Mucosal tissues in the human female genital tract are prone to invasion by various pathogens including Human Immunodeficiency Virus type 1 (HIV-1) and Human Papillomavirus (HPV). Further, they are primary sites for gynecological cancers and other sexually transmitted infections (1). HPV and HIV-1 infect or traverse the epithelium, respectively. Here we discuss the connection to and extent of involvement of the epithelium in HPV and HIV-1 infections.

Worldwide, HPV, a highly transmissible sexually transmitted virus, is responsible for 5% of all cancers (2), accounting for slightly more than 30% of infection-linked cancers (3). Of the various body sites that can be affected by HPV infection and associated cancers, cervical cancers account for over 90% of HPV-related cancers in women. The prevalence of cervical HPV is highest in Sub-Saharan Africa (SSA), followed by Latin America and the Caribbean, eastern Europe, and South-East Asia at 24%, 16%, 14% and 14%, respectively (2).

To date, at least 200 HPV types have been identified and grouped within 5 genera (4–6). The 65 alpha papillomaviruses known to target mucosal membranes can be divided into high-risk (hr) and low-risk (lr) groups based on their ability of oncogenic transformation of cells (5–8). Clinically, persistent hrHPV infections are associated with both invasive cancer of the cervix and cervical intraepithelial neoplasia (CIN), a precursor lesion for cervical carcinoma. Persistent infection with hrHPV has been linked to more than 99% of cervical cancer cases, whereas 90% of CIN cases occur in HPV-positive patients (9). HPV16 and HPV18 are associated with high grade intraepithelial lesions (HSIL), encompassing CIN2 and CIN3 lesions, and invasive cancer progression (10). HPV16 infection is closely associated with both intraepithelial lesions and invasive squamous neoplasia, as well as the occasional cervical glandular neoplasia (11). HPV18 on the other hand is associated with non-squamous cervical neoplasms and it has been detected in about 9% of HPV infections (12). However, more than 90% of any cervical HPV infection will regress (13). In the absence of regression, HPV infection can persist for decades, becoming a major risk factor for later neoplastic transformation of cervical epithelium and progression from intraepithelial lesions to invasive carcinomas (14).

HIV-1, another sexually transmitted pathogen, is a cause of acquired immunodeficiency syndrome (AIDS), a chronic multisystem and potentially life-threatening condition that compromises immunity, thereby interfering with the body's ability to fight infection and disease. Globally, an estimated 1.3 million people were newly infected with HIV-1 in 2022 (15). Furthermore, over the same period, 630 00 people died from AIDS (15). Globally, 39 million people were living with HIV (PLHIV) (15). While the incidence of HIV infection has been declining, it has not been declining at high rates in women and girls. Forty six percent of all new HIV infections in 2022 were in women and girls, and fifty three percent of all PLHIV were women and girls (15).

There is a high HPV prevalence among women living with HIV (WLHV). Stelzle et al., found that globally WLHV have six times the risk to develop cervical cancer than their uninfected counterparts (16). Mbulawa et al, in a study conducted in South Africa, showed that the prevalence of HPV among HIV infected women was 74.0% compared to 36.7% in HIV uninfected women, a difference that was statistically significant (17). In a meta-analysis by Clifford et al., HPV prevalence in HIV infected women with normal cytology was 36.3% for any HPV whereas for infection with multiple types of HPV, it was 12% (18). Further, out of a total of 5,578, HPV16 was the most common type of HPV found in HIV infected women with either atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL) (18). HPV16 was also found in 295 women with high-grade intraepithelial lesion (HSIL) (18). Lastly, together with Kaposi's sarcoma and B-cell non-Hodgkin lymphoma, invasive cervical cancer have been considered to be the three AIDS-defining cancers (ADCs) PLHIV (19). However, recently, additional cancers in various sites such as head and neck, anogenital, lung, and skin have been described and shown to be associated with HIV-1 infection (19).

The mucosa forms the innermost layer of the wall of luminal structures in the body, including the female genital tract (FGT). The mucosa consists of (i) the epithelium, as the topmost layer, (ii) an underlying loose connective tissue layer, (iii) a thin layer of smooth muscle called the lamina propria, and (iv) the muscularis mucosa. An intact epithelial barrier forms the predominant defense site against viral invasion and infection (20). A compromised epithelial barrier may enhance viral exposure to underlying target cells (20).

The female genital tract (FGT) is one of the organ systems of the body that connect the internal to the external environments and as such it is lined by the epithelium. The upper genital tract (UGT) comprises the uterus, fallopian tubes, ovaries, and endocervix while the lower genital tract (LGT) comprises the ectocervix, vagina and vulva (21) (Refer Figure 1). A single layer of simple columnar cells lines the UGT while multilayered pluristratified squamous cells line the lower genital tract (LGT) i.e., ectocervix and vagina.

The human vagina has a large surface area, ranging from 65.8 to 107.1 cm² with a mean of 87.5 cm² (22) and is the first mucosal surface in the LGT to come into contact with sexually transmitted pathogens (23), and is usually successful in impeding invasive infections. In contrast, albeit having a smaller surface area of approximately 4 cm in length and 3 cm in diameter, the endocervix (24), is a site frequently infiltrated by numerous sexually transmitted pathogens including HPV and HIV-1.

It is estimated that 30%–40% of all new HIV-1 infections in women occur following heterosexual intercourse via mucosal surfaces in the FGT (25), while an estimated sixty percent of HPV infections in women occur in the uterus (26). On entry into the FGT microorganisms such as HIV-1 and HPV interact with epithelial cells, and the initial innate immune responses are usually adequate to avert the infection at this stage. However, if they are not, then the epithelial signaling mechanisms of the host are activated and the infection is established (27).

Mucosal tissue serves as a protective barrier in the FGT and is the main target site for gynaecological cancers and infections by a spectrum of sexually transmitted pathogens, including HPV and HIV-1 (18). Consequently, a compromised mucosal barrier, and particularly the epithelium, increases the risk of acquiring these latter two viral infections. Recognised factors contributing to a broken or fragile epithelium include cervical ectopy (60), fluctuations in levels of reproductive hormones which may lead to a thin epithelium (38), high-risk sexual behaviour such as unprotected sex and early coitarche (61), co-presence of other sexually transmitted infections (62, 63), altered microbiome (64, 65) and inflammation in HIV-1 infection (66). In addition, there is an association between HPV and HIV-1, with the one worsening the other's pathogenesis (67, 68). Therefore, medical interventions directed at addressing these underlying mechanisms to acquiring HPV and HIV-1, could potentially prevent, halt or even treat these infections.

Primary prevention against HPV infection is by the HPV vaccine. The HPV vaccine first licensed in 2006 has been adopted by many countries (69). In 2022, an estimated 125 countries (64%) had adopted HPV vaccination in their national immunization programmes for girls (69). While this programme has largely been successful in protecting against HPV and curbing cervical neoplasia and invasive cervical cancer in many developing countries, there have, however, been structural and programmatic issues that have hindered it from being widely available and thus wholly successful (70). On the other hand, to date, there is no preventive vaccine against HIV-1.

With regards to FGT infection, the earliest phases of infection at the point of entry, where there are the most host immune strengths and most viral weaknesses, offer the best chances for effective interventions to prevent sexual viral transmission (54). As a compromised epithelium is the primary route for infection, targeting this area with products to mitigate infection is warranted. This is particularly the case as, by and large, there is understanding in the literature of (i) the baseline innate epithelial status as it pertains to secretion of infection-modulating molecules, (ii) endocrine regulation of these molecules over different phases of the menstrual cycle, and (iii) the earliest innate epithelial responses following exposure to viruses that achieve these aims. Thus, such pathogenetic pathways could be exploited to develop products that enhance the effectiveness of these immune responses.

Particularly, there are multipurpose prevention technologies (MPTs) which are products that aim to simultaneously prevent at least two sexual and reproductive health conditions inclusive of unintended pregnancy, HIV and other STIs including HPV (71). According to Boonstra, “There is a compelling need for new technologies that protect sexually active women against multiple sexual and reproductive health risks, especially in countries heavily burdened by HIV, HPV and by maternal and infant mortality” (72). To date, MPTs have come in various tested preparations and delivery methods, including intravaginal rings, vaginal and rectal gels, vaginal inserts and films, systemic delivery implants, subdermal microarray patches, and oral tablets containing contraceptives, anti-HIV and/or other STI prevention drugs (73). Particularly, Population Council looked at PC-1005 gel, also known as MZC gel, comprising of three key ingredients that provide broad-spectrum antiviral activity against HIV, HSV and HPV (74). In a Phase I clinical trial, this product was found to be promising with high acceptability levels (75). However, it is yet to be tested in higher clinical trial stages. Recently, the use of monoclonal antibodies (mAbs) as MPTs in the prevention and treatment of HIV-1 and other STIs have come to fore and several research studies are underway. Some of these have gone to clinical trial stages and they include MABgel and VRC01/MB66 topical vaginal film against HIV, amongst others, and 2C (HDIT101), E317 (UB-621) and HSV8 against HSV (76). Dohadwala et al., in their paper concluded that it is ideal to develop mAbs that will target multiple STIs concurrently (76).

Some other interesting studies have looked at the combination of antivirals as targets for both HIV and HPV. Specifically, Hampson et al., studied a combination of lopinavir and ritonavir, oral drugs used in the treatment of HIV, inserted intravaginally, as a potential treatment for CIN (77). Indeed, they were able to show at 12 weeks that there was an estimated 80% regression in cytology results from HSIL to either low grade or no dysplasia, a finding that was confirmed on histology (77). Further, about 50% had no detectable HPV. As the authors pointed out, these findings highlight the potential of the combination of anti-HIV drugs as a self-administered treatment for cervical lesions associated with HPV infection. What would be interesting is the use of these drugs as prevention of both these conditions.

In some regions of the world, such as Sub-Saharan Africa, there are high prevalence and incidence rates of both HPV and HIV-1 infections, and hence, they are overlapping public health enigmas, and eradicating one might impact the prevalence and impact of the other. To our knowledge, no side-by-side review has been done on the extent of the involvement of the epithelium in these two infections. This review therefore highlights areas of overlap and divergence between HPV and HIV-1 infections with regards to their involvement of the epithelium in their pathogenesis. The review ends by suggesting biomedical means of targeting both infections simultaneously. Conversely, the strength of this paper as a narrative review is that it remains broad, providing a general background on the topic. It could serve as a stepping stone to doing a more comprehensive review, such as a scoping review. Lastly, it does not necessarily shed light on guidelines for managing these infections.

Both FGT HPV and HIV-1 have varying degrees of epithelial involvement in their pathogenesis. HPV infection being exclusively intraepithelial and HIV-1 infection a systemic disease but requiring to traverse the epithelium to establish systemic infection. Breaches in the epithelium from various causes in the FGT enhance infection with both of them. We, therefore, need to focus our research on studying different formulations that can target both HIV and HPV simultaneously, and to prioritize research on different formulations that enhance the different aspects of the immune system to enforce their protective pathways.