CD4 T-cell regeneration in HIV-1 elite controllers.
BACKGROUND
Elite controllers spontaneously control HIV-1 replication, which in many cases is associated with preservation of normal CD4 T-cell counts. However, a subset of elite controllers has progressive CD4 T-cell losses despite undetectable viral loads, for reasons that remain undefined. Here, we assessed mechanisms of CD4 T-cell homeostasis in elite controllers with progressive vs. nonprogressive HIV-1 disease courses.


METHODS
Flow cytometry assays were used to determine the proliferation, activation and apoptosis levels of naive T cells in elite controllers with high or low CD4 T-cell counts and reference cohorts of HIV-1-negative and HAART-treated persons. Thymic output was measured by single-joint T-cell receptor excision circle (sjTREC)/β T-cell receptor excision circle (βTREC) ratios, and the frequency of circulating recent thymic emigrants was flow cytometrically determined by surface expression of protein tyrosine kinase 7.


RESULTS
Proportions of naive T cells in elite controllers were severely reduced and closely resemble those of HIV-1 patients with progressive disease. Despite reductions in naive T cells, most elite controllers were able to maintain normal total CD4 T-cell counts by preservation of uncompromised thymic function in conjunction with extrathymic processes that led to elevated levels of circulating recent thymic emigrants. In contrast, elite controllers with low CD4 T-cell counts had reduced thymic output that mirrored thymic dysfunction during untreated progressive HIV-1 infection.


CONCLUSIONS
These results indicate that both thymic and extrathymic mechanisms contribute to CD4 T-cell maintenance in elite controllers and support the idea that CD4 T-cell homeostasis and control of viral replication are distinct but frequently coinciding processes.
Infectious Disease Division, Massachusetts General Hospital, Boston, USA.
Yue
Y
Yang
Maha
M
Al-Mozaini
Maria J
MJ
Buzon
Jill
J
Beamon
Sara
S
Ferrando-Martinez
Ezequiel
E
Ruiz-Mateos
Eric S
ES
Rosenberg
Florencia
F
Pereyra
Xu G
XG
Yu
Mathias
M
Lichterfeld
D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D023241:Antiretroviral Therapy, Highly Active; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D016022:Case-Control Studies; D018450:Disease Progression; D005434:Flow Cytometry; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D015497:HIV-1 / Q000276:immunology*; D006684:HLA-DR Antigens / Q000378:metabolism; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D014779:Virus Replication
D006684:HLA-DR Antigens; D008562:Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1