Antiviral Therapy Reduces Viral Burden but Does Not Prevent Thymic Involution in Young Cats Infected with Feline Immunodeficiency Virus

Abstract

The thymus is a major target organ in human immunodeficiency virus type 1 (HIV-1)-infected children and feline immunodeficiency virus (FIV)-infected young cats (G.A. The purpose of this study was to evaluate the effect of drug-induced reduction of viral burden in the thymus on virusmediated thymic involution and peripheral blood CD4 decline using FIV-infected cats as a model for pediatric HIV-1 infection. Eight-week-old cats were randomly assigned to uninfected, saline-treated; uninfected, ZDVtreated; FIV-infected, saline-treated; and FIV-infected, ZDV-treated groups. Parameters measured included blood lymphocyte numbers, viral load in blood and thymic tissue, and thymic histopathology. While the viral burden was significantly reduced by ZDV monotherapy in peripheral blood lymphocytes, plasma, and thymus, thymic lesions were similar for the treated and untreated FIV-infected cats. Further, markedly lowering the viral burden did not increase blood CD4 lymphocyte numbers or prevent their decline. The data suggest that an inflammatory process continued in spite of reduced virus replication. These observations imply that reducing virus load and limiting thymic inflammation are separate factors that must be addressed when considering therapeutic strategies aimed at preserving thymic function.

Thymic Lesions in Cats Infected with a Pathogenic Molecular Clone or an ORF-A/2 -Deficient Molecular Clone of Feline Immunodeficiency Virus

“…These follicles are located within the perivascular spaces, areas outside the epithelial network that can be demonstrated histologically by a lack of cytokeratin staining (Fig. 4A) (10,20,23). In the present study, JSY3 and JSY3⌬ORF-A/2 produced this lesion with similar incidence and severity despite a marked difference in the level of productive infection.…”

“…In the present study, JSY3 and JSY3⌬ORF-A/2 produced this lesion with similar incidence and severity despite a marked difference in the level of productive infection. Similarly, Hayes et al (10) reported that follicles within the perivascular spaces persist even after virus replication is reduced by antiviral therapy. It is likely, therefore, that other mechanisms, such as altered cytokine secretion or unique cell trafficking, may contribute to formation and persistence of thymic lymphoid follicles.…”

“…Viral replication in the SCID-hu mouse system was shown to be highly correlated to depletion of thymus single-positive CD4 ϩ CD8 Ϫ cells, and it was shown that a minimum level of replication must be achieved before pathogenesis is evident. Attempts to tie virus replication to thymic involution by modulating replication using antiviral therapy during FIV infection of cats have been unsuccessful (10). In fact, thymotropic agents, such as insulin-like growth factor 1, have been shown to ameliorate thymic lesions and cause regeneration of the thymic cortex in FIV-infected cats, with little to no change in rates of viral replication (35).…”

Lentivirus-Specific Cytotoxic T-Lymphocyte Responses Are Rapidly Lost in Thymectomized Cats Infected with Feline Immunodeficiency Virus

“…FIV challenge consisted of 1,000 50% tissue culture infective dose units of the Maryland isolate of FIV (FIV-MD) propagated in primary peripheral blood mononuclear cell (PBMC) culture (9).…”

“…A major complication of lentivirus infection is the accelerated thymic involution observed in HIV-1-infected humans and FIV-infected cats (24) with the associated loss of thymic function and subsequent CD4 ϩ T-lymphocyte depletion (5,24). Thymic changes are most pronounced in pediatric subjects where HIV-1 (18,21) and FIV (9,24) infections cause structural damage to the thymus, manifested by depletion of CD4 ϩ…”