Evidence for Gag p24-specific CD4 T cells with reduced susceptibility to R5 HIV-1 infection in a UK cohort of HIV-exposed-seronegative subjects.
OBJECTIVE
To characterize HIV-1 Gag p24-specific CD4 cell responses in HIV-exposed-seronegative (ES) individuals.


METHODS
Twelve ES individuals, of diverse ethnicity and wild type for the CCR5 Delta-32 mutation, were identified. Controls were HIV-negative blood donors. Gag p24-specific and total Vbeta+ CD4 cells that expressed MIP-1beta, IFN-gamma and IL-2 were enumerated by intracytoplasmic cytokine staining. beta-Chemokine expression was correlated with susceptibility to R5 HIV-1 infection, as measured by polymerase chain reaction for integrated HIV-1 and by p24 enzyme-linked immunosorbent assay.


RESULTS
Similar numbers of mitogen-stimulated and Vbeta+ MIP-1beta+, IFN-gamma+ and IL-2+ T cells were found in ES and HIV-negative control subjects. However, all ES subjects tested had an HIV Gag p24-specific MIP-1beta+, IFN-gamma+ and IL-2+ CD4 T-cell response that was rare in controls. p24-Specific cells of all ES but no control subjects could be expanded by in-vitro Ag/IL-2 stimulation, and when re-stimulated with an overlapping peptide series showed evidence of a broad CD4 cell memory response directed against multiple regions of Gag p24. Mitogen-stimulated ES CD4 cells were as susceptible to HIV infection as those from control subjects, but p24-specific IFN-gamma+ CD4 cells of six out of seven ES subjects tested were less susceptible to R5 HIV-1 infection than the counterpart fraction depleted of p24-specific IFN-gamma+ cells. The addition of blocking anti-beta-chemokine antibodies did not promote R5 HIV-1 infection of p24-specific IFN-gamma+ cells.


CONCLUSIONS
Specific CD4 cell immunity, characterized by a broadly directed memory Gag-p24 CD4 cell response and reduced susceptibility of specific CD4 cells to R5 HIV-1 infection, is a likely correlate of non-transmission.
Eyeson
Josiah
J
Department of Immunology, Guy's, King's and St Thomas' School of Medicine and Dentistry, King's College Hospital, London SE5 9NU, UK.
King
Deborah
D
Boaz
Mark J
MJ
Sefia
Eseberuo
E
Tomkins
Sarah
S
Waters
Anele
A
Easterbrook
Philippa J
PJ
Vyakarnam
Annapurna
A
D000328:Adult; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D054407:Chemokine CCL4; D016207:Cytokines / Q000378:metabolism; D004198:Disease Susceptibility; D005260:Female; D016655:HIV Core Protein p24 / Q000276:immunology*; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000502:physiology; D006801:Humans; D008213:Lymphocyte Activation / Q000276:immunology; D019402:Macrophage Inflammatory Proteins / Q000096:biosynthesis; D008297:Male; D008875:Middle Aged; D008934:Mitogens / Q000276:immunology; D019713:Receptors, CCR5 / Q000097:blood; D014779:Virus Replication
D054407:Chemokine CCL4; D016207:Cytokines; D016655:HIV Core Protein p24; D019402:Macrophage Inflammatory Proteins; D008934:Mitogens; D019713:Receptors, CCR5