Leukemia inhibitor factor (LIF) and gp130 in early defence against HIV-1 infection

Leukemia inhibitor factor (LIF) is a polyfunctional cytokine that belongs to the IL-6 family which mainly signals through the Jak/Stat pathway via the gp130/LIFR-α heterodimer.

The focus of my research has been to investigate and understand if and how LIF exerts HIV1 suppressing activity. We therefore examined the expression of LIF, and its receptors (gp130 and LIFR-α) in lymphoid tissue biopsies from primary HIV-1 infected (PHI), chronic HIV-1 infected (cHI) individuals and from long term non progressors (LTNP). Furthermore, consecutively obtained HIV-plasma samples collected from PHI individuals were analysed for LIF and soluble gp130 levels.

Our data showed that LIF is one of the mediators of the innate immune response during HIV-1 infection. High production of LIF and gp130 were detected both in lymphoid tissue and in plasma from individuals with primary HIV-1 infection. Assessment of LIF plasma levels at PHI did not predict low levels of HIV-1 viremia after discontinuation of anti-retroviral treatment. However, a positive correlation between levels of plasma HIV-1 viral load and the production of LIF in lymphoid tissue or in plasma was found. In addition, a positive correlation between plasma levels of HIV-1 RNA and IFN-α, TNF-α, IL-1β, MIP-1α and MIP-1β were found in plasma from HIV-1 infected individuals that were in the primary phase of infection.

After cessation of antiretroviral treatment the levels of cytokines, including LIF, and chemokines were reduced as compared to the levels seen during primary HIV-1 infection. HIV-1 infected individuals that controlled their infection after cessation of treatment showed higher plasma levels of IFN-γ and MIP-1β as compared to individuals that did not control their HIV-1 infection. This suggests that during primary HIV-1 infection there is not a lack of a certain immune mediator that leads to immune failure, it is more like "too much and too many". However, individuals that do control the infection appear to have a recall response to the virus, since they produce IFN-γ and MIP-1β which are suggested to be beneficial for the host to be abel to control the HIV-1 replication.

We also found that even though more than 50% of the total CD4+ cells in lymphoid tissue expressed gp130, less than 5% of the total HIV-1 positive replicating cells (p24+) in lymphoid tissue were gp130+. Thus, LIF mediated a certain amount of control in CD4+gp130+ cells in lymphoid tissue. In addition, treatment of cMAGI cells with LIF prior to HIV-1 infection resulted in a dose dependent reduction in HIV-1 infected cells compared to untreated cells. Furthermore, both LIF and HIV-1 induced phosphorylation of Stat 3, and LIF pre-treatment resulted in a down modulation of the HIV-1 mediated Stat activation. Additionally, Jak/Stat inhibitors as well as siRNA against Stat 3 reduced HIV-1 replication. We suggest that the Jak/Stat pathway is important for HIV-1 replication and that LIF likely interferes with it.

In conclusion, LIF like many other cytokine and chemokines, is bifunctional since it has both HIV1 suppressive action if present prior to HIV-1 infection, and HIV-1 enhancing activity if present after established HIV-1 infection.

List of scientific papers

I. Tjernlund A, Fleener Z, Behbahani H, Connick E, Sonnerborg A, Brostrom C, Goh LE, Spetz AL, Patterson BK, Andersson J (2003). Suppression of leukemia inhibitor factor in lymphoid tissue in primary HIV infection: absence of HIV replication in gp130-positive cells. AIDS. 17(9): 1303-10.
https://doi.org/10.1097/01.aids.0000060417.84040.cc

II. Tjernlund A, Barqasho B, Nowak P, Kinloch S, Thorborn D, Perrin L, Sonnerborg A, Walther-Jallow L, Andersson J (2006). Early induction of leukemia inhibitor factor (LIF) in acute HIV-1 infection. AIDS. 20(1): 11-9.
https://doi.org/10.1097/01.aids.0000198082.16960.94

III. Barqasho B, Nowak P, Tjernlund A, Kinloch S, Thorborn D, Perrin L, Andersson J, Sönnerborg A (2006). Changes in plasma levels of cytokines and chemokines during primary HIV-1 infection and after cessation of antiretroviral therapy. [Manuscript]

IV. Tjernlund A, Walther Jallow L, Behbahani H, Screpanti V, Nowak P, Grandien A, Andersson J, Patterson BK (2006). Leukemia inhibitor factor (LIF) inhibits HIV-1 replication via restriction of Stat 3 activation. AIDS Research and Human Retroviruses. [Accepted]
https://doi.org/10.1089/aid.2006.0100