Combination antiretroviral therapy (cART) restores HIV-1 infection-mediated impairment of JAK-STAT signaling pathway

Abstract

JAK-STAT signaling pathway has a crucial role in host innate immunity against viral infections, including HIV-1. We therefore examined the impact of HIV-1 infection and combination antiretroviral therapy (cART) on JAK-STAT signaling pathway. Compared to age-matched healthy donors (n = 18), HIV-1-infected subjects (n = 18) prior to cART had significantly lower expression of toll-like receptors (TLR-1/4/6/7/8/9), the IFN regulatory factors (IRF-3/7/9), and the antiviral factors (OAS-1, MxA, A3G, PKR, and Tetherin). Three months’ cART partially restores the impaired functions of JAK-STAT-mediated antiviral immunity. We also found most factors had significantly positive correlations (p < 0.05) between each two factors in JAK-STAT pathway in healthy donors (98.25%, 168/171), but such significant positive associations were only found in small part of HIV-1-infected subjects (43.86%, 75/171), and stably increased during the cART (57.31%, 98/171 after 6 months’ cART). With regard to the restoration of some HIV-1 restriction factors, HIV-1-infected subjects who had CD4+ T cell counts > 350//μl responded better to cART than those with the counts < 350/μl. These findings indicate that the impairment of JAK-STAT pathway may play a role in the immunopathogenesis of HIV-1 disease.

The Significance of Type-I Interferons in the Pathogenesis and Therapy of Human Immunodeficiency Virus 1 Infection

“…In the cytosol of pDCs, HIV nucleic acid is presented to TLR7 located in endosomes, which is transferred from the endoplasmic reticulum (ER) to endosome via polytopic membrane protein UNC93B1 and heat shock protein gp96 ( 27 , 28 ). After the formation of endosomes, TLR7 rapidly catches up with single-strand RNA (ssRNA) ( 29 ). But the specific character of these ssRNA has not been identified.…”

Clinical outcomes and immunological response to SARS-CoV-2 infection among people living with HIV

“…Some HIV proteins have been reported to inhibit effective IFNα signalling by degrading certain components of the JAK/STAT signalling pathway like STAT1 and STAT3 [ 50 ]. The impaired JAK/STAT signalling pathway is however restored in the presence of uninterrupted combined Antiretroviral therapy (cART) for more than 6 months [ 51 ]. Per our search, we found one study available on HIV/COVID-19 signalling pathway that investigated STAT3 but did not look at other STAT pathways [ 52 ], and therefore creates a gap that needs to be researched.…”

The roles of apoptosis, autophagy and unfolded protein response in arbovirus, influenza virus, and HIV infections

“…Some efforts are in early stages and involve the use of combination antiretroviral therapy (cART). A recent study showed the impact of cART in HIV-1 infection by examining the JAK-STAT signaling pathway which plays a crucial role in host innate immunity against HIV-1 [26]. The JAK-STAT signaling pathway is involved in Toll-like receptor (TLR)-mediated pathogen recognition, IRF activation and the induction of IFN-inducible genes such as MxA and ISG56.…”

“…Therefore, they postulated that deficiencies in the JAK-STAT pathway may play a role in the immunopathogenesis of HIV-1 disease. These new directions are focused on latency-reversing agents to activate immunotherapies, gene therapies, and therapeutic vaccines to eliminate persistent HIV reservoirs or induce effective immune control of HIV infection [26].…”