HIV-1 binding to CD4 on CD4+CD25+ regulatory T cells enhances their suppressive function and induces them to home to, and accumulate in, peripheral and mucosal lymphoid tissues: an additional mechanism of immunosuppression

The establishment and persistence of many chronic infections have been demonstrated to depend on restraint of the vigor of the anti-microbial immune responses by CD4(+)CD25(+) regulatory T (Treg) cells. In HIV-infected individuals, Treg cells suppress both HIV-specific and general CD4(+) and CD8(+) T cell responses. Increases of CD4(+)CD25(+) Treg cell function during viral infections might be mediated by host-derived pro-inflammatory molecules or directly by viral infection or binding. We examined the effect HIV has upon binding to CD4(+)CD25(+) Treg cells by exposing human purified CD4(+)CD25(+) T cells from healthy donors to HIV-1 in vitro and assessing their Treg-associated functional marker profile and suppressive activities. We found that HIV-1 binding increased their suppressor activities by 2- to 5-fold, which was accompanied by enhanced expression of Treg-associated functional markers sCTLA-4, glucocorticoid-induced tumor necrosis factor receptor and FoxP3. Moreover, HIV-1 binding extended the survival of CD4(+)CD25(+) Treg cells and up-regulated the expression of homing receptors CD62L and integrin alpha 4 beta 7, which in turn would result in Treg cells migrating more rapidly to the peripheral lymph nodes and mucosal lymphoid tissues where anti-HIV immune responses are occurring. Importantly, CD4(+)CD25(+) Treg cells exposed to HIV were not susceptible to homing-induced apoptosis like are other resting CD4(+) cells following HIV-1 binding. We show that CD4(+)CD25(+) Treg cells respond directly to HIV-1 itself through HIV gp120 interactions with CD4 molecules. Collectively, our findings explain a mechanism that contributes to the abnormal accumulation of intensified Treg cells in lymphoid and mucosal tissues in HIV patients, resulting in impairment of immune responses which would greatly help HIV persistence.