Multifactorial Nature of Noncytolytic CD8⁺T Cell-Mediated Suppression of HIV Replication: β-Chemokine-Dependent and -Independent Effects

Abstract

Chemokines were originally characterized by their ability to direct migration and induce activation of selected leukocyte populations. The beta-chemokines MIP-1 alpha, MIP-beta, and RANTES have been implicated in the suppression of viral replication by CD8+ T cells from HIV-infected individuals. The present study was undertaken to evaluate the effect of beta-chemokines on HIV replication in cocultures of dendritic cells (DCs) and CD4+ T cells, and an in vitro model of the lymphoid microenvironment. In the acute infection system, where DCs from uninfected individuals are pulsed with HIV and cocultured with autologous CD4+ T cells, no inhibition of replication of monocytotropic or T cell tropic viral isolates by MIP-1 alpha, MIP-1 beta, and RANTES, alone or in combination, was observed. In contrast, in an endogenous infection system, where the DCs and CD4+ T cells were obtained from HIV-infected subjects, addition of recombinant beta-chemokines suppressed HIV replication. However, neutralizing antibodies to beta-chemokines did not affect the suppressive activity of CD8+ T cells from HIV-infected donors in either system, suggesting that CD8+ T cell-mediated suppression is not due exclusively to beta-chemokines. Furthermore, no significant differences in secretion of MIP-1 alpha, MIP-1 beta, and RANTES by purified CD8+ T cells were noted in uninfected versus HIV-infected donors, regardless of the stage of disease. These results indicate that HIV suppression by CD8+ T cells derived from HIV-infected donors is a multifactorial phenomenon and not limited to the action of MIP-1 alpha, MIP-1 beta, and RANTES.

Do beta-chemokines have clinical relevance in HIV infection?

“…Moreover, spontaneous chemokine production by the peripheral blood cells was also found to be quite variable. Similar findings on varying levels of chemokine production by T cells from HIV-infected or uninfected individuals have been reported by others (36,44).…”

Reduced naive and increased activated CD4 and CD8 cells in healthy adult Ethiopians compared with their Dutch counterparts

“…Conversely, the effector CD8 þ T cell subset, being higher in HIV ¹ Ethiopians than in HIV ¹ Dutch, decreased in Ethiopian HIV þ and AIDS subjects. This could result in less production of CCR-5 ligands (MIP-1a, MIP-1b, RANTES) and thus the potential inhibitory effect on HIV-1 cell entry would be decreased [41].…”

Initiation of Human Immunodeficiency Virus Type 1 (HIV-1) Transcription is Inhibited by Noncytolytic CD8+ Suppression

“…The most notable of these molecules are the natural ligands for the CCR5 coreceptors, the -chemokines RANTES, MIP-1 and MIP-1 , which do in fact inhibit viral replication by blocking viral entry. Since their discovery, however, several groups have shown that these soluble anti-viral factors cannot adequately explain the viral suppressive activity of CD8 + T cells [34,35]. Here we report that the anti-viral suppression occurs during transcriptional initiation of the HIV viral life cycle (using X4-tropic virus) and this will further ongoing studies into the precise molecules involved in suppressing viral transcriptional initiation.…”