title: Costimulation of T-cell activation and virus production by B7 antigen on activated CD4+ T cells from human immunodeficiency virus type 1-infected donors.
abstract: Infection with the human immunodeficiency virus type 1 (HIV-1) requires T-cell activation. Recent studies have shown that interactions of the T-lymphocyte receptors CD28 and CTLA-4 with their counter receptor, B7, on antigen-presenting cells are required for optimal T-cell activation. Here we show that HIV-1 infection is associated with decreased expression of CD28 and increased expression of B7 on CD4+ T-cell lines generated from seropositive donors by alloantigen stimulation. Loss of CD28 expression was not seen on CD4+ T-cell lines from seronegative donors, but up-regulation of B7 expression was observed upon more prolonged culture. Both T-cell proliferation and interleukin 2 mRNA accumulation in HIV-1-infected cultures required costimulation with exogenous B7 because these events were blocked by CTLA4Ig, a soluble form of CTLA-4 that binds B7 with high avidity. In contrast, levels of HIV-1 RNA were not affected by CTLA4Ig, indicating that regulation of virus transcription in these cultures did not depend upon CD28-B7 engagement. Infected T cells could present alloantigen to fresh, uninfected CD4+ T cells, leading to increased proliferation and virus spread to the activated cells. Both of these events were blocked by CTLA4Ig. Thus, chronic activation of HIV-1-infected CD4+ T cells reduces expression of CD28 and increases expression of B7, thereby enabling these T cells to become antigen-presenting cells for uninfected CD4+ T cells; this might be another mechanism for HIV-1 transmission via T-cell-T-cell contact.
authors.affiliation: Bristol-Myers Squibb Pharmaceutical Research Institute, Seattle, WA 98121.
authors.forename: O K
authors.initials: OK
authors.lastname: Haffar
authors.forename: M D
authors.initials: MD
authors.lastname: Smithgall
authors.forename: J
authors.initials: J
authors.lastname: Bradshaw
authors.forename: B
authors.initials: B
authors.lastname: Brady
authors.forename: N K
authors.initials: NK
authors.lastname: Damle
authors.forename: P S
authors.initials: PS
authors.lastname: Linsley
mesh_terms: D000069594:Abatacept; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism*; D018122:B7-1 Antigen / Q000502:physiology*; D001483:Base Sequence; D018106:CD28 Antigens / Q000235:genetics / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000382:microbiology*; D060908:CTLA-4 Antigen; D017931:DNA Primers / Q000737:chemistry; D015870:Gene Expression; D015658:HIV Infections / Q000276:immunology*; D006801:Humans; D018796:Immunoconjugates; D007376:Interleukin-2 / Q000235:genetics; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics; D014779:Virus Replication
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; D017931:DNA Primers; D018796:Immunoconjugates; D007376:Interleukin-2; D012333:RNA, Messenger; D000069594:Abatacept