Differential Cell Tropism of Feline Immunodeficiency Virus Molecular Clones In Vivo

Abstract

Independent studies have demonstrated different cell tropisms for molecular clones of feline immunodeficiency virus (FIV). In this report, we examined three clones, FIV-pF34, FIV-14, and FIV-pPPR, for replication in Crandell feline kidney (CrFK) cells, feline peripheral blood mononuclear cells (PBMC), and feline macrophage cultures. Importantly, cell tropism for these three clones was also examined in vivo. FIV-pF34 replication was efficient in CrFK cells but severely restricted in PBMC, whereas replication of FIV-pPPR was vigorous in PBMC but severely restricted in CrFK cells. FIV-14 replication was productive in both CrFK cells and PBMC. Interestingly, all three molecular clones replicated with similar efficiencies in primary feline monocyte-derived macrophages. In vivo, FIV-pF34 proved least efficient for establishing persistent infection, and proviral DNA when detectable, was localized predominately to nonlymphoid cell populations (macrophages). FIV-pPPR proved most efficient for induction of a persistent viremia in vivo, and proviral DNA was localized predominately in CD4+ and CD8+ lymphocyte subsets. FIV-14 inoculation of cats resulted in an infection characterized by seroconversion and localization of proviral DNA in CD4+ lymphocytes only. Results of this study on diverse FIV molecular clones revealed that in vitro replication efficiency of an FIV isolate in PBMC directly correlated with replication efficiency in vivo, whereas proficiency for replication in macrophages in vitro was not predictive for replication potential in vivo. Also, infection of both CD4+ and CD8+ lymphocyte subsets was associated with higher virus load in vivo. Results of the studies on these three FIV clones, which exhibited differential cell tropism, indicated a correlation between in vitro and in vivo cell tropism and virus replication.

FIV as a Model for HIV: An Overview

“…[4][5][6][7]10,11,21,[190][191][192][193][194] Early studies revealed that targets for FIV in vitro and in vivo included CD4 T-cells, macrophages, dendritic cells, microglia, and astrocytes similar to those for HIV infection in humans, but also included CD8 T-cells, and B-cells (Table II). 4,18,23,186,[195][196][197][198][199][200][201][202][203][204][205][206][207][208][209][210] Early reports also demonstrated that continuous passage of particular FIV isolates in cell culture selected for virus variants capable of replication in feline adherent cell lines, including Crandell feline kidney cells (CrFK) and G355-5 cells, as well as established feline interleukin (IL)-2-independent T-cell lines. 2,25,42,211 Importantly, experimental inoculation studies in cats revealed that cell culture-adapted viruses represented a particular subset of viral variants that exhibited reduced replication and virulence in vivo.…”

“…2,25,42,211 Importantly, experimental inoculation studies in cats revealed that cell culture-adapted viruses represented a particular subset of viral variants that exhibited reduced replication and virulence in vivo. 111,192,197,212 FIV infection of feline CD4-negative adherent cell lines provided indirect evidence that FIV differs with HIV-1 and does not utilize CD4 as a primary receptor. In addition, direct evidence refuting FIV usage of CD4 was provided by studies revealing an absence of virus infectivity for nonlymphoid cells expressing feline CD4.…”

“…Replication phenotypes in vitro and in vivo clearly distinguish cell culture-adapted FIV isolates from primary isolates. Most primary FIV isolates examined to date require both CD134 and CXCR4 for infection and exhibit a cell tropism restricted to primary feline PBMC, selected IL-2dependent T-cell lines, and possibly primary macrophages and astrocytes, 2,42,61,[196][197][198][199]238 although testing for tropism to the latter two cell types has been infrequently reported (Table II). In contrast, FIV variants passaged in vitro utilize CXCR4 solely for efficient infection and replication in feline adherent cell lines including CrFK cells, 33,36,[218][219][220][221]223,224 as well as feline PBMC, IL-2-dependent and independent feline T-cell lines and macrophages.…”

“…In contrast, FIV variants passaged in vitro utilize CXCR4 solely for efficient infection and replication in feline adherent cell lines including CrFK cells, 33,36,[218][219][220][221]223,224 as well as feline PBMC, IL-2-dependent and independent feline T-cell lines and macrophages. 2,42,61,187,190,197,211,[239][240][241][242] These highly passaged isolates, however, exhibit severely restricted virus replication and pathogenicity in vivo as discussed above. 111,192,197,212 Multiple studies using FIV molecular clones have mapped Env as a major determinant that expands cell tropism to include feline adherent cell lines including CrFK cells and G355-5 cells (feline glial cell line), as well as feline astrocytes (Table II).…”

“…2,42,61,187,190,197,211,[239][240][241][242] These highly passaged isolates, however, exhibit severely restricted virus replication and pathogenicity in vivo as discussed above. 111,192,197,212 Multiple studies using FIV molecular clones have mapped Env as a major determinant that expands cell tropism to include feline adherent cell lines including CrFK cells and G355-5 cells (feline glial cell line), as well as feline astrocytes (Table II). 33,212,223,[243][244][245][246][247][248] Similar to the V3 domain of HIV-1 Env, the V3 domain of the FIV SU encodes specific tropism determinants 212,223,243,244,[249][250][251] in addition to important neutralizing antibody epitopes ( Figure 3).…”