HIV-1 infection impairs cell cycle progression of CD4(+) T cells without affecting early activation responses.
Failure of CD4(+) T cells to proliferate in response to antigenic stimulation is a characteristic of HIV infection. Analysis of the proliferation defect has been hampered by an inability to identify CD4(+) cells with T cell receptor specificity for antigen. To focus only on cells that had been stimulated through the T cell receptor, CD4(+) T cells were stimulated with an anti-Vbeta3 Ab that activates approximately 3-5% of peripheral blood T cells. This approach revealed proliferation defects in cells from HIV-infected patients that were not appreciated using anti-CD3 Ab stimulation and provided the capacity to examine responses on a single cell basis. After anti-Vbeta3 Ab stimulation, CD4(+)Vbeta3(+) cells from HIV-infected patients demonstrated defects in expression of cell cycle-associated proteins, D-type cyclins, and cyclin A. However, the expression of early activation markers, CD69 and CD25, was not significantly impaired in cells from most patients. Thus, CD4(+) T cell proliferation failure in HIV disease is characterized by dysregulated activation that precludes cell cycle progression. This proliferation defect was most apparent in patients with diminished CD4(+) T cell numbers and higher plasma HIV RNA levels. CD4(+) T cell proliferation failure may be a key determinant of immune impairment in HIV disease.
Sieg
S F
SF
Department of Medicine, Division of Infectious Diseases, Center for AIDS Research, Case Western Reserve University, Cleveland, Ohio, USA.
Harding
C V
CV
Lederman
M M
MM
D000906:Antibodies / Q000276:immunology; D015703:Antigens, CD / Q000096:biosynthesis; D000945:Antigens, Differentiation, T-Lymphocyte / Q000096:biosynthesis; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology; D002453:Cell Cycle; D002455:Cell Division; D002478:Cells, Cultured; D056741:Cyclin D; D016213:Cyclins / Q000096:biosynthesis; D005434:Flow Cytometry; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000254:growth & development; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000276:immunology; D037181:Lectins, C-Type; D008213:Lymphocyte Activation; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D014779:Virus Replication; D000099192:CD69 Antigens
D000906:Antibodies; D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D056741:Cyclin D; D016213:Cyclins; D007135:Immunoglobulin Variable Region; D037181:Lectins, C-Type; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015375:Receptors, Interleukin-2; D000099192:CD69 Antigens