FOXP3 expression is upregulated in CD4T cells in progressive HIV-1 infection and is a marker of disease severity.
BACKGROUND
Understanding the role of different classes of T cells during HIV infection is critical to determining which responses correlate with protective immunity. To date, it is unclear whether alterations in regulatory T cell (Treg) function are contributory to progression of HIV infection.


METHODS
FOXP3 expression was measured by both qRT-PCR and by flow cytometry in HIV-infected individuals and uninfected controls together with expression of CD25, GITR and CTLA-4. Cultured peripheral blood mononuclear cells were stimulated with anti-CD3 and cell proliferation was assessed by CFSE dilution.


RESULTS
HIV infected individuals had significantly higher frequencies of CD4(+)FOXP3(+) T cells (median of 8.11%; range 1.33%-26.27%) than healthy controls (median 3.72%; range 1.3-7.5%; P = 0.002), despite having lower absolute counts of CD4(+)FOXP3(+) T cells. There was a significant positive correlation between the frequency of CD4(+)FOXP3(+) T cells and viral load (rho = 0.593 P = 0.003) and a significant negative correlation with CD4 count (rho = -0.423 P = 0.044). 48% of our patients had CD4 counts below 200 cells/microl and these patients showed a marked elevation of FOXP3 percentage (median 10% range 4.07%-26.27%). Assessing the mechanism of increased FOXP3 frequency, we found that the high FOXP3 levels noted in HIV infected individuals dropped rapidly in unstimulated culture conditions but could be restimulated by T cell receptor stimulation. This suggests that the high FOXP3 expression in HIV infected patients is likely due to FOXP3 upregulation by individual CD4(+) T cells following antigenic or other stimulation.


CONCLUSIONS
FOXP3 expression in the CD4(+) T cell population is a marker of severity of HIV infection and a potential prognostic marker of disease progression.
Suchard
Melinda S
MS
Haematology and Molecular Medicine, National Health Laboratory Service and University of the Witwatersrand, Johannesburg, South Africa. thesuchards@telkomsa.net
Mayne
Elizabeth
E
Green
Victoria A
VA
Shalekoff
Sharon
S
Donninger
Samantha L
SL
Stevens
Wendy S
WS
Gray
Clive M
CM
Tiemessen
Caroline T
CT
D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D015703:Antigens, CD / Q000235:genetics*; D017252:CD3 Complex / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D060908:CTLA-4 Antigen; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000235:genetics*; D053450:Glucocorticoid-Induced TNFR-Related Protein; D015658:HIV Infections / Q000235:genetics* / Q000503:physiopathology*; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects; D017475:Receptors, Nerve Growth Factor / Q000235:genetics*; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000906:Antibodies; D015703:Antigens, CD; D017252:CD3 Complex; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053450:Glucocorticoid-Induced TNFR-Related Protein; D053645:Interleukin-2 Receptor alpha Subunit; D017475:Receptors, Nerve Growth Factor; D018124:Receptors, Tumor Necrosis Factor; C491405:TNFRSF18 protein, human