognizing the RGD amino acid sequence. Proc. Natl. Acad. Sci. USA 1993, 90, 7941–7945.
  35. Neuveut, C.; Jeang, K.T. Recombinant human immunodeficiency virus type 1 genomes with tat unconstrained by overlapping reading frames reveal residues in Tat important for replication in tissue culture. J. Virol. 1996, 70, 5572–5581.
  36. Neuveut, C.; Scoggins, R.M.; Camerini, D.; Markham, R.B.; Jeang, K.-T. Requirement for the second coding exon of Tat in the optimal replication of macrophage-tropic HIV-1. J. Biomed. Sci. 2003, 10, 651–660.
  37. Rodríguez-Mora, S.; Mateos, E.; Moran, M.; Martín, M.; López, J.A.; Calvo, E.; Terrón, M.C.; Luque, D.; Muriaux, D.; Alcamí, J.; et al. Intracellular expression of Tat alters mitochondrial functions in T cells: A potential mechanism to understand mitochondrial damage during HIV-1 replication. Retrovirology 2015, 12, 78.
  38. Wu, Y.; Marsh, J.W. Selective transcription and modulation of resting T cell activity by preintegrated HIV DNA. Science 2001, 293, 1503–1506.
  39. Chertova, E.; Chertov, O.; Coren, L.V.; Roser, J.D.; Trubey, C.M.; Bess, J.W.; Sowder, R.C.; Barsov, E.; Hood, B.L.; Fisher, R.J.; et al. Proteomic and biochemical analysis of purified human immunodeficiency virus type 1 produced from infected monocyte-derived macrophages. J. Virol. 2006, 80, 9039–9052.
  40. Schatz, M.; Marty, L.; Ounadjela, C.; Tong, P.B.V.; Cardace, I.; Mettling, C.; Milhiet, P.-E.; Costa, L.; Godefroy, C.; Pugnière, M.; et al. A Tripartite Complex HIV-1 Tat-Cyclophilin A-Capsid Protein Enables Tat Encapsidation That Is Required for HIV-1 Infectivity. J. Virol. 2023, 97, e0027823.
  41. Harrich, D.; Ulich, C.; García-Martínez, L.F.; Gaynor, R.B. Tat is required for efficient HIV-1 reverse transcription. EMBO J. 1997, 16, 1224–1235.
  42. Mele, A.R.; Marino, J.; Chen, K.; Pirrone, V.; Janetopoulos, C.; Wigdahl, B.; Klase, Z.; Nonnemacher, M.R. Defining the molecular mechanisms of HIV-1 Tat secretion: PtdIns(4,5)P2 at the epicenter. Traffic 2018, 19, 655–665.
  43. Ghanam, R.H.; Eastep, G.N.; Saad, J.S. Structural Insights into the Mechanism of HIV-1 Tat Secretion from the Plasma Membrane. J. Mol. Biol. 2023, 435, 167880.
  44. Jost, M.; Simpson, F.; Kavran, J.M.; Lemmon, M.A.; Schmid, S.L. Phosphatidylinositol-4,5-bisphosphate is required for endocytic coated vesicle formation. Curr. Biol. 1998, 8, 1399–1402.
  45. Botelho, R.J.; Teruel, M.; Dierckman, R.; Anderson, R.; Wells, A.; York, J.D.; Meyer, T.; Grinstein, S. Localized biphasic changes in phosphatidylinositol-4,5-bisphosphate at sites of phagocytosis. J. Cell Biol. 2000, 151, 1353–1368.
  46. Debaisieux, S.; Lachambre, S.; Gross, A.; Mettling, C.; Besteiro, S.; Yezid, H.; Henaff, D.; Chopard, C.; Mesnard, J.-M.; Beaumelle, B. HIV-1 Tat inhibits phagocytosis by preventing the recruitment of Cdc42 to the phagocytic cup. Nat. Commun. 2015, 6, 6211.
  47. Tryoen-Tóth, P.; Chasserot-Golaz, S.; Tu, A.; Gherib, P.; Bader, M.-F.; Beaumelle, B.; Vitale, N. HIV-1 Tat protein inhibits neurosecretion by binding to phosphatidylinositol 4,5-bisphosphate. J. Cell Sci. 2013, 126, 454–463.
  48. Harwig, A.; Jongejan, A.; van Kampen, A.H.C.; Berkhout, B.; Das, A.T. Tat-dependent production of an HIV-1 TAR-encoded miRNA-like small RNA. Nucleic Acids Res. 2016, 44, 4340–4353.
  49. Sampey, G.C.; Saifuddin, M.; Schwab, A.; Barclay, R.; Punya, S.; Chung, M.-C.; Hakami, R.M.; Zadeh, M.A.; Lepene, B.; Klase, Z.A.; et al. Exosomes from HIV-1-infected Cells Stimulate Production of Pro-inflammatory Cytokines through Trans-activating Response (TAR) RNA. J. Biol. Chem. 2016, 291, 1251–1266.
  50. Chen, L.; Feng, Z.; Yue, H.; Bazdar, D.; Mbonye, U.; Zender, C.; Harding, C.V.; Bruggeman, L.; Karn, J.; Sieg, S.F.; et al. Exosomes derived from HIV-1-infected cells promote growth and progression of cancer via HIV TAR RNA. Nat. Commun. 2018, 9, 4585.
  51. Chettimada, S.; Lorenz, D.R.; Misra, V.; Dillon, S.T.; Reeves, R.K.; Manickam, C.; Morgello, S.; Kirk, G.D.; Mehta, S.H.; Gabuzda, D. Exosome markers associated with immune activation and oxidative stress in HIV patients on antiretroviral therapy. Sci. Rep. 2018, 8, 7227.
  52. Johnson, T.P.; Patel, K.; Johnson, K.R.; Maric, D.; Calabresi, P.A.; Hasbun, R.; Nath, A. Induction of IL-17 and nonclassical T-cell activation by HIV-Tat protein. Proc. Natl. Acad. Sci. USA 2013, 110, 13588–13593.
  53. Dahl, V.; Lee, E.; Peterson, J.; Spudich, S.S.; Leppla, I.; Sinclair, E.; Fuchs, D.; Palmer, S.; Price, R.W. Raltegravir treatment intensification does not alter cerebrospinal fluid HIV-1 infection or immunoactivation in subjects on suppressive therapy. J. Infect. Dis. 2011, 204, 1936–1945.
  54. Xiao, H.; Neuveut, C.; Tiffany, H.L.; Benkirane, M.; Rich, E.A.; Murphy, P.M.; Jeang, K.-T. Selective CXCR4 antagonism by Tat: Implications for in vivo expansion of coreceptor use by HIV-1. Proc. Natl. Acad. Sci. USA 2000, 97, 11466–11471.
  55. Poggi, A.; Zocchi, M.R. HIV-1 Tat triggers TGF-beta production and NK cell apoptosis that is prevented by pertussis toxin B. J. Immunol. Res. 2006, 13, 369–372.
  56. Westendorp, M.O.; Frank, R.; Ochsenbauer, C.; Stricker, K.; Dhein, J.; Walczak, H.; Debating, K.-M.; Krammer, P.H. Sensitization of T cells to CD95-mediated apoptosis by HIV-1 Tat and gp120. Nature 1995, 375, 497–500.
  57. Marchiò, S.; Alfano, M.; Primo, L.; Gramaglia, D.; Butini, L.; Gennero, L.; De Vivo, E.; Arap, W.; Giacca, M.; Pasqualini, R.; et al. Cell surface-associated Tat modulates HIV-1 infection and spreading through a specific interaction with gp120 viral envelope protein. Blood 2005, 105, 2802–2811.
  58. Weinberger, L.S.; Burnett, J.C.; Toettcher, J.E.; Arkin, A.P.; Schaffer, D.V. Stochastic gene expression in a lentiviral positive-feedback loop: HIV-1 Tat fluctuations drive phenotypic diversity. Cell 2005, 122, 169–182.
  59. Buonaguro, L.; Buonaguro, F.M.; Giraldo, G.; Ensoli, B. The human immunodeficiency virus type 1 Tat protein transactivates tumor necrosis factor beta gene expression through a TAR-like structure. J. Virol. 1994, 68, 2677–2682.
  60. Nappi, F.; Chiozzini, C.; Bordignon, V.; Borsetti, A.; Bellino, S.; Cippitelli, M.; Barillari, G.; Caputo, A.; Tyagi, M.; Giacca, M.; et al. Immobilized HIV-1 Tat protein promotes gene transfer via a transactivation-independent mechanism which requires binding of Tat to viral particles. J. Gene Med. 2009, 11, 955–965.
  61. Zauli, G.; Gibellini, D.; Celeghini, C.; Mischiati, C.; Bassini, A.; La Placa, M.; Capitani, S. Pleiotropic effects of immobilized versus soluble recombinant HIV-1 Tat protein on CD3-mediated activation, induction of apoptosis, and HIV-1 long terminal repeat transactivation in purified CD4+ T lymphocytes. J. Immunol. 1996, 157, 2216–2224.
  62. Ott, M.; Emiliani, S.; Van Lint, C.; Herbein, G.; Lovett, J.; Chirmule, N.; McCloskey, T.; Pahwa, S.; Verdin, E. Immune hyperactivation of HIV-1-infected T cells mediated by Tat and the CD28 pathway. Science 1997, 275, 1481–1485.
  63. Li, C.J.; Ueda, Y.; Shi, B.; Borodyansky, L.; Huang, L.; Li, Y.-Z.; Pardee, A.B. Tat protein induces self-perpetuating permissivity for productive HIV-1 infection. Proc. Natl. Acad. Sci. USA 1997, 94, 8116–8120.
  64. Gavioli, R.; Gallerani, E.; Fortini, C.; Fabris, M.; Bottoni, A.; Canella, A.; Bonaccorsi, A.; Marastoni, M.; Micheletti, F.; Cafaro, A.; et al. HIV-1 tat protein modulates the generation of cytotoxic T cell epitopes by modifying proteasome composition and enzymatic activity. J. Immunol. 2004, 173, 3838–3843.
  65. Campbell, G.R.; Loret, E.P. What does the structure-function relationship of the HIV-1 Tat protein teach us about developing an AIDS vaccine? Retrovirology 2009, 6, 50.
  66. Fanales-Belasio, E.; Moretti, S.; Nappi, F.; Barillari, G.; Micheletti, F.; Cafaro, A.; Ensoli, B. Native HIV-1 Tat protein targets monocyte-derived dendritic cells and enhances their maturation, function, and antigen-specific T cell responses. J. Immunol. 2002, 168, 197–206.
  67. Fanales-Belasio, E.; Moretti, S.; Fiorelli, V.; Tripiciano, A.; Cossut, M.R.P.; Scoglio, A.; Collacchi, B.; Nappi, F.; Macchia, I.; Bellino, S.; et al. HIV-1 Tat Addresses Dendritic Cells to Induce a Predominant Th1-Type Adaptive Immune Response That Appears Prevalent in the Asymptomatic Stage of Infection. J. Immunol. 2009, 182, 2888–2897.
  68. Li, J.C.-B.; Yim, H.C.-H.; Lau, A.S. Role of HIV-1 Tat in AIDS pathogenesis: Its effects on cytokine dysregulation and contributions to the pathogenesis of opportunistic infection. AIDS 2010, 24, 1609–1623.
  69. Chopard, C.; Tong, P.B.V.; Tóth, P.; Schatz, M.; Yezid, H.; Debaisieux, S.; Mettling, C.; Gross, A.; Pugnière, M.; Tu, A.; et al. Cyclophilin A enables specific HIV-1 Tat palmitoylation and accumulation in uninfected cells. Nat. Commun. 2018, 9, 2251.
  70. Baggaley, R.F.; White, R.G.; Boily, M.-C. HIV transmission risk through anal intercourse: Systematic review, meta-analysis and implications for HIV prevention. Leuk. Res. 2010, 39, 1048–1063.
  71. Vittinghoff, E.; Scheer, S.; O’Malley, P.; Colfax, G.; Holmberg, S.D.; Buchbinder, S.P. Combination antiretroviral therapy and recent declines in AIDS incidence and mortality. J. Infect. Dis. 1999, 179, 717–720.
  72. Jin, F.; Jansson, J.; Law, M.; Prestage, G.P.; Zablotska, I.; Imrie, J.C.; Kippax, S.C.; Kaldor, J.M.; Grulich, A.E.; Wilson, D.P. Per-contact probability of HIV transmission in homosexual men in Sydney in the era of HAART. AIDS 2010, 24, 907–913.
  73. Boily, M.-C.; Baggaley, R.F.; Wang, L.; Masse, B.; White, R.G.; Hayes, R.J.; Alary, M. Heterosexual risk of HIV-1 infection per sexual act: Systematic review and meta-analysis of observational studies. Lancet Infect. Dis. 2009, 9, 118–129.
  74. Ward, H.; Rönn, M. Contribution of sexually transmitted infections to the sexual transmission of HIV. Curr. Opin. HIV AIDS 2010, 5, 305–310.
  75. Quinn, T.C.; Wawer, M.J.; Sewankambo, N.; Serwadda, D.; Li, C.; Wabwire-Mangen, F.; Meehan, M.O.; Lutalo, T.; Gray, R.H. Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N. Engl. J. Med. 2000, 342, 921–929.
  76. Baeten, J.M.; Kahle, E.; Lingappa, J.R.; Coombs, R.W.; Delany-Moretlwe, S.; Nakku-Joloba, E.; Mugo, N.R.; Wald, A.; Corey, L.; Donnell, D.; et al. Genital HIV-1 RNA predicts risk of heterosexual HIV-1 transmission. Sci. Transl. Med. 2011, 3, 77ra29.
  77. Wawer, M.J.; Gray, R.H.; Sewankambo, N.K.; Serwadda, D.; Li, X.; Laeyendecker, O.; Kiwanuka, N.; Kigozi, G.; Kiddugavu, M.; Lutalo, T.; et al. Rates of HIV-1 transmission per coital act, by stage of HIV-1 infection, in Rakai, Uganda. J. Infect. Dis. 2005, 191, 1403–1409.
  78. Hollingsworth, T.D.; Anderson, R.M.; Fraser, C. HIV-1 transmission, by stage of infection. J. Infect. Dis. 2008, 198, 687–693.
  79. Caputo, V.; Libera, M.; Sisti, S.; Giuliani, B.; Diotti, R.A.; Criscuolo, E. The initial interplay between HIV and mucosal innate immunity. Front. Immunol. 2023, 14, 1104423.
  80. Kariuki, S.M.; Selhorst, P.; Ariën, K.K.; Dorfman, J.R. The HIV-1 transmission bottleneck. Retrovirology 2017, 14, 22.
  81. Oberle, C.S.; The Swiss HIV Cohort Study (SHCS); Joos, B.; Rusert, P.; Campbell, N.K.; Beauparlant, D.; Kuster, H.; Weber, J.; Schenkel, C.D.; Scherrer, A.U.; et al. Tracing HIV-1 transmission: Envelope traits of HIV-1 transmitter and recipient pairs. Retrovirology 2016, 13, 62.
  82. Monini, P.; Cafaro, A.; Srivastava, I.K.; Moretti, S.; Sharma, V.A.; Andreini, C.; Chiozzini, C.; Ferrantelli, F.; Cossut, M.R.P.; Tripiciano, A.; et al. HIV-1 Tat Promotes Integrin-Mediated HIV Transmission to Dendritic Cells by Binding Env Spikes and Competes Neutralization by Anti-HIV Abs. PLoS ONE 2012, 7, e48781.
  83. Ward, A.B.; Wilson, I.A. Insights into the trimeric HIV-1 envelope glycoprotein structure. Trends Biochem. Sci. 2015, 40, 101–107.
  84. Huet, T.; Dazza, M.-C.; Brun-Vézinet, F.; Roelants, G.E.; Wain-Hobson, S. A highly defective HIV-1 strain isolated from a healthy Gabonese individual presenting an atypical Western blot. AIDS 1989, 3, 707–716.
  85. Anderson, E.M.; Simonetti, F.R.; Gorelick, R.J.; Hill, S.; Gouzoulis, M.A.; Bell, J.; Rehm, C.; Pérez, L.; Boritz, E.; Wu, X.; et al. Dynamic Shifts in the HIV Proviral Landscape During Long Term Combination Antiretroviral Therapy: Implications for Persistence and Control of HIV Infections. Viruses 2020, 12, 136.
  86. Botha, J.C.; Demirov, D.; Gordijn, C.; Katusiime, M.G.; Bale, M.J.; Wu, X.; Wells, D.; Hughes, S.H.; Cotton, M.F.; Mellors, J.W.; et al. The largest HIV-1-infected T cell clones in children on long-term combination antiretroviral therapy contain solo LTRs. mBio 2023, 14, e01116-23.
  87. Lorenzo-Redondo, R.; Fryer, H.R.; Bedford, T.; Kim, E.Y.; Archer, J.; Kosakovsky Pond, S.L.K.; Chung, Y.S.; Penugonda, S.; Chipman, J.G.; Fletcher, C.V.; et al. Persistent HIV-1 replication maintains the tissue reservoir during therapy. Nature 2016, 530, 51–56.
  88. Fletcher, C.V.; Staskus, K.; Wietgrefe, S.W.; Rothenberger, M.; Reilly, C.; Chipman, J.G.; Beilman, G.J.; Khoruts, A.; Thorkelson, A.; Schmidt, T.E.; et al. Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. Proc. Natl. Acad. Sci. USA 2014, 111, 2307–2312.
  89. Sigal, A.; Kim, J.T.; Balazs, A.B.; Dekel, E.; Mayo, A.; Milo, R.; Baltimore, D. Cell-to-cell spread of HIV permits ongoing replication despite antiretroviral therapy. Nature 2011, 477, 95–98.
  90. Martinez-Picado, J.; Zurakowski, R.; Buzón, M.J.; Stevenson, M. Episomal HIV-1 DNA and its relationship to other markers of HIV-1 persistence. Retrovirology 2018, 15, 15.
  91. Lassen, K.G.; Ramyar, K.X.; Bailey, J.R.; Zhou, Y.; Siliciano, R.F. Nuclear retention of multiply spliced HIV-1 RNA in resting CD4+ T cells. PLoS Pathog. 2006, 2, e68.
  92. Wietgrefe, S.W.; Anderson, J.; Duan, L.; Southern, P.J.; Zuck, P.; Wu, G.; Howell, B.J.; Reilly, C.; Kroon, E.; Chottanapund, S.; et al. Initial productive and latent HIV infections originate in vivo by infection of resting T cells. J. Clin. Investig. 2023, 133, e171501.
  93. Weinberger, L.S.; Dar, R.D.; Simpson, M.L. Transient-mediated fate determination in a transcriptional circuit of HIV. Nat. Genet. 2008, 40, 466–470.
  94. Razooky, B.S.; Pai, A.; Aull, K.; Rouzine, I.M.; Weinberger, L.S. A Hardwired HIV Latency Program. Cell 2015, 160, 990–1001.
  95. Zerbato, J.M.; Purves, H.V.; Lewin, S.R.; Rasmussen, T.A. Between a shock and a hard place: Challenges and developments in HIV latency reversal. Curr. Opin. Virol. 2019, 38, 1–9.
  96. Moranguinho, I.; Valente, S.T. Block-And-Lock: New Horizons for a Cure for HIV-1. Viruses 2020, 12, 1443.
  97. Ensoli, B.; Bellino, S.; Tripiciano, A.; Longo, O.; Francavilla, V.; Marcotullio, S.; Cafaro, A.; Picconi, O.; Paniccia, G.; Scoglio, A.; et al. Therapeutic immunization with HIV-1 Tat reduces immune activation and loss of regulatory T-cells and improves immune function in subjects on HAART. PLoS ONE 2010, 5, e13540.
  98. Mediouni, S.; Darque, A.; Baillat, G.; Ravaux, I.; Dhiver, C.; Tissot-Dupont, H.; Mokhtari, M.; Moreau, H.; Tamalet, C.; Brunet, C.; et al. Antiretroviral therapy does not block the secretion of the human immunodeficiency virus tat protein. Infect. Disord. Drug Targets 2012, 12, 81–86.
  99. Nicoli, F.; Gallerani, E.; Sforza, F.; Finessi, V.; Chachage, M.; Geldmacher, C.; Cafaro, A.; Ensoli, B.; Caputo, A.; Gavioli, R. The HIV-1 Tat protein affects human CD4+ T-cell programing and activation, and favors the differentiation of naïve CD4+ T cells. AIDS 2018, 32, 575–581.
  100. Shan, L.; Deng, K.; Gao, H.; Xing, S.; Capoferri, A.A.; Durand, C.M.; Rabi, S.A.; Laird, G.M.; Kim, M.; Hosmane, N.N.; et al. Transcriptional reprogramming during effector-to-memory transition renders CD4+ T cells permissive for latent HIV-1 infection. Immunity 2017, 47, 766–775.
  101. Zauli, G.; Gibellini, D.; Caputo, A.; Bassini, A.; Negrini, M.; Monne, M.; Mazzoni, M.; Capitani, S. The human immunodeficiency virus type-1 Tat protein upregulates Bcl-2 gene expression in Jurkat T-cell lines and primary peripheral blood mononuclear cells. Blood 1995, 86, 3823–3834.
  102. Ensoli, B.; Moretti, S.; Borsetti, A.; Maggiorella, M.T.; Buttò, S.; Picconi, O.; Tripiciano, A.; Sgadari, C.; Monini, P.; Cafaro, A. New insights into pathogenesis point to HIV-1 Tat as a key vaccine target. Arch. Virol. 2021, 166, 2955–2974.
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