Acute mucosal pathogenesis of feline immunodeficiency virus is independent of viral dose in vaginally infected cats

Abstract

BackgroundThe mucosal pathogenesis of HIV has been shown to be an important feature of infection and disease progression. HIV-1 infection causes depletion of intestinal lamina propria CD4+ T cells (LPL), therefore, intestinal CD4+ T cell preservation may be a useful correlate of protection in evaluating vaccine candidates. Vaccine studies employing the cat/FIV and macaque/SIV models frequently use high doses of parenterally administered challenge virus to ensure high plasma viremia in control animals. However, it is unclear if loss of mucosal T cells would occur regardless of initial viral inoculum dose. The objective of this study was to determine the acute effect of viral dose on mucosal leukocytes and associated innate and adaptive immune responses.ResultsCats were vaginally inoculated with a high, middle or low dose of cell-associated and cell-free FIV. PBMC, serum and plasma were assessed every two weeks with tissues assessed eight weeks following infection. We found that irrespective of mucosally administered viral dose, FIV infection was induced in all cats. However, viremia was present in only half of the cats, and viral dose was unrelated to the development of viremia. Importantly, regardless of viral dose, all cats experienced significant losses of intestinal CD4+ LPL and CD8+ intraepithelial lymphocytes (IEL). Innate immune responses by CD56+CD3- NK cells correlated with aviremia and apparent occult infection but did not protect mucosal T cells. CD4+ and CD8+ T cells in viremic cats were more likely to produce cytokines in response to Gag stimulation, whereas aviremic cats T cells tended to produce cytokines in response to Env stimulation. However, while cell-mediated immune responses in aviremic cats may have helped reduce viral replication, they could not be correlated to the levels of viremia. Robust production of anti-FIV antibodies was positively correlated with the magnitude of viremia.ConclusionsOur results indicate that mucosal immune pathogenesis could be used as a rapid indicator of vaccine success or failure when combined with a physiologically relevant low dose mucosal challenge. We also show that innate immune responses may play an important role in controlling viral replication following acute mucosal infection, which has not been previously identified.

Feline Leukemia Virus (FeLV) Disease Outcomes in a Domestic Cat Breeding Colony: Relationship to Endogenous FeLV and Other Chronic Viral Infections

“…of enFeLV copies, while others have used the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) gene as a reference (10). Multiple copies of GAPDH pseudogene sequences have been found in the feline genome, indicating that GAPDH may not be the best reference gene for estimating cell copy number (42); in contrast, CCR5 is present as a diploid gene (2 copies/cell [43]). These differences likely account for the higher number of enFeLV copies than that estimated by fluorescent in situ hybridization (FISH) (9) or qPCR detecting the U3 region in the enFeLV LTR (the same region as detected in this study) and the enFeLV env gene (10).…”

Suppression of NK cells and regulatory T lymphocytes in cats naturally infected with feline infectious peritonitis virus

“…NK cell lymphopenia is also seen during other viral infections, both human and feline. Explanations for this lymphopenia vary from virus-induced NK cell apoptosis to sequestration and altered trafficking of NK cells (Denney et al, 2010) (He et al, 2005;Mao et al, 2009;Howard et al, 2010). The Treg depletion that is seen during FIPV infection, somewhat contrasts other viral infections, which are nearly always associated with either an increase in Treg frequency or function (Keynan et al, 2008).…”

“…Since both NK cells and Tregs represent important players in CMI and given their crucial role in the development of adaptive immune responses (Kos and Engleman, 1996;Robbins et al, 2007), it is worth to dissect their roles during a FIPV infection. A strong innate NK cellmediated immune response is often responsible for an acute viral control, exemplified during FIV and cytomegalovirus infections (Zingoni et al, 2005;Howard et al, 2010), while Treg enhancement suppresses anti-viral responses (Li et al, 2008). NK cell deficiencies regularly lead to severe recurrent viral diseases (Wood et al, 2011) and Treg deficiencies lead to damaging pathology (Luhn et al, 2007).…”

Blocking CXCL9 Decreases HIV-1 Replication and Enhances the Activity of Prophylactic Antiretrovirals in Human Cervical Tissues

“…This process however also provides an immunological microenvironment that drives viral replication and disease progression in HIV-1–infected individuals. 1 – 3 …”