HIV infection may disrupt the balance of cytokines produced by Th1, Th2, and Th17 T cells and B cells, and NK cells. Previous studies have shown that the Th1 response dominates in the early stage of HIV infection. IL-2 and IFN-γ produced by Th1 cells stimulate the activation of CD8+ cytotoxic T cells and maintain viremia. Then, during chronic HIV infection, the Th2 response begins to dominate, causing the increased production of IL-4 and IL-10. These studies revealed the importance of understanding the production of cytokines secreted by T cells during HIV infection [13]. In this study, the serum cytokines of HIV-infected patients were measured and compared, and we found that the levels of IL-1β, IL-2, IL-4, IL-7, IL-10, IL-17, IFN-γ and TNF-α, which are produced from different immune cells, were higher in the HIV-infected group, which indicates that these cytokines may act as biomarkers for HIV-1 infection and predictors of different types of immune cells involved in HIV progression.
In mucosa-associated lymphoid tissue (MALT), the presence of a large number of infected CD4+ T cells is directly related to the inflammation of mucosal tissue and destroys the integrity of the mucosa, allowing microorganisms to migrate from the intestinal tract to peripheral blood [14]. Th17 cells play an important role in maintaining mucosal integrity, and our results indicated a higher level of IL-17 in HIV-infected patients, which is consistent with previous studies [15]. Monocytes are target cells of HIV infection, and their function is affected by the virus. IL-1β and TNF-α are proinflammatory cytokines secreted by monocytes. Their augment may be due to the persistent stimulation of HIV regulatory proteins by HIV antigens, resulting in an increased monocyte release of IL-1β and TNF-α [16, 17]. IL-7 secreted by bone marrow stromal cells promotes the development and differentiation of T cells, and HIV replication in infected patients is maintained by IL-7 [18]. IL-6 can activate latent viruses and induce them to replicate in vitro [19]. IL-17 plays an important role in activating neutrophils against infection. The above results show that IL-17 and IL-6 participate in the pathogenesis of HIV and can predict the severity of the disease, providing a new indicator for the clinical observation of disease progression. In this study, our results showed that the levels of IL-6 and IL-17 increased in patients with CD4+ T cell counts < 200/mL, which indicates that these cytokines may be biomarkers for the terminal stage of AIDS. This study indicated that HIV infection maintains a state of long-term immune activation in the whole body. This chronic activation state causes T cells to generally lose their immune function, leading to progressive degradation of the immune system and the development of AIDS.
HIV-1 entry into cells is mediated by Env consisting of two subunits, gp120 and gp41. The initial interaction occurs between HIV-1 and host cell mediated by combination of gp120 and the cell surface receptor CD4 [3–5]. Subsequently, structural gp120 rearrangements emerge, which causes exposure of the coreceptor binding sites and secondary combination of CCR5 or CXCR4 chemokine receptor [10]. This combination between gp120 and CCR5 or CXCR4 coreceptor lead to next conformational changes in Env accompanied by exposure of the gp41 fusion peptide. CCR5 antagonists are a relatively novel armamentarium of anti-HIV-1 drugs. In recent investigations of the complex regulation of cytokines during HIV infection, HIV strains should also be taken into account. Previous studies have suggested that IL-4 can upregulate the expression of CXCR4 and inhibit the expression of CCR5, while IL-2 can downregulate the expression of CXCR4 and increase the expression of CCR5 [20]. Other studies suggested that the level of IL-2 increased in the group infected with CCR5-tropic HIV strains, which was consistent with our results [21]. These results indicated that cytokines may influence HIV infection and replication differently depending on the type of virus, suggesting the importance of different cytokine adjuvants in the design of effective vaccines for viruses with different tropisms.
In conclusion, our study demonstrated that the levels of the serum cytokines IL-2, IFN-γ, IL-4, IL-10, IL-17, IL-1β, TNF-α, and IL-7 were elevated in HIV-infected patients, which indicated that HIV infection caused activation of the immune system. Higher levels of IL-6 and IL-17 could predict the severity of HIV disease. The higher level of IL-2 in patients infected with CCR5-tropic HIV strains indicated that cytokines regulated HIV infection and replication differently depending on the type of virus strain.