Abstract Introduction Sexually transmitted infections (STIs) are a major public health concern, significantly increasing susceptibility to HIV acquisition through multiple biological mechanisms. These infections trigger localized genital inflammation, compromise epithelial barrier integrity, and recruit HIV-target immune cells, creating favorable conditions for HIV entry and replication. Understanding these biological interactions is critical for developing effective prevention strategies, particularly in high-burden settings. Objective This narrative review aimed to synthesize current evidence on the biological mechanisms through which STIs increase vulnerability to HIV acquisition, focusing on genital inflammation, mucosal barrier disruption, and immune cell recruitment, and to identify key STI cofactors contributing to HIV transmission risk. Methods A comprehensive narrative review was conducted using the Scopus database, covering studies published between 2019 and 2024. Search terms included "sexually transmitted infections," "HIV susceptibility," "genital inflammation," "mucosal barrier," and "immune activation." Studies examining biological and immunological mechanisms linking STIs to increased HIV vulnerability were selected based on methodological quality, clinical relevance, and evidence strength. Results Analysis of current evidence reveals that several STIs substantially increase vulnerability to HIV acquisition through distinct biological pathways. Herpes Simplex Virus Type 2 (HSV-2) emerged as one of the strongest cofactors, with large-scale epidemiological studies demonstrating that women infected with HSV-2 have approximately a three-fold higher risk of HIV acquisition. Research from South Africa demonstrates that common bacterial STIs, including Chlamydia trachomatis, Neisseria gonorrhoeae, and Mycoplasma genitalium, induce strong genital inflammation accompanied by elevated pro-inflammatory cytokines (IL-1β, IL-6, IL-8, and soluble CD40L). These infections substantially elevate HIV entry across compromised mucosal surfaces. The interaction between HIV and STIs is bidirectional. STI-related lesions compromise epithelial barrier integrity, facilitating HIV entry, while HIV-induced immunosuppression accelerates STI disease progression, creating a vicious cycle of increased vulnerability. Studies among South African female sex workers reveal that high-risk human papillomavirus (HPV) types significantly increase HIV acquisition risk. Each additional high-risk HPV type is associated with approximately 70% increased susceptibility per additional high-risk type, demonstrating the cumulative impact of multiple STI coinfections on HIV vulnerability. Conclusions This review demonstrates that common STIs substantially enhance HIV acquisition through synergistic mechanisms involving genital inflammation, epithelial barrier compromise, and immune cell recruitment. Key findings highlight HSV-2 as a major cofactor and the cumulative impact of HPV types. These mechanistic insights underscore the critical importance of integrated STI prevention strategies, including routine screening, prompt treatment, and coordinated management approaches, particularly among high-risk populations. Future research should focus on developing and evaluating targeted interventions that integrate STI control and HIV prevention strategies, particularly for high-risk populations, to maximize public health impact. Disclosure No
Occulis et al. (Mon,) studied this question.