Anna Kuzina

This study examined Toll-like receptors (TLRs)/chemokine receptors (CCRs) gene expression levels in HIV-infected individuals at different stages of HIV infection. It has been demonstrated that in the advanced stages of HIV infection, aggravated by Mycobacterium tuberculosis (M. tuberculosis) infection, there was a significant increase in TLR2, TLR4, TLR7, and TLR9 expression levels (181-, 8.4-, 15-, and 3.4-fold, respectively), compared to the early stages of the disease, which also correlated with an increase in viral load. The advanced stages of HIV infection were also characterized by an increased CCR5 expression level (8.08-fold, p < 0.0001) on patients’ mononuclear cells, which was not observed in the early stages of the disease. A positive correlation was found between the enhanced levels of TLR2/TLR4 and CCR5 expression, which facilitates the entry of HIV-1 into the cell (r = 0.03564, p = 0.0423 for TLR2/TLR4; r = 0.3793, p = 0.0269 for CCR5). The advanced stages of HIV infection were characterized by a sharp increase in the expression levels of CXCR4 and CCR8 co-receptors which also play an important role in the entry of HIV-1 into the host cell (more than 537-fold, p = 0.0006, and 5000-fold, p = 0.004, respectively). At the advanced stages of HIV infection, a positive correlation was found between increased production of TLR and CCR and elevated expression of IL-12 and IL-18. These factors contribute to virus persistence and chronic immune activation observed in patients with opportunistic infections. Thus, the obtained data indicate that HIV-1 in the advanced stages of infection induces an increased TLRs and CCRs expression, which, together with enhanced viral production, leads to chronic inflammation and can contribute to tissue damage and exacerbate the disease’s progression.

Recent studies suggest that immune response to pathogens may vary depending on changes in hormone levels. Toll-like receptors (TLRs) are the key components of the innate immune system and play a crucial role in HIV infection. Given the significant genetic diversity of HIV-1, this study examined the effect of female sex hormones on the several TLR2, TLR4, and TLR9 expression in human peripheral blood mononuclear cells (PBLs) isolated from different female donors and infected with different variants of HIV-1 subtypes A6 and B. Thus, high doses of hormones upregulated the TLR2 and TLR9 expression in PBLs infected only with v1.A6, which also correlated with an increased viral load: by 3.8 times (p = 0.0033) when cells were treated with estradiol and by 4.4 times (p = 0.006) when treated with progesterone. Hormones did not modulate TLRs expression in the cells infected with subtype B, with the exception of one donor. In PBLs from this donor infected with the v1.B variant, hormones upregulated TLRs expression, which also correlated with the increased viral load (1.3-fold increase (p = 0.0036)). Hence, it was shown that gonadal steroids can play an important role in HIV-1 replication and immune response to a pathogen. Moreover, it was shown that different isolates of the same subtype may have distinct biological properties. The detected diversity in the TLRs expression in infected PBLs from different donors indicates that host genetics may also play an important role in HIV susceptibility.