@article{joshi_garg_tompkins_tompkins_2005, title={Different thresholds of T cell activation regulate FIV infection of CD4(+)CD25(+) and CD4(+)CD25(-) cells}, volume={335}, ISSN={["0042-6822"]}, DOI={10.1016/j.virol.2005.02.016}, abstractNote={Cellular activation plays an important role in retroviral replication. Previously, we have shown that CD4+CD25+ T cells by the virtue of their partially activated phenotype represent ideal candidates for a productive feline immunodeficiency virus (FIV) infection. In the present study, we extended our previous observations with regard to FIV replication in CD4+CD25+ and CD4+CD25− cells under different stimulation conditions. Both CD4+CD25+ and CD4+CD25− cells remain latently infected in the absence of IL-2 or concanvalinA (ConA), respectively; harboring a replication competent provirus capable of reactivation several days post-infection. While CD4+CD25+ cells require low levels of exogenous IL-2 and virus inputs for an efficient FIV replication, CD4+CD25− T cells can only be productively infected in the presence of either high concentrations of IL-2 or high virus titers, even in the absence of mitogenic stimulation. Interestingly, while high virus input activates CD4+CD25− cells to replicate FIV, it induces apoptosis in a high percentage of CD4+CD25+ T cells. High IL-2 concentrations but not high virus inputs lead to surface upregulation of CD25 and significant cellular proliferation in CD4+CD25− cells. These results suggest that CD4+CD25+ and CD4+CD25− T cells have different activation requirements which can be modulated by both viral and cytokine stimuli to reach threshold activation levels in order to harbor a productive FIV infection. This holds implications in vivo for CD4+CD25+ and CD4+CD25− cells to serve as potential reservoirs of a productive and latent FIV infection.}, number={2}, journal={VIROLOGY}, author={Joshi, A and Garg, H and Tompkins, MB and Tompkins, WA}, year={2005}, month={May}, pages={212–221} }
 @article{joshi_garg_tompkins_tompkins_2005, title={Preferential feline immunodeficiency virus (FIV) infection of CD4(+) CD25(+) T-regulatory cells correlates both with surface expression of CXCR4 and activation of FIV long terminal repeat binding cellular transcriptional factors}, volume={79}, ISSN={["0022-538X"]}, DOI={10.1128/JVI.79.8.4965-4976.2005}, abstractNote={ABSTRACT}, number={8}, journal={JOURNAL OF VIROLOGY}, author={Joshi, A and Garg, H and Tompkins, MB and Tompkins, WA}, year={2005}, month={Apr}, pages={4965–4976} }
 @article{garg_joshi_tompkins_2004, title={Feline immunodeficiency virus envelope glycoprotein mediates apoptosis in activated PBMC by a mechanism dependent on gp41 function}, volume={330}, ISSN={["0042-6822"]}, DOI={10.1016/j.virol.2004.10.007}, abstractNote={Feline Immunodeficiency Virus (FIV) is a lentivirus that causes immunodeficiency in cats, which parallels HIV-1-induced immunodeficiency in humans. It has been established that HIV envelope (Env) glycoprotein mediates T cell loss via a mechanism that requires CXCR4 binding. The Env glycoprotein of FIV, similar to HIV, requires CXCR4 binding for viral entry, as well as inducing membrane fusion leading to syncytia formation. However, the role of FIV Env in T cell loss and the molecular mechanisms governing this process have not been elucidated. We studied the role of Env glycoprotein in FIV-mediated T cell apoptosis in an in vitro model. Our studies demonstrate that membrane-expressed FIV Env induces apoptosis in activated feline peripheral blood mononuclear cells (PBMC) by a mechanism that requires CXCR4 binding, as the process was inhibited by CXCR4 antagonist AMD3100 in a dose-dependent manner. Interestingly, studies regarding the role of CD134, the recently identified primary receptor of FIV, suggest that binding to CD134 may not be important for induction of apoptosis in PBMC. However, inhibiting Env-mediated fusion post CXCR4 binding by FIV gp41-specific fusion inhibitor also inhibited apoptosis. Under similar conditions, a fusion-defective gp41 mutant was unable to induce apoptosis in activated PBMC. Our findings are the first report suggesting the potential of FIV Env to mediate apoptosis in bystander cells by a process that is dependent on gp41 function.}, number={2}, journal={VIROLOGY}, author={Garg, H and Joshi, A and Tompkins, WA}, year={2004}, month={Dec}, pages={424–436} }
 @article{garg_fuller_tompkins_2004, title={Mechanism of feline immunodeficiency virus envelope glycoprotein-mediated fusion}, volume={321}, ISSN={["0042-6822"]}, DOI={10.1016/j.virol.2004.01.006}, abstractNote={Feline immunodeficiency virus (FIV) shares remarkable homology to primate lentiviruses, human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV). The process of lentiviral env glycoprotein-mediated fusion of membranes is essential for viral entry and syncytia formation. A detailed understanding of this phenomenon has helped identify new targets for antiviral drug development. Using a model based on syncytia formation between FIV env-expressing cells and a feline CD4+ T cell line we have studied the mechanism of FIV env-mediated fusion. Using this model we show that FIV env-mediated fusion mechanism and kinetics are similar to HIV env. Syncytia formation could be blocked by CXCR4 antagonist AMD3100, establishing the importance of this receptor in FIV gp120 binding. Interestingly, CXCR4 alone was not sufficient to allow fusion by a primary isolate of FIV, as env glycoprotein from FIV-NCSU1 failed to induce syncytia in several feline cell lines expressing CXCR4. Syncytia formation could be inhibited at a post-CXCR4 binding step by synthetic peptide T1971, which inhibits interaction of heptad repeat regions of gp41 and formation of the hairpin structure. Finally, using site-directed mutagenesis, we also show that a conserved tryptophan-rich region in the membrane proximal ectodomain of gp41 is critical for fusion, possibly at steps post hairpin structure formation.}, number={2}, journal={VIROLOGY}, author={Garg, H and Fuller, FJ and Tompkins, WAF}, year={2004}, month={Apr}, pages={274–286} }
 @article{joshi_vahlenkamp_garg_tompkins_tompkins_2004, title={Preferential replication of FIV in activated CD4(+)CD25(+)T cells independent of cellular proliferation}, volume={321}, ISSN={["0042-6822"]}, DOI={10.1016/j.virol.2004.01.014}, abstractNote={Studies attempting to identify reservoirs of HIV-1 latency have documented that the virus persists as both a latent and productive infection in subsets of CD4+ cells. Reports regarding establishment of a stable HIV-1 infection in quiescent T cells in vitro, however, are controversial. In the present study, we investigated the susceptibility of naive and activated CD4+ cell subsets (distinguished by differential expression of CD25) to feline immunodeficiency virus (FIV) infection, their ability to replicate the virus, and potentially act as a reservoir for virus persistence in infected animals. While both CD4+CD25+ and CD4+CD25− cells are susceptible to FIV infection in vitro and in vivo, only CD4+CD25+ cells produce infectious virions when cultured with interleukin-2 (IL-2). Latently infected CD4+CD25− cells produce infectious virions following ConcanvalinA (ConA) stimulation, which correlates with upregulated surface expression of CD25. In contrast to CD4+CD25− cells, CD4+CD25+ cells remain unresponsive to mitogen stimulation and are relatively resistant to apoptosis whether or not infected with FIV. The ability of CD4+CD25+ cells to replicate FIV efficiently in the presence of IL-2 but remain anergic and unresponsive to apoptotic signaling suggests that these cells may provide a reservoir of productive FIV infection. On the contrary, CD4+CD25− cells seem to establish as latent viral reservoirs capable of being reactivated after stimulation.}, number={2}, journal={VIROLOGY}, author={Joshi, A and Vahlenkamp, TW and Garg, H and Tompkins, WAF and Tompkins, MB}, year={2004}, month={Apr}, pages={307–322} }