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

Abstract

Introduction: Human Immunodeficiency Virus (HIV) is a retrovirus that infects human immune cells, primarily CD4+ T cells and macrophages. During HIV disease progression, infected individuals have declining CD4+ T cell counts and increasing HIV RNA, indicative of virus replication. Numerous studies have identified important roles for cytokines in immune responses during the course of HIV 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 infection. Methods: We conducted a literature review categorizing pertinent cytokines on the basis of four criteria: correlations with HIV 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 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 bear 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 replication. This work provides a focus for future research aiming to better understand HIV pathogenesis and informs novel preventative and therapeutic designs.