CD4+ T cells residing in gut associated lymphoid tissue (GALT) are predominant targets of HIV-1 during the acute phase of infection. CD4+ T cells expressing a high level of gut-homing receptor integrin α4β7 are more susceptible to productive infection. It has been reported that HIV-1 envelop protein gp120 can bind to the activated integrin α4β7, which has an important role in HIV infection. However, whether and how the gp120-α4β7 binding is regulated by physiological stimuli like chemokines remains obscure.
In a recent study published in Signal Transduction and Targeted Therapy on July 16, 2021, a research team led by Dr. CHEN JianFeng from Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, has demonstrated that distinct gut-expressing chemokines selectively trigger α4β7-gp120 binding by inducing conformer-specific activation of α4β7. They found that gp120 was able to bind certain α4β7 active conformers induced by CCL19 and CCL25 through an interaction between Asp in LDI motif in gp120 V2-loop and the metal ion-dependent adhesion site (MIDAS) in integrin β7 I domain. However, gp120 failed to bind to α4β7 active conformers with less extended conformations triggered by CCL4, CCL5 and CCL10. The binding of gp120 to α4β7 on T cells activated multiple intracellular pathways, including FAK, Src, ERK, p38, Akt pathways which have important roles in HIV-1 infection and virus replication. Thus, only certain chemokines have the capacity to promote HIV-1 infection by inducing gp120 binding to α4β7 on T cells and the consequent activation of integrin downstream signaling during HIV-1 infection. The infection of T cells by HIV could be dependent on the chemokine receptor types on different T cells and the chemokine expression patterns in the tissue. Specific chemokine receptors might be potential drug target for treatment of HIV infection.