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Anti-Tat Immunity in HIV-1 Infection: Effects of Naturally Occurring and Vaccine-Induced Antibodies Against Tat on the Course of the Disease

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Anti-Tat Immunity in HIV-1 Infection: Effects of Naturally Occurring and Vaccine-Induced Antibodies Against Tat on the Course of the Disease Review Anti-Tat Immunity in HIV-1 Infection: Effects of Naturally Occurring and Vaccine-Induced Antibodies Against Tat on the Course of the Disease Aurelio Cafaro , Antonella Tripiciano, Orietta Picconi, Cecilia Sgadari , Sonia Moretti, Stefano Buttò, Paolo Monini and Barbara Ensoli * National HIV/AIDS Research Center, Istituto Superiore di Sanità, Rome 00161, Italy * Correspondence: [email protected]; Tel.: +39-06-4990-3209; Fax: +39-06-4990-3002 Received: 16 July 2019; Accepted: 15 August 2019; Published: 26 August 2019 Abstract: HIV-1 Tat is an essential protein in the virus life cycle, which is required for virus gene expression and replication. Most Tat that is produced during infection is released extracellularly and it plays a key role in HIV pathogenesis, including residual disease upon combination antiretroviral therapy (cART). Here, we review epidemiological and experimental evidence showing that antibodies against HIV-1 Tat, infrequently occurring in natural infection, play a protective role against disease progression, and that vaccine targeting Tat can intensify cART. In fact, Tat vaccination of subjects on suppressive cART in Italy and South Africa promoted immune restoration, including CD4+ T-cell increase in low immunological responders, and a reduction of proviral DNA even after six years of cART, when both CD4+ T-cell gain and DNA decay have reached a plateau. Of note, DNA decay was predicted by the neutralization of Tat-mediated entry of Env into dendritic cells by anti-Tat antibodies, which were cross-clade binding and neutralizing. Anti-Tat cellular immunity also contributed to the DNA decay. Based on these data, we propose the Tat therapeutic vaccine as a pathogenesis-driven intervention that effectively intensifies cART and it may lead to a functional cure, providing new perspectives and opportunities also for prevention and virus eradication strategies. Keywords: HIV-1 Tat; anti-Tat antibodies; natural vs. vaccine-induced antibody response; crossclade antibodies; HIV-1 vaccine development; HIV-1 Tat therapeutic vaccine; HIV reservoir; cART intensification; functional cure; perspective for clinical implications 1. Introduction An HIV vaccine is still the most valuable and cost-effective intervention to end the HIV/AIDS pandemic [1]. We focused on the HIV-1 Tat (TransActivator of Transcription) protein as an optimal pathogenetic vaccine target because of the inherent difficulties in developing vaccine strategies capable of inducing cross clade broadly neutralizing antibodies (bNAbs) against HIV-1 Env [2]. This strategy stems from the results of epidemiological and basic research studies on the role of Tat and anti-Tat immunity in the course of HIV infection. Here, we briefly review epidemiological and experimental evidence showing the role of Tat in the virus life cycle, with particular emphasis on extracellular Tat and on its effects on both the virus and the immune system. Conversely, we examine and discuss data on the protective effect of anti-Tat antibodies (Abs), naturally occurring or vaccine-induced, on the course of the disease including in suppressive cART. Further, we will discuss evidence on the role of anti-Tat Abs in blocking the formation of the Tat/Env complex that allows for Tat-mediated HIV entry through the RGD (arginyl-glycyl-aspartic acid tripeptide) binding integrins α5β1, αvβ3, and αvβ5, and it enhances the infection of cells expressing these integrins, such as dendritic cells (DCs). This is a novel path of virus entry and cell infection, likely Vaccines 2019, 7, 99; doi:10.3390/vaccines7030099 www.mdpi.com/journal/vaccines Vaccines 2019, 7, 99 2 of 26 increasing HIV acquisition, as indicated by results in monkeys’ studies, and most likely contributes to Vaccinesreservoir 2019, 7, generationx and maintenance. Finally, we examine the effects of anti-Tat Abs in accelerating2 of 26 the decay of the CD4+ T-cell HIV reservoir under long-term cART. Taken together, the results from the acquisition,studies described as indicated here suggestby results that in targeting monkeys’ HIV-1 studies, Tat, a veryand earlymost HIVlikely protein, contributes may represent to reservoir a generationvaluable and strategy maintenance. to intensify Finally, cART we to achieve examine HIV the functional effects of cureanti-Tat or eradication. Abs in accelerating Similarly, the a vaccine decay of the targetingCD4+ T-cell the TatHIV/Env reservoir complex under may represent long-term a novelcART strategy. Taken totogether, prevent the HIV results acquisition, from asthe will studies be describeddiscussed here below. suggest that targeting HIV-1 Tat, a very early HIV protein, may represent a valuable strategy to intensify cART to achieve HIV functional cure or eradication. Similarly, a vaccine targeting the Tat/Env2. Role complex of Tat inmay the represent Virus Life a novel Cycle strategy to prevent HIV acquisition, as will be discussed below. Tat is generated in two forms through alternative splicing. The first form is encoded by the 2. Role of Tat in the Virus Life Cycle multiply spliced two-exon transcript and it varies in length between 86 and 101 amino acids (aa), dependingTat is generated on the in viral two isolate. forms through The other alternative is encoded sp bylicing. a singly The first spliced form one-exon is encoded transcript by the andmultiply it splicedis 72 two-exon aa long. transcript Both Tat variantsand it varies transactivate in length thebetween LTR e86ffi ciently,and 101 butamino the acids two-exon (aa), depending Tat appears on to the viralexert isolate. additional The other effects is onencoded the infected by a singly cell, which spliced aff ectone-exon cytoskeleton transcript structure and it and is function72 aa long. [3], Both delay Tat variantsFas-mediated transactivate apoptosis the LTR [4], efficiently, and reduce but the the triggering two-exon of Tat innate appears and to adaptive exert additional immune effects responses, on the infectedsuch ascell, the which downregulation affect cytoskel of interferon-stimulatedeton structure and function genes and[3], delay MHC Fas-mediated class-I and II moleculesapoptosis gene[4], and reduceexpression the triggering in antigen of innate presenting and adaptive cells [5 –immune7]. Although responses, both such the one- as the and downregulation the two- exons of forms interferon- of stimulatedTat are producedgenes and and MHC functional, class-I theand latter II molecules is the form gene prevalently expression found in antigenin vivo (101presenting aa) and cellsin vitro [5–7]. Although(86 aa) both [8]. As the shown one- and in Figure the two-1, Tat exons contains forms six of domains: Tat are produced a proline-rich and functional, acidic N-terminus the latter (aa is 1–21),the form prevalentlya cysteine-rich found regionin vivo (aa(101 22–37), aa) and a hydrophobicin vitro (86 aa) core [8]. region As shown (aa 38–48), in Figure an arginine-rich1, Tat contains basic six domains: domain a proline-rich(aa 49–57), acidic a glutamin-rich N-terminus region (aa 1–21), (aa 60–76), a cysteine and-rich a C-terminal region (aa domain 22–37), containing a hydrophobic the RGD core sequence, region (aa 38–48),as recognized an arginine-rich by RGD-binding basic domain integrins. (aa 49–57), Of note, a glutamin-rich Tat is largely region unstructured (aa 60–76), and veryand a flexible, C-terminal a domainproperty containing that permits the RGD interactions sequence, with as recognized numerous partners,by RGD-binding as reported integrins. [8–12]. Of Unless note, Tat diff erentlyis largely unstructuredstated, thereafter and very the flexible, terms Tata property refers to that the two-exonpermits interactions Tat, particularly with numerous to the shortest partners, form as of reported 86 aa [8–12].in length. Unless differently stated, thereafter the terms Tat refers to the two-exon Tat, particularly to the shortest form of 86 aa in length. Figure 1. Functional domains of HIV-1 Tat (HXB2). Amino acid numbering according to the IIIB/Lai Figure 1. Functional domains of HIV-1 Tat (HXB2). Amino acid numbering according to the IIIB/Lai sequence. Tat can be divided into six domains: a proline-rich acidic N-terminus (aa 1–21), a cysteine-rich sequence. Tat can be divided into six domains: a proline-rich acidic N-terminus (aa 1–21), a cysteine-rich region (aa 22–37), a hydrophobic core region (aa 38–48), an arginine-rich basic domain (aa 49–57), a region (aa 22–37), a hydrophobic core region (aa 38–48), an arginine-rich basic domain (aa 49–57), a glutamin-rich region (aa 60–76) and a C-terminal domain containing the RGD sequence, recognized by glutamin-rich region (aa 60–76) and a C-terminal domain containing the RGD sequence, recognized by RGD-binding integrins. Shown is the 86 aa long form of Tat, commonly found in cell lines and used RGD-binding integrins. Shown is the 86 aa long form of Tat, commonly found in cell lines and used experimentally. However, in field isolates the 101 aa long form of Tat is mostly found [8]. experimentally. However, in field isolates the 101 aa long form of Tat is mostly found [8]. Although prominently known for its role in promoting transcription elongation, Tat participates Although prominently known for its role in promoting transcription elongation, Tat participates and and regulates several aspects of the HIV gene transcription program (Table1), both in the acute phase regulates several aspects of the HIV gene transcription program (Table 1), both in the acute phase of of infection and reactivation, irrespective of cART [13–17].
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