Disease progression in macaques with low SIV replication levels: on the relevance of TREC counts.
BACKGROUND
An attenuated immunodeficiency virus has been long considered innocuous. Nevertheless, converging data suggest that low levels of viral replication can still provoke AIDS. Pathogenesis of these attenuated infections is not understood.


OBJECTIVE
To determine the pathogenicity of a long-term attenuated infection and to delineate T-cell dynamics during such an infection.


METHODS
This is a cross-sectional study of 12 rhesus macaques infected with SIV Delta nef for 8 years. We evaluated apoptosis (annexin V), activation (HLA-DR, Ki67), and newly generated T cells (TCR excision circle: TREC).


RESULTS
Infection with SIV Delta nef induced pathological CD4 T-cell depletion after 8 years of infection. Virus replication and CD8 T-cell activation positively correlated with the rate of disease progression. The frequency of TREC within CD8+CD45RA+ cells increased in SIV Delta nef-infected animals compared to age-matched non-infected controls. Moreover, in the cohort of infected animals, TREC+CD45RA+CD4+ T-cell counts correlated strongly with non-progression to AIDS. The animal with the lowest rate of disease progression exhibited a 115-fold increase in TREC+CD45RA+CD4+ T-cell counts compared to age-matched non-infected controls. In contrast, the animal showing the fastest rate of progression to AIDS displayed 600-fold lower TREC+CD45RA+CD4+ T-cell counts compared to age-matched non-infected controls.


CONCLUSIONS
Our results suggest that the thymus plays a major role in the pathogenesis of an attenuated SIV infection and that a sustained thymic output could maintain CD4 T-cell homeostasis in the context of low viral loads.
Ho Tsong Fang
Raphaël
R
Unité de Physiopathologie des Infections Lentivirales, Institut Pasteur, Paris, France. rhotsong@ucla.edu
Khatissian
Emmanuel
E
Monceaux
Valérie
V
Cumont
Marie-Christine
MC
Beq
Stéphanie
S
Ameisen
Jean-Claude
JC
Aubertin
Anne-Marie
AM
Israël
Nicole
N
Estaquier
Jérôme
J
Hurtrel
Bruno
B
D000818:Animals; D017209:Apoptosis; D018791:CD4 Lymphocyte Count; D016516:CD4-CD8 Ratio; D018414:CD8-Positive T-Lymphocytes; D049109:Cell Proliferation; D018450:Disease Progression; D015693:Gene Products, nef; D015329:Gene Rearrangement, T-Lymphocyte; D017493:Leukocyte Common Antigens / Q000032:analysis; D008213:Lymphocyte Activation; D008253:Macaca mulatta; D016097:Simian Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000821:virology*; D015302:Simian Immunodeficiency Virus / Q000502:physiology*; D013997:Time Factors; D019562:Viral Load; D014779:Virus Replication
D015693:Gene Products, nef; D017493:Leukocyte Common Antigens