Although human immunodeficiency virus (HIV) gag/pol DNA can be detected in naive T cells, whether naive T cells can be productively infected by HIV is still questionable. Given that interleukin-7 (IL-7) is a prospective therapeutic immunomodulator for the treatment of HIV, we evaluated the effect of IL-7 on promoting naive T-cell infection of laboratory-adapted (IIIB), Mtropic, and primary isolates of HIV. Initially, we determined that the 3 cell surface markers widely used to identify naive T cells (CD45RA ؉ CD45RO ؊ , CD45RA ؉ CD62L ؉ , and CD45RO ؊ CD27 ؉ CD95 low ) are all equivalent in T-cell receptor excision circle content, a marker for the replicative history of a cell as well as for de novo T cells. We therefore used CD45RA ؉ CD45RO ؊ expression to define naive T cells in this study. We demonstrate that although untreated or IL-2-treated naive T cells are not productively infected by HIV, IL-7 pretreatment mediated the productive infection of laboratory-adapted, M-tropic, and primary isolates of HIV as determined by p24 core antigen production. This upregulation was between 8-and 58-fold, depending on the HIV isolate used. IL-7 pretreatment of naive T cells also potently up-regulated surface expression of CXCR4 but not CCR5 and mediated the expansion of naive T cells without the acquisition of the primed CD45RO phenotype. Collectively, these data indicate that IL-7 augments naive T-cell susceptibility to HIV and that under the appropriate environmental milieu, naive T cells may be a source of HIV productive infection. This information needs to be considered in evaluating IL-7 as an immunomodulator for HIV-infected patients.
IntroductionCD4 ϩ primed/memory T cells constitute the main target for productive human immunodeficiency virus (HIV) infection. [1][2][3] Whether HIV productively infects naive T cells in vivo is still controversial. 4-9 Naive T cells were shown to harbor replicationcompetent HIV, 7,10 but are not an active site of HIV replication in the absence of mitogen stimulation. 11 Even in studies demonstrating HIV infection of naive T cells, further analysis of integrated HIV indicated that HIV DNA did not always integrate into the genome. 5,10 Infected naive T cells, nonetheless, have been identified in HIV-seropositive individuals, 7,10 but it is unclear if such in vivo naive T cells were once primed cells that reverted to a naive phenotype 12,13 or are truly naive T cells that are infected in vivo. In the simian immunodeficiency virus (SIV) model, SIV RNA was detected by in situ hybridization in naive T cells, suggesting that these cells may serve as an additional reservoir for HIV. 14 Collectively, the consensus is that naive T cells, either in vivo or in vitro, do not support HIV productive infection mainly because these cells exist in a quiescent stage, a concept that is being challenged. The association between productive HIV replication and cell turnover is presumably due to the higher level of deoxyribonucleotides present for reverse transcription 15 during cell division or due to t...