MAdCAM costimulation through Integrin-α4β7 promotes HIV replication

Nawaz, Fatima; Goes, Livia R; Ray, Jocelyn C; Olowojesiku, Ronke; Sajani, Alia; Ansari, Aftab A.; Perrone, Ian; Hiatt, Joseph; Ryk, Donald Van; Wei, Darmood; Waliszewski, Mia; Soares, Marcelo A.; Jelicic, Katija; Connors, Mark; Migueles, Stephen A.; Martinelli, Elena; Villinger, François; Cicala, Claudia; Fauci, Anthony S.; Arthos, James

doi:10.1038/s41385-018-0044-1

Cited by 29 publications

(43 citation statements)

References 59 publications

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“…In addition, α 4 β 7 can deliver costimulatory signals to CD4 + T cells that impact cell activation, proliferation and apoptosis [ 81 , 82 ]. We recently reported that MAdCAM -mediated costimulation supports HIV replication in α 4 β 7 high CD4 + T cells [ 19 ]. Whether V2 signaling through α 4 β 7 can similarly facilitate HIV replication requires additional investigation.…”

Section: Discussionmentioning

confidence: 99%

“…It is possible that α 4 β 7 functions simply as an attachment factor [ 18 ]. However, gp120 binding to α 4 β 7 , like mucosal addressin cellular adhesion molecule (MAdCAM) transduces signals to primary CD4 + T cells, suggesting that such signals may be relevant to infection in vivo [ 9 , 17 , 19 ]. In this regard we have recently reported that MAdCAM delivers a signal to CD4 + T cells that promotes cellular activation and viral replication [ 19 ].…”

Section: Introductionmentioning

confidence: 99%

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Select gp120 V2 domain specific antibodies derived from HIV and SIV infection and vaccination inhibit gp120 binding to α4β7

et al. 2018

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The GI tract is preferentially targeted during acute/early HIV-1 infection. Consequent damage to the gut plays a central role in HIV pathogenesis. The basis for preferential targeting of gut tissues is not well defined. Recombinant proteins and synthetic peptides derived from HIV and SIV gp120 bind directly to integrin α4β7, a gut-homing receptor. Using both cell-surface expressed α4β7 and a soluble α4β7 heterodimer we demonstrate that its specific affinity for gp120 is similar to its affinity for MAdCAM (its natural ligand). The gp120 V2 domain preferentially engages extended forms of α4β7 in a cation -sensitive manner and is inhibited by soluble MAdCAM. Thus, V2 mimics MAdCAM in the way that it binds to α4β7, providing HIV a potential mechanism to discriminate between functionally distinct subsets of lymphocytes, including those with gut-homing potential. Furthermore, α4β7 antagonists developed for the treatment of inflammatory bowel diseases, block V2 binding to α4β7. A 15-amino acid V2 -derived peptide is sufficient to mediate binding to α4β7. It includes the canonical LDV/I α4β7 binding site, a cryptic epitope that lies 7–9 amino acids amino terminal to the LDV/I, and residues K169 and I181. These two residues were identified in a sieve analysis of the RV144 vaccine trial as sites of vaccine -mediated immune pressure. HIV and SIV V2 mAbs elicited by both vaccination and infection that recognize this peptide block V2-α4β7 interactions. These mAbs recognize conformations absent from the β- barrel presented in a stabilized HIV SOSIP gp120/41 trimer. The mimicry of MAdCAM-α4β7 interactions by V2 may influence early events in HIV infection, particularly the rapid seeding of gut tissues, and supports the view that HIV replication in gut tissue is a central feature of HIV pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Select gp120 V2 domain specific antibodies derived from HIV and SIV infection and vaccination inhibit gp120 binding to α4β7

et al. 2018

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“…Rh-α 4 β 7 does not block viral entry into CD4 + T cells and has weak anti-HIV-1 activity in vitro [8, 18, 19]. We have recently shown that signaling through α 4 β 7 can promote HIV-1 replication [20] and, in this regard, we previously demonstrated that Rh-α 4 β 7 blocks α 4 β 7 from adopting an active conformation that is critical for this signaling [21].…”

Section: Introductionmentioning

confidence: 99%

Delayed vaginal SHIV infection in VRC01 and anti-α4β7 treated rhesus macaques

et al. 2019

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VRC01 protects macaques from vaginal SHIV infection after a single high-dose challenge. Infusion of a simianized anti-α 4 β 7 mAb (Rh-α 4 β 7 ) just prior to, and during repeated vaginal exposures to SIVmac251 partially protected macaques from vaginal SIV infection and rescued CD4 + T cells. To investigate the impact of combining VRC01 and Rh-α 4 β 7 on SHIV infection, 3 groups of macaques were treated with a suboptimal dosing of VRC01 alone or in combination with Rh-α 4 β 7 or with control antibodies prior to the initiation of weekly vaginal exposures to a high dose (1000 TCID 50 ) of SHIV AD8-EO . The combination Rh-α 4 β 7 -VRC01 significantly delayed SHIV AD8-EO vaginal infection. Following infection, VRC01-Rh-α 4 β 7 -treated macaques maintained higher CD4 + T cell counts and exhibited lower rectal SIV-DNA loads compared to controls. Interestingly, VRC01-Rh-α 4 β 7 -treated macaques had fewer IL-17-producing cells in the blood and the gut during the acute phase of infection. Moreover, higher T cell responses to the V2-loop of the SHIV AD8-EO envelope in the VRC01-Rh-α 4 β 7 group inversely correlated with set point viremia. The combination of suboptimal amounts of VRC01 and Rh-α 4 β 7 delayed infection, altered antiviral immune responses and minimized CD4 + T cell loss. Further exploration of the effect of combining bNAbs with Rh-α 4 β 7 on SIV/HIV infection and antiviral immune responses is warranted and may lead to novel preventive and therapeutic strategies.

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“…13 Of note, MAdCAM-mediated T-cell costimulation through 4 7 was shown to enhance HIV-1 replication in vitro. 20 Interestingly, the Envs of some transmitter/founder (T/F) HIV-1 strains were reported to bind efficiently to 4 7 21 and there was an association between a motif in the gp120 leader sequence and viral transmission, 22 suggesting that posttranslational modifications of gp120, such as the level and quality of glycosylation, may influence 4 7 interaction. However, some authors have questioned the frequency of interaction with 4 7 among different HIV-1 isolates, including T/F isolates.…”

Section: Is a Non-essential Receptor For Hiv-1 Gp120mentioning

confidence: 99%

Integrin α4β7 in HIV-1 infection: A critical review

Liu

Lusso

2020

Journal of Leukocyte Biology

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Over the past decade, a series of observations linking 4 7, the principal gut-homing integrin, with various aspects of HIV-1 infection have generated considerable interest in the field of HIV-1 research. After the initial report that the major HIV-1 envelope glycoprotein, gp120, can bind to 4 7, intensive research efforts have been focused on the role of 4 7 as a key factor in HIV-1 pathogenesis and as a potential target for prevention and treatment. The interaction between 4 7 and its natural ligand, MAdCAM-1, directs infected CD4 + T cells and HIV-1 virions carrying incorporated 4 7 to the gut mucosa, which may facilitate HIV-1 seeding and replication in the intestinal compartment during the early stages of infection. In addition, cells that express high levels of 4 7, such as Th17 cells, represent preferential targets for infection, and their frequency in the circulation was shown to correlate with susceptibility to HIV-1 infection and disease progression. A number of in vivo studies in nonhuman primates have investigated whether blockage of 4 7 may affect SIV transmission and pathogenesis. Administration of a primatized anti-4 7 antibody that blocks MAdCAM-1 binding to 4 7 was reported to reduce SIV mucosal transmission in rhesus macaques. However, the mechanism responsible for such a protective effect is still undefined, and conflicting results have been reported on the effects of the same antibody, in combination with ART, during the early chronic phase of SIV infection. Thus, despite a series of tantalizing results accrued over the past decade, the jury is still out on the role of 4 7 in HIV-1 infection.

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MAdCAM costimulation through Integrin-α4β7 promotes HIV replication

Cited by 29 publications

References 59 publications

Select gp120 V2 domain specific antibodies derived from HIV and SIV infection and vaccination inhibit gp120 binding to α4β7

Select gp120 V2 domain specific antibodies derived from HIV and SIV infection and vaccination inhibit gp120 binding to α4β7

Delayed vaginal SHIV infection in VRC01 and anti-α4β7 treated rhesus macaques

Integrin α4β7 in HIV-1 infection: A critical review

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