The Role of Cationic Polypeptides in Modulating HIV-1 Infection of the Cervicovaginal Mucosa

Abstract

The mucosa and overlying fluid of the female reproductive tract (FRT) are portals for the heterosexual transmission of HIV-1. Toward the ongoing development of topically applied microbicides and mucosal vaccines against HIV-1, it is evermore important to understand how the dynamic FRT mucosa is involved in controlling transmission and infection of HIV-1. Cationic peptides and proteins are the principal innate immune effector molecules of mucosal surfaces, and interact in a combinatorial fashion to modulate HIV-1 infection of the cervix and vagina. While cationic peptides and proteins have historically been categorized as antimicrobial or have other host-benefitting roles, an increasing number of these molecules have been found to augment HIV-1 infection and potentially antagonize host defense. Complex environmental factors such as hormonal fluctuations and/or bacterial and viral co-infections provide additional challenges to both experimentation and interpretation of results. In the context of heterosexual transmission of HIV-1, this review explores how various cationic peptides and proteins participate in modulating host defense against HIV-1 of the cervicovaginal mucosa.

Keywords: HIV-1; antimicrobial; cationic; cervix; mucosa; peptide; protein; vagina.

Figure 1

Anti-HIV-1 mechanisms of action of cationic peptides and peptides of the female reproductive tract (FRT). Depicted is the lifecycle of HIV-1 infecting a target CD4⁺ cell, beginning from a free virion (“1”) to integration of viral cDNA into genomic DNA of the target cell (“7”); “8” indicates other aspects, including receptor downmodulation and cell signaling, that indirectly affect the ability of the virus to infect or propagate within host cells. Cationic peptides and proteins in green font are antiviral at the respective stage in the lifecycle, while peptides and proteins in red font promote HIV-1 infection. Viral envelope proteins (gp120, gp41), cellular receptor (CD4) and coreceptor (CXCR4 or CCR5) required for viral attachment and entry are provided. Events downstream of viral cDNA integration into host DNA are not depicted.