Human Immunodeficiency Virus Immune Cell Receptors, Coreceptors, and Cofactors: Implications for Prevention and Treatment

Abstract

In the last three decades, extensive research on human immunodeficiency virus (HIV) has highlighted its capability to exploit a variety of strategies to enter and infect immune cells. Although CD4(+) T cells are well known as the major HIV target, with infection occurring through the canonical combination of the cluster of differentiation 4 (CD4) receptor and either the C-C chemokine receptor type 5 (CCR5) or C-X-C chemokine receptor type 4 (CXCR4) coreceptors, HIV has also been found to enter other important immune cell types such as macrophages, dendritic cells, Langerhans cells, B cells, and granulocytes. Interestingly, the expression of distinct cellular cofactors partially regulates the rate in which HIV infects each distinct cell type. Furthermore, HIV can benefit from the acquisition of new proteins incorporated into its envelope during budding events. While several publications have investigated details of how HIV manipulates particular cell types or subtypes, an up-to-date comprehensive review on HIV tropism for different immune cells is lacking. Therefore, this review is meant to focus on the different receptors, coreceptors, and cofactors that HIV exploits to enter particular immune cells. Additionally, prophylactic approaches that have targeted particular molecules associated with HIV entry and infection of different immune cells will be discussed. Unveiling the underlying cellular receptors and cofactors that lead to HIV preference for specific immune cell populations is crucial in identifying novel preventative/therapeutic targets for comprehensive strategies to eliminate viral infection.

FIG. 1.

Summary of receptors used by HIV to enter CD4⁺ T cells. CD4 is the primary receptor for gp120, while either CXCR4 or CCR5 can act as coreceptors. On attachment to these moieties, the gp41 fusion protein is exposed and facilitates viral membrane fusion. CD26 and α4β7 have been shown to aid in catalyzing these interactions as cofactors. When ICAM-1 is incorporated into the viral envelope during budding events, it can interact with its receptor LFA-1 to enhance infectivity (interaction indicated by *). CCR5, C-C chemokine receptor type 5; CD4, cluster of differentiation 4; CXCR4, C-X-C chemokine receptor type 4; HIV, human immunodeficiency virus; ICAM-1, intercellular adhesion molecule-1; LFA-1, lymphocyte function-associated antigen 1. (Color image is available at www.liebertpub.com/apc).

FIG. 2.

Summary of receptors used by HIV to enter MΦ. CD4 is the primary receptor for gp120, while CCR5 or CXCR4 can act as coreceptors. During viral propagation, surface proteins such as MHC II, PS, or ICAM-1 have been shown to incorporate into the viral envelope and act as ligands that enhance virus-MΦ interactions through binding to their receptors CD4, annexin A2, and LFA-1, respectively (protein interactions indicated by *, **, and ***). Syndecans, integrins, alternate chemokine/cytokine receptors, and MMR have also been shown to be cofactors that play a role in HIV infection of MΦs. CCR5, C-C chemokine receptor type 5; CD4, cluster of differentiation 4; CXCR4, C-X-C chemokine receptor type 4; HIV, human immunodeficiency virus; ICAM-1, intercellular adhesion molecule-1; LFA-1, lymphocyte function-associated antigen 1; MHC II, major histocompatibility complex class II; MMR, macrophage mannose receptor; PS, phosphatidylserine. (Color image is available at www.liebertpub.com/apc).

FIG. 3.

Summary of receptors used by HIV to enter professional APCs (i.e., DCs and LCs). CD4 is a primary receptor for gp120, while CCR5 or CXCR5 can act as coreceptors. Entry through these pathways can yield productive infections. Alternatively, HIV has been shown to interact with the C-type lectin receptors DC-SIGN, DCIR, and langerin at the surface of DCs and LCs. Association with these receptors can result in viral transmission to T cells via trans-infection, or potentially in viral degradation. APC, antigen-presenting cell; CCR5, C-C chemokine receptor type 5; CD4, cluster of differentiation 4; CXCR5, C-X-C chemokine receptor type 5; DCs, dendritic cells; DCIR, DC immunoreceptor; DC-SIGN, DC-specific ICAM-3-grabbing nonintegrin; LCs, Langerhans cells; HIV, human immunodeficiency virus. (Color image is available at www.liebertpub.com/apc).