Infection of CD127⁺ (interleukin-7 receptor⁺) CD4⁺ cells and overexpression of CTLA-4 are linked to loss of antigen-specific CD4 T cells during primary human immunodeficiency virus type 1 infection

We recently found that human immunodeficiency virus (HIV)-specific CD4 ⁺ T cells express coreceptor CCR5 and activation antigen CD38 during early primary HIV-1 infection (PHI) but then rapidly disappear from the circulation. This cell loss may be due to susceptibility to infection with HIV-1 but could also be due to inappropriate apoptosis, an expansion of T regulatory cells, trafficking out of the circulation, or dysfunction. We purified CD38 ⁺⁺⁺CD4⁺ T cells from peripheral blood mononuclear cells, measured their level of HIV-1 DNA by PCR, and found that about 10% of this population was infected. However, a small subset of HIV-specific CD4⁺ T cells also expressed CD127, a marker of long-term memory cells. Purified CD127⁺CD4⁺ lymphocytes contained fivefold more copies of HIV-1 DNA per cell than did CD127-negative CD4⁺ cells, suggesting preferential infection of long-term memory cells. We observed no apoptosis of antigen-specific CD4⁺ T cells in vitro and only a small increase in CD45RO⁺CD25⁺CD127dimCD4⁺ T regulatory cells during PHI. However, 40% of CCR5⁺CD38⁺⁺⁺ CD4⁺ T cells expressed gut-homing integrins, suggesting trafficking through gut-associated lymphoid tissue (GALT). Furthermore, 80% of HIV-specific CD4 ⁺ T cells expressed high levels of the negative regulator CTLA-4 in response to antigen stimulation in vitro, which was probably contributing to their inability to produce interleukin-2 and proliferate. Taken together, the loss of HIV-specific CD4⁺ T cells is associated with a combination of an infection of CCR5⁺ CD127⁺ memory CD4⁺ T cells, possibly in GALT, and a high expression of the inhibitory receptor CTLA-4.