An initial examination of the potential role of T-cell immunity in protection against feline immunodeficiency virus (FIV) infection

Abstract

The importance of vaccine-induced T-cell immunity in conferring protection with prototype and commercial FIV vaccines is still unclear. Current studies performed adoptive transfer of T cells from prototype FIV-vaccinated cats to partial-to-complete feline leukocyte antigen (FLA)-matched cats a day before either homologous FIVPet or heterologous-subtype pathogenic FIVFC1 challenge. Adoptive-transfer (A–T) conferred a protection rate of 87% (13 of 15, p<0.001) against FIVPet using FLA-matched T cells, whereas all 12 control cats were unprotected. Furthermore, A-T conferred protection rate of 50% (6 of 12, p<0.023) against FIVFC1 using FLA-matched T cells, whereas all 8 control cats were unprotected. Transfer of FLA-matched T and B cells demonstrated that T cells are needed to confer A-T protection. In addition, complete FLA-matching and addition of T-cell numbers >13×106 cells were required for A-T protection against FIVFC1 strain, reported to be a highly pathogenic virus resistant to vaccine-induced neutralizing-antibodies. The addition of FLA-matched B cells alone was not protective. The poor quality of the anti-FIV T-cell immunity induced by the vaccine likely contributed to the lack of protection in an FLA-matched recipient against FIVFC1. The quality of the immune response was determined by the presence of high mRNA levels of cytolysin (perforin) and cytotoxins (granzymes A, B, and H) and T helper-1 cytokines (interferon-γ [IFNγ] and IL2). Increased cytokine, cytolysin and cytotoxin production was detected in the donors which conferred protection in A-T studies. In addition, the CD4+ and CD8+ T-cell proliferation and/or IFNγ responses to FIV p24 and reverse transcriptase increased with each year in cats receiving 1X-3X vaccine boosts over 4 years. These studies demonstrate that anti-FIV T-cell immunity induced by vaccination with a dual-subtype FIV vaccine is essential for prophylactic protection against AIDS lentiviruses such as FIV and potentially HIV-1.

Lessons Learned in Developing a Commercial FIV Vaccine: The Immunity Required for an Effective HIV-1 Vaccine

“…The latter finding is noteworthy since prototype vaccine afforded 100% protection against FIV FC1 ( Table 1 , Study 4b). Since prototype vaccine-induced FIV-specific CTL and polyfunctional T-cell activities [ 61 , 62 ], the likelihood of vaccine-induced T-cell immunity playing a major role in protection against heterologous subtype viruses was a strong possibility.…”

“…Above studies, however, did not demonstrate whether the transferred vaccine-induced memory B cells were working in synergy with the transferred anti-FIV T cells. In recent studies, purified T and B cells from vaccinated AT donors were adoptively transferred to partial-to-compete MHC matched recipients ( Table 6 , Studies 4–7) [ 62 ]. In Study 4 that was based on MHC matching by mixed leukocyte reaction (MLR) ( Table 6 , Study 4), 3/4 (75%) AT recipients of MLR-matched immune T cells were protected, whereas none (0/4) of the recipients receiving either MLR-matched immune B cells or unrelated non-immune PBMC were protected.…”

“…This assumption was confirmed when purified T cells from prototype IWV-vaccinated cats showed significant AT protection in (6/9) recipients of completely MHC-matched immune T cells but no protection in the control recipients of non-immune/MHC-unmatched T cells, PBS, or without AT (0/8) ( p = 0.009). The authors concluded that the AT protection was mediated by vaccine-induced T cells based on the following three observations: (1) the AT preparation of the purified T cells contained minimal-to-nil contaminating B cells; (2) no vaccine-induced antibodies were detected before or at 3 wpc, the initial time when only one control cat developed FIV immunoblot Abs; and (3) AT protection required complete MHC matching, demonstrating MHC-restricted T-cell immunity instead of MHC-unrestricted Ab immunity [ 62 ]. Hence, vaccine-induced T-cell immunity is vital for the prophylactic protection afforded by the prototype IWV vaccine as well as perhaps by the Fel-O-Vax ® FIV vaccine.…”

“…The FIV-specific T-cell immunity generated by the prototype vaccine consisted of FIV-specific polyfunctional CD4 + T-cell activities (perforin, granzyme A, granzyme H, TNFα, IFNγ, IL-2, IL-4, IL-10), polyfunctional CD8 + T-cell activities (perforin, granzyme A, granzyme B, granzyme H, IFNγ, IL-2), CD4 + CTL activities (perforin, granzymes A and H), CD8 + CTL activities (perforin, granzymes A, B, H), and FIV-specific CD4 + and CD8 + T-cell proliferation responses [ 61 , 62 ]. A note of caution must be placed on IFNγ and possibly on TNFα.…”

Major Histocompatibility Complex Class I (FLA-E*01801) Molecular Structure in Domestic Cats Demonstrates Species-Specific Characteristics in Presenting Viral Antigen Peptides

“…Studies have shown that major histocompatibility complex class I (MHC-I) molecules are critical for activating cytotoxic T lymphocytes (CTLs) to control HIV infection (9)(10)(11)(12). CD8 ϩ T-cell proliferation responses control FIV infection, and MHC-I molecule expression on microglial cells is transiently upregulated at the onset of FIV reproduction (13)(14)(15)(16)(17). Elevated MHC expression can also be observed in HIV and simian immunodeficiency virus (SIV) (18,19).…”