In Vitro Restoration of Th17 Response During HIV Infection with an Antiretroviral Drug and Th17 Differentiation Cytokines

Abstract

The Th17 subset is preferentially depleted as compared to the Th1 subset in chronically HIV-infected patients, even after successful antiretroviral therapy. In this study, we have established an in vitro system utilizing primary human CD4 T cell cultures that recapitulates the dramatic loss of Th17 response upon HIV-1 infection that is accompanied with a less profound Th1 decrease. With this experimental system, we showed that blocking viral entry with CCR5 ligands or TAK779 reduced the infection and enhanced Th17 response but not Th1 response. Antiretroviral drug 3TC (lamivudine), given at the time of infection, completely prevented the loss of Th17 and Th1 responses but was ineffective when given after infection was already established. Only when Th17 differentiation cytokines were given along with 3TC to the cultures with established HIV infection was Th17 response fully restored and virus replication kept suppressed. Finally, a significant increase of Th17 response was achieved in peripheral lymphocytes of HIV-infected patients on antiretroviral therapy after treatment with Th17 differentiation cytokines. These data demonstrate the presence of CD4 T cells remaining capable of mounting Th17 response during HIV infection and indicate the potential use of immunotherapeutic modalities to supplement antiretroviral drugs for restoring Th17 response in chronically HIV-infected patients.

Preferential HIV Infection of CCR6 + Th17 Cells Is Associated with Higher Levels of Virus Receptor Expression and Lack of CCR5 Ligands

“…These results are consistent with our previous studies showing that virus suppression with antiretroviral drug was not sufficient to restore the Th17 cells in chronically HIV-infected CD4 T cell cultures (28). However, a combination of antiretroviral drug and Th17 differentiating cytokines was effective to expand Th17 cells in the face of established HIV infection (28). Other studies also showed that while Th17 cells could be induced early in response to acute HIV infection, these cells gradually declined in the course of HIV disease (29).…”

“…To understand better the differential effects of HIV infection ϩ cells. These results were in accord with our previous findings with unfractionated CD4 T cells (28) and recapitulated the dramatic loss of Th17 response compared to Th1 response reported in HIV-infected patients and in SIV/macaque models ( Fig. 1) (2, 3, 5, 7).…”

“…The data demonstrate that the proportion of peripheral Th17 cells in chronically HIV-infected subjects was low relative to that of Th1 cells, although the patients had controlled viremia and CD4 counts of Ͼ500 cells/l. These results are consistent with our previous studies showing that virus suppression with antiretroviral drug was not sufficient to restore the Th17 cells in chronically HIV-infected CD4 T cell cultures (28). However, a combination of antiretroviral drug and Th17 differentiating cytokines was effective to expand Th17 cells in the face of established HIV infection (28).…”

“…8B). These results corroborate published data that the capacity of CD4 T cells to produce CCR5 ligands offers survival advantage and that the CCR5 ligand-producing CD4 T cell subsets become the predominant population during HIV infection (24)(25)(26)(27)(28).…”

Induction of Intestinal Immunity by Mucosal Vaccines As a Means of Controlling HIV Infection

“…41 Furthermore, once the Th17 cells are lost, HIV control with an antiretroviral drug alone is not sufficient to restore this cell population; rather, a combination of anti-retroviral drugs and IL-1b, IL-6, and IL-23 is needed for full expansion of Th17 cells to the levels seen in uninfected controls. 42 HIV infection also damages the intestinal architecture by inducing apoptosis of enterocytes and eliminating mucosal repair mechanisms mediated by Th17 cells and their cytokines IL-17 and IL-22. [43][44][45] Because the integrity of the mucosal barrier is compromised, bacterial products such as lipopolysaccharide (LPS) can translocate into the periphery and fuel the chronic immune activation that contributes to AIDS progression.…”