α
4β
7 is closely associated with CD4, the HIV-1 entry receptor, on CD4
+ T cells in GALT. The interaction between gp120 and α
4β
7 triggers a signal, that is not yet fully defined [
14,
16]; however, it has been reported that the gp120-mediated signal transduction in several cellular subsets impacts viral replication. In this regard, a number of reports conclude that HIV-1 gp120 mediates signals that facilitate viral replication [
32‐
36]. In this regard, HIV-1 gp120 is a unique ligand that can mediate signals in a near simultaneous manner through CD4, a chemokine receptor and α
4β
7. The first gp120-mediated signal to be reported involved a protein tyrosine kinase. In response to gp120 treatment, CD4
+ T-cells rapidly phosphorylate p56lck, which then dissociates from the cytoplasmic domain of CD4 [
37]. The identification of chemokine receptors as HIV coreceptors opened up new questions regarding the role of chemokine receptor signaling in viral infection and pathogenesis [
3,
4,
38]. gp120 was shown to trigger rapid calcium fluxes by engaging CCR5 [
39]. There is some evidence suggesting that the differential capacity of genetically distinct gp120s to signal correlates with their capacity to facilitate replication [
32]. HIV-1 gp120 induces phosphorylation of several proteins, many involved in cytoskeleton rearrangement, including Pyk2 [
40] and FAK [
41]. Binding of gp120 to both CCR5 and CXCR4, activates several intracellular signaling cascades, mimicking the natural ligands of the chemokine receptors. HIV-1 gp120 has also been shown to trigger signaling in resting cells. In resting cells gp120 mediates the nuclear translocation of the transcription factor NFAT that can enhance viral transcription by binding to NFAT recognition sites on the HIV long terminal repeat (LTR) [
33]. gp120 can mediate chemotaxis, actin cytoskeleton rearrangement [
42] and the activation of an actin depolymerization factor, cofilin, in resting cells [
43]. The density of cell surface CCR5 determines post-entry efficiency of replication of an R5 virus [
44] and in unstimulated primary T cells, CCR5 signaling supports HIV-1 infection [
45]. Moreover, gp120-CCR5 signaling can induce a distinct gene expression profile in primary cells and a signaling cascade, associated with cellular activation, that favors viral replication in non-proliferating target cells [
33,
34]. As noted above, R5 viruses dominate the early stages of infection, largely infecting activated memory CD4
+ T cells in the draining lymphoid tissue, particularly the GALT [
6,
46‐
48]. Both activated and “ostensibly resting” CD4
+ T cells are involved in the early stages of infection in the GALT [
6]. The capacity of gp120 to trigger signals that promote viral replication in both activated and resting cells, may facilitate infection. This activity may be particularly important during mucosal transmission. Studies of transmission in an SIV macaque model [
6,
47,
49] indicate that the first cells infected are not fully activated. It is in these cells that gp120 signals may provide the necessary metabolic stimulus to achieve productive infection. Although our knowledge of gp120-α
4β
7 signaling is incomplete, we can speculate that it is in this setting that gp120-α
4β
7 signal transduction may play an important role and may be a major factor in the transmission of HIV at the mucosal surface.