Strong generalized immune activation is commonly described during acute HIV infection [22,41]. Studies of simian models have highlighted the role of immune activation in CD4 cell depletion and immunopathogenesis in HIV infection [42–44]. We and others [22,41] have shown that HIV-specific CD8+ T cells are strongly activated during PHI. We found a negative correlation between CD127 expression and CD38 expression on HIV-specific CD8+ T cells. This may simply reflect the reported relationship between immune activation and viral load [45,46]. However, at the single-cell level, we found that CD127+ HIV-specific CD8+ T cells were less activated than their CD127− counterparts. This high level of activation may also be responsible for a generalized nonspecific bystander phenomenon, as demonstrated by increased levels of CD38 and HLA-DR expression on EBV-specific and CMV-specific CD8+ T cells, both in the present study and elsewhere . This may explain the reduced CD127 expression that we observed during PHI on these non-HIV-specific CD8+ T cells as also observed by Paiardini et al. but not by Sabbaj et al..
Early treatment initiation during PHI has been shown to preserve HIV-specific CD4+ T cell responses and to rapidly attenuate the associated immune activation . Both phenomena are known to be associated with the development of efficient memory CD8+ T cells. The timing of ART initiation appears to be essential for the development of an effective CD127+ memory population [28,29,37,40,47,53].
Two different profiles of nonprogression have been described in HIV infection: first, patients with immunological control (stable CD4+ cell counts) and long-term nonprogression, who are referred to as ‘viremic nonprogressors’; and second, patients with spontaneous virological control, who are referred to here as ‘aviremic nonprogressors’ and elsewhere as ‘HIV or elite controllers’. Both situations are associated with efficient CD8+ T cell responses.
Taken together, these results suggest that early treatment initiation promotes the development of an effective CD127+ memory pool similar to that seen in nonprogressors and endowed with high proliferative capacity.
In summary, the persistence of viremia in most untreated HIV-infected individuals leads to permanent differentiation of HIV-specific CD8+ T cells toward an effector phenotype and to a concurrent defect in efficient memory T cell differentiation, as shown by CD127 expression status. This phenomenon is reversed when viral replication is inhibited by ART, especially when treatment is started during the acute infection. Further studies are needed to determine whether these treatment-induced changes in HIV-specific immune responses are associated with long-term clinical benefits.
This work was supported in part by institutional grants from Institut National de la Santé et de la Recherche Médicale, Agence Nationale de Recherches sur le SIDA et les hépatites virales, and Sidaction. C.L. is supported by grants from Ministère de l'Enseignement Supérieur et de la Recherche, and Sidaction.
C.L. performed the research, analyzed data, and wrote the article. M.S. and A.V. managed and designed the research and participated in writing the article. B.A. designed the research and participated in data centralization and coordination of the French ALT cohort (Agence Nationale de Recherche sur le SIDA, CO-15). C.G., O.L. and L.M. participated in data centralization and coordination of the French PRIMO cohort and HIV-Controllers Study Group (ANRS, CO-6 and EP36). I.G. and A.U. participated in performing the research and analyzing data. F.B., M.-L.C. and V.M. participated in performing the research.
The authors thank Christiane Deveau and Faroudy Boufassa for the coordination of the French PRIMO cohort and the French HIV-Controllers Study Group as well as the clinicians and patients from all the participating centers of the French PRIMO cohort, the French ALT cohort, and the EP36-HIC study group (Agence Nationale de Recherches sur le SIDA, CO 06-PRIMO Cohort, AC51-ALT Cohort and EP36-HIC Study Group). We also thank David Young for editorial assistance.
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