Human gut associated lymphoid tissues (GALT) play a key role in the acute phase of HIV infection. The propensity of HIV to replicate in these tissues however, is not fully understood. Access and migration of naïve and memory CD4+ T cells to these sites is mediated by interactions between integrin α4β7, expressed on CD4+ T cells, and MAdCAM, expressed on high endothelial venules. We report here that MAdCAM delivers a potent costimulatory signal to naïve and memory CD4+ T cells following ligation with α4β7. Such costimulation promotes high-levels of HIV replication. An anti-α4β7 mAb that prevents mucosal transmission of SIV blocks MAdCAM signaling through α4β7 and MAdCAM-dependent viral replication. MAdCAM costimulation of memory CD4+ T cells is sufficient to drive cellular proliferation and the up-regulation of CCR5, while naïve CD4+ T cells require both MAdCAM and retinoic acid to achieve the same response. The pairing of MAdCAM and retinoic acid is unique to the GALT, leading us to propose that HIV replication in these sites is facilitated by MAdCAM-α4β7 interactions. Moreover, complete inhibition of MAdCAM signaling by an anti-α4β7 mAb, an analogue of a clinically approved therapeutic (vedolizumab), highlights the potential of such agents to control acute HIV infection.

Acute HIV infection is characterized by rapid viral seeding of immunologic inductive sites in the gut followed by the severe depletion of gut CD4+T cells. Trafficking of α4β7-expressing lymphocytes to the gut is mediated by MAdCAM, the natural ligand of α4β7that is expressed on gut endothelial cells. MAdCAM signaling through α4β7costimulates CD4+T cells and promotes HIV replication. Similar to MAdCAM, the V2 domain of the gp120 HIV envelope protein binds to α4β7. In this study, we report that gp120 V2 shares with MAdCAM the capacity to signal through α4β7resulting in CD4+T cell activation and proliferation. As with MAdCAM-mediated costimulation, cellular activation induced by gp120 V2 is inhibited by anti-α4β7monoclonal antibodies (mAbs). It is also inhibited by anti-V2 domain antibodies including nonneutralizing mAbs that recognize an epitope in V2 that has been linked to reduced risk of acquisition in the RV144 vaccine trial. The capacity of the V2 domain of gp120 to mediate signaling through α4β7likely impacts early events in HIV infection. The capacity of nonneutralizing V2 antibodies to block this activity reveals a previously unrecognized mechanism whereby such antibodies might impact HIV transmission and pathogenesis.

Although naive T cells comprise about 90% of circulating and 20% of tissue restricted T cells, most studies on T cells emphasize effector, regulatory or memory functions. The consensus that all naive cells comprise a functionally monomorphic population is challenged by our recent findings. A redefinition of the naive T cell state shows that these cells are heterogeneous, with pre-programed differentiation trajectories. VISTA (V-domain Ig suppressor of T cell activation) is an immune checkpoint restricted to the hematopoietic compartment. Here, using single cell sequencing, we demonstrate unexpected loss of quiescence in VISTA deficient CD4+ T cells compared to Wild Type CD4+ T cells. The quiescence module, defined by Klf2, Klf6, Btg1, Btg2 expression, is lost in VISTA deficient mice. Conversely, there is an expansion of the stem-cell memory-like cluster, defined by Tcf7, Bcl2, and Il7r. This altered subset make-up due to VISTA deficiency demonstrates that naive T cell heterogeneity is tightly regulated. Consequently, we identified 5 subsets in healthy adult mice using single cell sequencing of naive CD4+ T cells. These include a quiescence cluster, memory-like cluster, TCR reactive cluster, IFN responsive cluster and T cell undifferentiated cluster. This heterogeneity is imprinted in the thymus, maintained in the periphery, and is not influenced by the TCR repertoire. Tracking the differentiation trajectory of these naive CD4+ T cells shows biased lineage commitment dependent on progenitor cluster identity. Thus, thymic imprinting and peripheral maintenance of varied naive T cell identities determines T cell fate. Supported by 5R01AR070760-05