Partial Regulatory T Cell Depletion Prior to Acute Feline Immunodeficiency Virus Infection Does Not Alter Disease Pathogenesis

Abstract

Feline immunodeficiency virus (FIV) infection in cats follows a disease course similar to HIV-1, including a short acute phase characterized by high viremia, and a prolonged asymptomatic phase characterized by low viremia and generalized immune dysfunction. CD4+CD25hiFoxP3+ immunosuppressive regulatory T (Treg) cells have been implicated as a possible cause of immune dysfunction during FIV and HIV-1 infection, as they are capable of modulating virus-specific and inflammatory immune responses. Additionally, the immunosuppressive capacity of feline Treg cells has been shown to be increased during FIV infection. We have previously shown that transient in vivo Treg cell depletion during asymptomatic FIV infection reveals FIV-specific immune responses suppressed by Treg cells. In this study, we sought to determine the immunological influence of Treg cells during acute FIV infection. We asked whether Treg cell depletion prior to infection with the highly pathogenic molecular clone FIV-C36 in cats could alter FIV pathogenesis. We report here that partial Treg cell depletion prior to FIV infection does not significantly change provirus, viremia, or CD4+ T cell levels in blood and lymphoid tissues during the acute phase of disease. The effects of anti-CD25 mAb treatment are truncated in cats acutely infected with FIV-C36 as compared to chronically infected cats or FIV-naïve cats, as Treg cell levels were heightened in all treatment groups included in the study within two weeks post-FIV infection. Our findings suggest that the influence of Treg cell suppression during FIV pathogenesis is most prominent after Treg cells are activated in the environment of established FIV infection.

Control of regulatory T cells is necessary for vaccine-like effects of antiviral immunotherapy by monoclonal antibodies

“…on March 28, 2019. by guest www.bloodjournal.org From but had no effect on the antiviral humoral response. 28 Along with our present results, these data indicate that, despite possible species/system differences, the in vivo manipulation of Tregs may be used to strengthen immunotherapeutical approaches aiming at containing viral propagation and counteracting disease progression. 20,22,24 The most striking observation of the present study was that the mAb-based immunotherapy rapidly inhibited the induction of Tregs normally associated with FrCas E infection.…”

“…Mice were infected perinatally and rechallenged at 8 weeks of age before analysis of both types of responses ( Figure 3A) in the presence or absence ( Figure 3B) of Tregs, which were depleted via repeated IP administration of an anti-CD25 mAb (96% efficiency), as described previously. 28 The anti-FrCas E humoral response was 5-fold more elevated in Treg-depleted mice compared with control animals ( Figure 3C), was predominantly of the IgG2a isotype, and was as neutralizing as that found in infected/667-treated mice of the same age (not shown). Treg depletion restored humoral immunity in both infected/672-treated and infected/667-F(abЈ) 2 -treated mice with endogenous IgG levels comparable to those observed in infected/667-treated mice (not shown).…”

“…28 Infected/nontreated mice received 4 injections (25 g each) of this mAb on days 2, 4, 7, and 9 after challenge. Depletion of Tregs was monitored by flow cytometry of CD25 high FoxP3 ϩ CD4 ϩ T cells.…”

Regulatory T Cells in Infection

“…An important retroviral pathogen is feline immunodeficiency virus (FIV), which expands functionally suppressive CD25 þ T cells in chronically-infected cats (Vahlenkamp et al, 2004). In vivo depletion of CD25 þ T cells in infected cats resulted in transient increases in both anti-viral and bystander responses (Mikkelsen et al, 2010), although depletion prior to infection did not alter the course of disease (Mikkelsen et al, 2011). In human retrovirus infection, Treg activity is largely inferred from phenotypic analysis of ex vivo lymphocytes, with reports showing a positive correlation between viral load and FOXP3 þ Treg numbers (Andersson et al, 2005;Nilsson et al, 2006;Tsunemi et al, 2005).…”

Host immune responses that promote initial HIV spread

“…Though it has been observed that Treg cells from hosts infected with HIV and FIV (feline immunodeficiency virus) suppress antiviral responses during the chronic stage of infection [1, 33, 45], a recent study in FIV shows that Treg cell depletion of approximately 78% prior to infection does not significantly impact viral load or CD4+ T cell levels in tissues [44]. When simulations were carried out with reduced R m (0) values from 10 7 mL −1 to 10 5 mL −1 and then to 10 −10 mL −1 , there was no change in the time of viral peak in either tissue site and < 8% increase in peak vRNA values in the GLN and ≤ 13.5% increase in peak vRNA value in the LP, in accordance with these FIV results.…”