Effect of lentivirus encoding HIV-1 Nef-U3 shRNA on the function of HIV-specific memory CD4(+) T cells in patients with chronic HIV-1 infection.

Objective: To determine whether HIV-1-specific CD4 + T cells with proliferative capacity are eliminated or functionally defective because of HIV-1 reactivation. Design: The loss of proliferative capacity by HIV-1-specific CD4 + T cells compromises the host's ability to maintain protective immunity against HIV-1 and is a hallmark of disease progression. We used a recombinant lentivirus encoding an HIV-specific short hairpin (sh)RNA (Lenti shNef366) with known HIV-inhibitory activity to analyze the functional state of HIV-1-specific CD4 + T cells. Methods: T lymphocytes from untreated chronically HIV-infected patients with documented high viral loads (above 10000 HIV-RNA) were transduced with Lenti shNef366, and the proliferation, differentiation, and cytokine production of HIV-specific CD4 + T cells were analyzed. Results: Lenti shNef366 restored the proliferation of HIV p24-specific CD4 + T cells in eight of 12 patients tested, affecting primarily CD27 + or CD28 + CD4 + T cells that were at an intermediate stage of differentiation. Although cytokine production by CD4 + T cells remained poor after transduction with Lenti shNef366, improved proliferative capacity was associated with significantly higher levels of expression of CD107a. Conclusion: In chronic stages of HIV-1 infection with high levels of HIV replication, proliferation-competent HIV-specific CD4 + T cells in an intermediate stage of differentiation are present but are exquisitely and strongly impaired. Blocking HIV reactivation may restore a key functional property of memory T cells.