The hallmark of primary HIV type 1 (HIV-1) infection is the rapid dissemination of virus to gut-associated lymphoid tissues (GALTs) wherein CD4+ T cells are infected and subsequently depleted [1–3]. Despite antiretroviral therapy (ART), this early structural damage to and depletion of GALT CD4+ T cells is not fully restored [4]. The transmembrane integrin α4β7 facilitates CD4+ T cell and plasmacytoid dendritic cell (pDC) homing to GALT through the adhesion receptor mucosal addressin cell adhesion molecule-1 (MAdCAM-1) expressed on endothelial cells. CD4+ T cells expressing high levels of α4β7 are preferentially infected and depleted in vivo[5–7]. In addition, the HIV-1 envelope protein gp120 binds to α4β7 on CD4+ T cells, which enhances the spread of infection [8]. Infected cells release new HIV-1 virions by budding from their cell membrane, which enables incorporation of integrin α4β7 into the lipid bilayer of budding HIV-1 virions [9]. In humans, the expression of integrin α4β7 on circulating CD4+ T cells predicts HIV-1 acquisition as well as disease progression [4]. On the basis of the importance of the gut as a target in the early phase of HIV-1 pathogenesis, blocking integrin α4β7 using mAbs has been proposed as a strategy to prevent HIV-1 infection. In support of this concept, nonhuman primates (NHPs) studies suggest that anti-α4β7 mAb may prevent and/or delay transmission of infection upon repeated intravaginally challenges with simian immunodeficiency virus (SIV) [10,11]. In a highly profiled report, NHPs intravenously SIV-infected were given anti-α4β7 mAb during ART that led to long-term CD8+ T cell mediated virological control after ART was stopped [12]. However, the challenge virus isolate used had a stop codon in the Nef gene, which could have resulted in a less pathogenic infection. A repeat of the study showed no evidence of long-term virological control in the absence of ART [13]. The administration of anti-α4β7 mAb prior to intrarectal SIV-challenge resulted in a significant decrease in pDC recruitment leading to lower T-cell activation and immune activation in the gut [14]. In SIV prevention experiments, anti-α4β7 mAb decreased plasma and tissue viral loads, and preserved CD4+ T cells in both gut and blood [10,11]. In humans, vedolizumab (Entyvio; Millennium Pharmaceuticals, Inc./Takeda Oncology, Cambridge, Massachusetts, USA), a humanized anti-α4β7 mAb, is licensed for the treatment of inflammatory bowel disease (IBD) [15]. Vedolizumab has been given to individuals with IBD and concomitant HIV-1 infection leading to attenuation of lymphoid aggregates in the gut due to blocked T cell homing [16,17]. However, in a clinical trial, vedolizumab administered to virally suppressed chronic HIV-1 infected individuals had no effect on HIV-1 control after stopping ART [18]. Our clinical case was diagnosed in 2009 with left-sided ulcerative colitis grade E2 by the Montreal Classification. Due to a relapse of ulcerative colitis, vedolizumab at 300 mg was started on 18 September 2017 resulting in rapid clinical remission. Vedolizumab was administered again week 2 and 6, and continued every 8 weeks thereafter. The individual reported unprotected receptive anal intercourse on 31 December 2017 during which he may have been exposed to HIV-1 (day 104 on vedolizumab). In addition, the individual described flu-like symptoms and swollen lymph nodes the following month. The most recent administration of vedolizumab (300 mg) prior to the presumed time of infection was on 1 December 2017, which suggests that the serum concentrations of vedolizumab would have been high enough to saturate α4β7 receptors on 31 December [15,19]. On 18 June 2018, the individual was diagnosed with HIV-1 subtype B, plasma viral load (pVL) was 429 000 copies/ml and the CD4+ T cell count was 600 cells/μl (Fig. 1a)[20–22]. ART (tenofovir, lamivudine and ritonavir-boosted darunavir) was started 10 days after diagnosis. Here, pVL was 260 000 copies/ml and CD4+ and CD8+ T cell counts were 770 and 2020 cells/μl, respectively. At ART initiation, levels of total HIV-1 DNA and cell-associated unspliced HIV-1 RNA (CA usHIV-1)/million peripheral CD4+ T cells were 2351 [95% confidence interval (95% CI): 2016–2688] copies and 29 (95% CI: 22–38) copies, respectively. Total HIV-1 DNA and CA usHIV-1 levels decreased to 285 (95% CI: 188–409) and 0.99 (95% CI: 0.10–3.21) copies/million peripheral CD4+ T cells after 357 days of ART (Fig. 1b,c). CD4+ T cells carrying replication-competent HIV-1 proviruses were also detected after 357 days of ART (and vedolizumab) at a level of 0.0156 (95% CI: 0.0022–0.1110) infectious units/million peripheral CD4+ T cells (Fig. 1d).Fig. 1: Kinetics of CD4+ T cell count and plasma HIV-1 RNA level from time of HIV-1 diagnosis (a) and HIV-1 reservoir measurements: levels of total HIV-1 DNA (b), cell-associated unspliced HIV-1 RNA (c) and infectious units/million (d) peripheral CD4+ T cells.The decline in proviral DNA, CA usHIV-1 and replication-competent reservoir in our case resembles that of other individuals who started ART less than 6 months after HIV-1 infection (Fig. 1b,c) [23,24]. The level of pVL was undetectable 151 days after ART initiation, which is comparable to other individuals starting a protease-inhibitor based ART regimen with a viral set-point of 260 000 copies/ml [25]. Immunologically, we cannot rule out a discrete benefit from vedolizumab, as the restoration of CD4+ T cells in blood was higher and faster than previously described [26]. A possible explanation for this finding could be reduced homing to the gut of β7-expressing CD4+ T cells that has been observed among HIV-1 infected individuals receiving vedolizumab [16,17]. Although we think it unlikely, the question of whether the administration of vedolizumab at ART initiation among ART-naive HIV-1-infected individuals [ClinicalTrials.gov Identifiers: NCT03577782 (recruiting)] or during the chronic suppressive phase of ART-treated HIV-1 infected individuals [NCT03147859 (recruiting)] will result in durable viral control in the absence of ART is going to be addressed in two upcoming studies. Interestingly, for safety reasons, vedolizumab is manufactured with two mutations in its Fc region to reduce engagement of the immune system [15] due to the potential increased risk of progressive multifocal leukoencephalopathy (PML) linked to treatment with natalizumab, a dual anti-α1 and α4 mAb in IBD. Therefore, Fc-mediated functions are not mediated by vedolizumab, which is in contrast to broadly neutralizing antibodies against HIV-1 [27]. Notably, our case might have had a more vulnerable rectal mucosa linked to ulcerative colitis despite clinical remission, and thus more susceptible to infection. In the NHP studies, preventive effect was observed after intravaginal challenges, while therapeutic effect was seen after intravenous or intrarectal challenges [10–12,14]. The differences in the mucosal barrier at site of infection might also be of importance. Another aspect is that the binding capacity of the gp120 V2 loop region to a4b7 receptors might be higher for certain HIV-1 subtypes, for example subtype C [28]. In conclusion, our findings indicate that vedolizumab cannot prevent HIV-1 infection nor block formation of a latent replication-competent reservoir. Ethical statement The individual provided informed consent under the approved protocol by the Danish National Committee on Health Research Ethics (reference number: M-2015-260-15) and the Danish Data Protection Agency (reference number: 1-16-02-424-15). Three individuals were included as controls, and provided informed consent under another approved protocol by the Danish National Committee on Health Research Ethics (reference number: M-2016-110-16) and the Danish Data Protection Agency (reference number: 1-16-02-546-15). Acknowledgements We thank Lene Svinth Jøhnke (Department of Infectious Diseases, Aarhus University Hospital, Palle Juul-Jensens Boulevard 45, 8200 Aarhus N, Denmark) for her technical assistance in the laboratory. Recruitment of the samples was performed by JDG. Quantitative viral outgrowth assay was performed by MHS. HIV-1 DNA and RNA quantification were performed by MHP. The experiments were conceived and designed by all the authors. Data were analysed by all the authors. The article was written by JDG and OS, with input from all authors. Conflicts of interest The authors do not have any commercial or other associations that might pose a conflict of interest.
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May 4, 2023
Narender Kumar + 6
Open Access