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.


METHODS
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 10 000 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.


CONCLUSIONS
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.
Yamamoto
Takuya
T
Department of Immunology, National Institute of Infectious Diseases, Shinjuku-ku, Japan.
Samri
Assia
A
Marcelin
Anne-Geneviève
AG
Mitsuki
Yu-ya
YY
Vincent
Calvez
C
Autran
Brigitte
B
Tsunetsugu-Yokota
Yasuko
Y
D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000502:physiology*; D002460:Cell Line; D049109:Cell Proliferation; D015658:HIV Infections / Q000235:genetics / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D016086:Lentivirus / Q000472:pathogenicity*; D008213:Lymphocyte Activation / Q000502:physiology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D034741:RNA, Small Interfering / Q000276:immunology; D019562:Viral Load; D014779:Virus Replication; D054311:nef Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology*
D019402:Macrophage Inflammatory Proteins; D034741:RNA, Small Interfering; D054311:nef Gene Products, Human Immunodeficiency Virus