Pleiotropic Roles of Cytokines in HIV-1 Pathogenesis and Control: A Literature Review

Introduction: Human Immunodeficiency Virus 1 (HIV-1) is a retrovirus that infects human immune cells, primarily CD4+ T cells and macrophages. During HIV-1 disease progression, infected individuals have declining CD4+ T cell counts and increasing HIV-1 RNA, indicative of virus replication. Numerous studies have identified important roles for cytokines in immune responses during the course of HIV-1 infection. Cytokines are small molecular weight proteins that communicate signals between a broad range of cells in the immune system. This review aims to highlight a key subset of cytokines that bear potential as targets for the prevention and treatment of HIV-1 infection.  Methods: We conducted a literature review categorizing pertinent cytokines on the basis of four criteria: correlations with HIV-1 replication, impact on host innate immune cells, characteristic expression in elite controllers, and therapeutic applications. Results: We identified several cytokines in the interleukin (IL) family and the C-C and C-X-C chemokine families with important roles in HIV-1 control. Indeed, the expression of many cytokines was correlated with reduced HIV-1 replication (e.g. IL-21, IL-32, IL-27). Several cytokines directly impact cells of the innate immune system in their HIV-1 control mechanisms. Among many, IL-7 and IL-15 are able to enhance natural killer cell function, while IL-27 enhances macrophage resistance to HIV-1 infection. Elite controllers, individuals who have suppressed HIV-1 replication and preserved CD4+ T cell levels without exogenous antiviral drug treatment, express a uniquely characteristic array of chemokines. Namely, CCL14, CCL27, CCL21, XCL1 and CXCL12 are upregulated in elite controllers compared to non-controllers. Finally, considering the diversity and pleiotropic roles of cytokines during HIV-1 infection, many show potential for inclusion in therapeutic designs. Conclusion: Herein, we have highlighted the antiviral roles of several cytokines, demonstrating that many cytokines are key regulators of HIV-1 replication. This work provides a focus for future research aiming to better understand HIV pathogenesis and informs novel preventative and therapeutic designs.