Human immunodeficiency virus (HIV) infection has been a major public health issue for the past four decades. Despite extensive global research and study (1–3), a cure for HIV infection has, thus far, proven elusive. Recently, our research group has proposed novel potential therapeutic options for HIV infection (4, 5) which, we believe, could inspire future clinical trials into curative therapeutic options for HIV. Our first proposition concerns the promotion of P-selectin glycoprotein ligand 1 (PSGL-1), an important receptor from innate immunity, which (i) induces the production of membrane defective virions that are unable to attach to or infect new target cells, and (ii) blocks the HIV reverse transcription process. Our second proposition involves the selective elimination of host cells capable of producing HIV virions via the use of a therapeutic cocktail of drugs (latency reversal agents, autophagy inhibitors, apoptosis activators, and antiretroviral drugs).

The World Health Organization (WHO) has proposed that HIV infection may be divided into four clinical stages in adults and adolescents 15 years-of-age and above (6). HIV-positive patients who are asymptomatic or have persistent generalized lymphadenopathy (lymphadenopathy of at least two sites [not including inguinal] for longer than 6 months) are categorized as being in stage 1. Clinical findings included in stage 2 (mildly symptomatic stage) are unexplained weight loss of less than 10 percent of total body weight and recurrent respiratory infections (such as sinusitis, bronchitis, otitis media, and pharyngitis), as well as a range of dermatological conditions including herpes zoster flares, angular cheilitis, recurrent oral ulcerations, papular pruritic eruptions, seborrhoeic dermatitis, and fungal nail infections. Manifestations included in clinical stage 3 (the moderately symptomatic stage) are weight loss of greater than 10 percent of total body weight, prolonged (more than 1 month) unexplained diarrhea, pulmonary tuberculosis, and severe systemic bacterial infections including pneumonia, pyelonephritis, empyema, pyomyositis, meningitis, bone and joint infections, and bacteremia. Stage 4 (the severely symptomatic stage) includes all of the AIDS-defining illnesses, e.g., HIV wasting syndrome, Pneumocystis pneumonia (PCP), recurrent severe or radiological bacterial pneumonia, extrapulmonary tuberculosis, HIV encephalopathy, CNS toxoplasmosis, chronic (more than 1 month) or orolabial herpes simplex infection, esophageal candidiasis, and Kaposi’s sarcoma. WHO HIV clinical staging utilizes standardized clinical parameters to direct medical decision making for patients with HIV/AIDS, and can be used based solely on patient clinical features, thus accommodating treatment facilities that may have limited or no access to sophisticated laboratory testing, such as those in low- and middle-income countries and regions (7). There is, also, the existence of the Fiebig staging system of HIV infection (first published in 2003, and comprising 6 stages), which describes the emergence of virological and immunological markers following infection by HIV. Several discrete clinical phases can thus be recognized for HIV infection; however, it has been generally accepted that HIV infection exhibits an acute phase, a chronic phase, and the acquired immunodeficiency syndrome (AIDS) phase (8).

In 2020, it was estimated that 36.7 million people globally were infected by HIV (9), and thus, the global HIV pandemic continues to pose a material threat to the health of mankind. The large majority of new HIV infections occur in low- and middle-income countries (10). Poverty, stigma associated with HIV disease, cultural and social barriers to appropriate testing and treatment, insufficient and inadequate health care infrastructure to support the large patient pool, poor health literacy, limited provider training, inadequate and inappropriate medical equipment, scarcity of appropriately-trained medical manpower to distribute health care throughout specific regions, and an inadequately low number of accredited medical laboratory facilities are some of the numerous factors that contribute to the almost inexorable global propagation of HIV (11).

At the same time, hepatitis B virus (HBV) is also silently spreading amongst the global population, especially in low- and middle-income countries (12). In 2019, the WHO estimated that 296 million people were living with chronic HBV (with 1.5 million new infections each year). More specifically, the WHO Western Pacific Region and the WHO African Region presents the highest chronic hepatitis B infection rates, with 116 million and 81 million people infected, respectively. Lower proportions occur in (i) the WHO Eastern Mediterranean Region (with 60 million people infected), (ii) the WHO South-East Asia Region (with 18 million people infected), (iii) the WHO European Region (with 14 million people infected), and (iv) the WHO Americas Region (with 5 million people infected) (13). Thus, HBV affects hundreds of millions of people worldwide, and is responsible for progressive liver fibrosis and hepatocellular carcinoma, amongst other chronic health sequelae (14, 15) during the chronic phase of HBV disease. Most cases of HBV infection in adults are arrested early, and are defined as an acute infection that is generally successfully limited by the patient’s own immune system. Only adults with an immunocompromised immune system tend to progress to chronic HBV (16–18). Unfortunately, most cases of HBV infection acquired in infancy or early childhood however, do become chronic (16–18). According to WHO, around one third of the world’s population has been infected by HBV at some point of their lives (16–18). Thus, HIV-HBV coinfection is relatively common (19). Estimations suggest that 10 to 28% of HIV-infected individuals are chronically infected with HBV (20–25). Indeed, the rates of HIV-HBV coinfection vary significantly between regions and risk-based groups. For instance, a study in Vietnam has shown that HIV-HBV coinfection is significantly higher among people who inject drugs (28%) or who are sex workers (15%) (23). Similarly, Xie et al. (26), have reported an estimation of 10% with respect to the existing HIV-HBV coinfection rate in China in general; however, they also state that the prevalence of such HIV-HBV coinfection in China varies between regions from 5% to 15%. In an extensive review on HIV-HBV coinfection, Singh et al. (27), suggested that West Africa and South Africa possess the highest prevalence of HIV-HBV coinfection in the world.

Several past studies have explored the impact of HIV-HBV coinfection on patients’ health, and have found that this comorbid association accelerates HBV progression (higher levels of hepatitis B viremia, higher risk of developing cirrhosis and hepatocellular carcinoma) (28), and materially amplifies the complexities related to treatment (27, 29–31). Among the mechanisms triggered by HIV infection which accelerate the progression of HBV infection, we can list (i) HIV replication in the liver, (ii) HIV-associated microbial translocation and immune activation, and (iii) immune exhaustion and tolerance. Each of these mechanisms mediated by HIV pathogenesis has significant effects on liver disease, as noted by Singh et al. (27). However, to the best of our knowledge, there remains a paucity of published research investigation in the literature which critically describes the influence and consequences of HIV clinical staging that potentially favor HBV establishment in HIV-infected individuals.

We therefore propose, herein, to review the appropriate literature to elucidate the potential mechanisms favoring HBV infection at each clinical stage of HIV infection. In the first part, we discuss the transmission routes of both HIV and HBV, and their subsequent life cycles once they have entered the human body. In the second part, we critically discuss the potential influence of each of the HIV acute, chronic, and AIDS phases that either lead to or may potentially lead to HBV infection.

It is well-established that HIV and HBV share the same transmission routes. Indeed, both viruses are known to be transmitted from person to person through sexual intercourse, via contaminated needles used for intravenous drug delivery, from mother to child, and by the therapeutic use of HIV or HBV-infected blood or blood products (32). Thus, individuals who have casual sex in the absence of a condom and those who inject recreational drugs are at a particularly high risk for acquiring not only HIV infection, but also HBV infection (29). Once a person is infected by either HIV or HBV, these viruses exhibit two distinct life cycles within the infected persons body ( Figure 1 ).

HIV targets immune cells, preferentially CD4+ T-lymphocytes. Then, a viral envelope glycoprotein molecule (gp120) binds to a host cell receptor or co-receptor, such as CCR5 or CXCR4, responsible for HIV entry into lymphocytes and macrophages. The binding of gp120 to these receptors results in a cascade of molecular conformational changes and the exposure of gp41, bringing the HIV virion in much closer proximity to the target cell. Subsequent fusion of the viral envelope with the host cell membrane is essential for the entry of the inner matrix core of the virus into the intracytoplasmic realm of the host cell (33). Within the viral inner core are two strands of viral RNA held together by two small proteins (P6 and P7), and three of the enzymes essential for viral replication, viz., integrase, protease, and reverse transcriptase. Accessory proteins such as Nef, Vpr, and Vif are also found in the core matrix of the virus. Although these accessory proteins are not essential for viral replication, they play crucial roles in counteracting defensive mechanisms activated by the host cell (34, 35). Once within the host cell cytoplasm, the core matrix of the virion disintegrates, releasing the viral capsid as well as the genome of the virus. The viral RNA, together with the essential viral enzymes, is thus exposed to the host cell cytoplasm. The viral RNA then undergoes reverse transcription into viral DNA through a process mediated by the viral reverse transcriptase. Earlier investigations have revealed that the viral DNA generated by the reverse transcription process within the host cytoplasm is part of a broad nucleoprotein complex known as the pre-integration complex (PIC) (36), which also comprises Vpr and the integrase enzyme. Subsequent migration and entry of the PIC into the nucleus is followed by the process termed integration, which is mediated by the integrase enzyme. The preceding view, that conversion of the HIV RNA genome into DNA occurs in the cytoplasm before nuclear entry has, however, been challenged recently. Indeed, Dharan et al., have provided evidence to support the hypothesis that reverse transcription and uncoating can occur in the nucleus of non-dividing cells, such as macrophages or cells treated with the tetracyclic antibiotic, aphidicolin (37). For integration to occur, the integrase within the PIC acts by slicing through the DNA of the host cell, and thus allowing viral DNA to be inserted at a variety of sites on the host DNA, i.e., integrase catalyzes the insertion of viral dsDNA into the host chromosome (38, 39). For HIV, and most viruses that integrate into the host genome (e.g., murine leukemia virus, Herpes simplex virus-1, Ebola virus), observations from past studies (40, 41) reveal evidence of the DNA splicing and joining steps. It is critical to keep in mind that, usually, two nucleotides are removed from 3’ end of the viral DNA. Then, these 3’ ends attack a pair of phosphodiester bonds on opposite strands of the target DNA, across the major groove, leading to a bonding of the covalent 3’ ends of the viral DNA to the target DNA. Finally, the single-strand gaps and the two-nucleotide overhang at the viral DNA’s 5’ ends are repaired by cellular enzymes, in order for integration to be complete. For HIV, the sites are five base pairs apart instead of two, resulting in a five base-pair duplication (42). Once HIV DNA is integrated into the host cell genome in this manner, the host cell is considered to be infected for life. Thus, the integrated viral DNA, referred to as provirus, can be used to generate genomic RNA, which can serve as messenger RNA (mRNA) for the synthesis of viral proteins in the host cytoplasm ( Figure 1A ).

HBV targets and replicates solely in the parenchymal cells of the liver (the hepatocytes) (43–46) ( Figure 1B ). Moreover, it has been established that HBV infects only humans, chimpanzees, and to a lesser extent, tree shrews (Tupaia belangeri) (47, 48). Once in contact with the liver, the circulating virion initially attaches to heparan sulfate proteoglycans (HSPGs) (49, 50). Then, the interaction of a specific domain of the HBV L envelope protein with the sodium taurocholate co-transporting polypeptide [NTCP, a hepatocyte-specific transporter of bile acids that is predominantly localized in the basolateral membrane that faces the sinusoidal lumen (51)] on the surface of the hepatocytes contributes to viral entry into the hepatocyte (52). Following entry and uncoating, the nucleocapsid carrying the HBV genome is transported into the nucleus, where it is released as relaxed circular (rc) DNA. There, the rcDNA is converted into an episomal covalently closed circular (ccc) DNA minichromosome by host enzymes (46, 53). Reports suggest that cccDNA is very stable, persisting indefinitely, and is one of the main barriers to cure for hepatitis B disease (46), as it is the template for all HBV RNA transcripts (27, 54) that leave the nucleus unspliced, and produces the viral structural and non-structural proteins (53). Thus, HBV can initiate viral replication with an estimated doubling time of 2-4 days (55, 56). Interestingly, HBV polymerase can encode the pre-genomic RNA (pgRNA) and the reverse transcription of pgRNA can also lead to the formation of double stranded linear HBV DNA (dslDNA). Once in the nucleus, the dslDNA, in a similar manner to HIV, can integrate into the host genome (27). In contrast to HIV, the integrated dslDNA cannot enable viral replication, but it does allow the expression of certain gene products, like the envelope proteins (Env), which are dissimilar to the envelope proteins generated from cccDNA, which coat filamentous and spherical subviral particles (SVPs) (54). In general, acute manifestation of HBV infection occurs within 6 months after a person is exposed to HBV (57). From an acute infection, it can subsequently progress into a chronic infection. Indeed, although most people with healthy immune systems are able to clear the virus at the acute stage, immature immune systems and/or impaired immunity can lead to the establishment of chronic HBV infection in infants and/or adults (58, 59). Once the disease becomes chronic, it becomes a lifelong infection which, in the absence of effective treatment, can cause liver cancer or significant liver damage and scarring, leading to eventual liver failure.

In vitro and in vivo reports suggest that HIV can also infect hepatic stellate cells, sinusoidal endothelial cells, Kupffer cells, and the resident macrophages of the liver [as reported by Chamroonkul and Bansal (60), Housset et al. (61) and Cao et al. (62)]. HIV RNA sequences from the livers of untreated HIV-positive individuals show distinct compartmentalized sequences when compared to RNA sequences from other tissue sites (63). Further studies have demonstrated that HIV can persist in the liver even in patients on antiretroviral therapy (ART), primarily in Kupffer cells (64–66). In this review, therefore, we explore and discuss the influence of HIV infection on the establishment of HBV infection, especially being cognizant of the fact that HIV is known to provoke the fundamentally profound immune system impairment necessary for the onset of chronic HBV. Normally, most people with healthy immune systems are able to clear HBV during the acute phase. Utilizing the combined actions of HBV-specific CD4+ T-cells [essential for the induction and the maintenance of both CD8+ T-cells and antibody responses (67, 68)] and HBV-specific CD8+ T-cells [which kill infected hepatocytes and induce local production of proinflammatory cytokines (69–71)], a healthy person can easily overcome acute HBV infection, and thus avoid the chronic and life-threatening phase of the infection. Subsequently, our discussions will consider HIV as the primary infection, and we reflect further on the immunological consequences of HIV infection that favor HBV infection.

The various mechanisms through which liver injury may occur in patients with HIV infection are numerous; a general breakdown of these mechanisms is presented in Table 1 . A reasonable understanding of these mechanisms is of significant importance to the comprehension of HIV/HBV pathological processes, and any liver injury may further represent an ‘open door’ for HBV to enter hepatocytes and subsequently establish infection. This preceding assertion is speculative at this stage, and further investigation is required to establish precisely how liver injury induced by HIV infection could facilitate HBV invasion of hepatocytes.

During the seroconversion phase, which occurs after the acute phase ( Figure 2 ), the body starts producing detectable levels of HIV-specific antibodies. A seropositive individual may have flu-like symptoms, such as fever and body aches during this phase. The duration for HIV disease progression with clinical symptoms varies widely across individuals, although it usually progresses slowly (120). Most HIV-positive individuals are diagnosed during or after the seroconversion phase [as HIV diagnostic tests generally target HIV-specific antibodies (121)]. During this period, the earlier detection and earlier initiation of appropriate treatment leads to a reduced risk of onward transmission. Due to HIV-specific antibody production, HIV-infection is stabilized at this stage of the infection, meaning that the plasma viral RNA load, despite being high, remains stable, CD4+ T-cells counts increase slightly, and the immune system activation remains persistent. HIV causes several structural, functional, and immunological impairments, resulting from a persisting underlying chronic inflammatory state (122–124). HBV establishment is likely to be favored by HIV infection during the seroconversion and the chronic phases as HIV infection sustains the immunological impairments present during the acute phase, in conjunction with other mechanisms, as described in the following paragraphs.

The global success of ART in treating HIV infection and AIDS has led some to some doubt whether a curative solution to AIDS is necessary. Only patients not on ART or those who are infected with HIV strains resistant to ART can progress to the AIDS phase of HIV infection (166). In general, in untreated people or inadequately treated people, it takes several years to gradually progress from primary HIV infection to the AIDS phase, which is characterized by the onset of symptoms and signs of severe HIV illnesses and profound immunosuppression. The immunological and other issues encountered during the acute and the chronic phases of HIV infection are significantly exacerbated in the AIDS phase. A patient at this stage of the infection may have a substantially high viral load, which may, in addition to a very low CD4+ T-cell count ( Figure 2 ), lead to further liver injury, thus favoring HBV infection. The overtly symptomatic stage of HIV illness denotes the late stage of HIV disease (AIDS) in which patients (i) have a CD4+ T-cell count of less than 200 cells/mm³ and (ii) are vulnerable to additional opportunistic infections (OIs) (167) (such as infections by Mycobacterium avium complex, Mycobacterium tuberculosis, Pneumocystis jirovecii, Cytomegalovirus, Toxoplasma gondii, and Candida species) or the occurrence of aggressive forms of Kaposi’s sarcoma or B-cell lymphoma (32). Unfortunately, numerous OIs are known to be associated with liver injury, which is a vital facilitator for HBV invasion of the liver (168–173). The liver is frequently affected by opportunistic infections, most commonly in infections by mycobacteria and Cytomegalovirus (174). Compared with non-TB HIV-infected patients, TB-HIV co-infected patients present with more significantly aberrant liver function profiles, with higher serum total bilirubin, alanine transaminase (ALT) and alkaline phosphatase (ALK-P) levels (175). Dey et al., showed that Mycobacterium tuberculosis can be an etiological factor for liver abscesses in HIV-infected patients (168). Infection by Toxoplasma gondii has also been reported to promote chronic liver disease in HIV-infected individuals (169). Hepatitis C virus infection is also known to act as an opportunistic disease in AIDS patients, directly causing progressive liver damage, which may also result in liver cirrhosis and hepatocellular carcinoma (176, 177).

Moreover, the medications associated with the drug treatment of opportunistic diseases are further contributing factors to persisting liver damage. The current first-line drug treatment for TB is a regimen of four drugs, i.e., isoniazid (INH), rifampicin (RIF), ethambutol (EMB), and pyrazinamide (PZA) (178). However, hepatotoxicity has been frequently observed as a serious adverse reaction following the use of these anti-TB drugs, especially with use of PZA, INH, and RIF, with a 2–28% incidence rate (179–183). Among PLWH, a higher incidence of hepatotoxicity has been seen, and Araújo-Mariz et al., have reported a 30.6% cumulative incidence rate of hepatotoxicity in PLWH following the use of recommended drugs for TB treatment (184). Sulfonamides, including trimethoprim/sulfamethoxazole (TMP/SMZ) and sulfadiazine, are other drugs which have been widely used in AIDS patients, and have been recommended as drugs of first choice for infections by Pneumocystis jirovecii and Toxoplasma gondii in HIV-infected patients (185). These drugs have also been frequently reported to induce hepatotoxicity (186–189).

Other contributing factors that may occur during the AIDS stage, such as paradoxical and unmasking immune reconstitution inflammatory syndrome (IRIS) and drug-drug interactions, may also result in liver disease or toxicity (190, 191). However, further studies of the baseline liver status of patients (uninfected by HBV) during the AIDS stage and studies of liver enzyme profiles in these patients during the AIDS stage are warranted to further assess other potential influencing factors for HBV establishment in patients with AIDS.

It is known that HIV infection induces an immunodeficiency syndrome, rendering the patient vulnerable to infections, including HBV infection. The present review is the first to critically discuss the specific mechanisms leading to HBV establishment in a patient who is already HIV-positive. We report that the acute phase is responsible for a sudden immune system defense subversion, a CD4+ T-cell depletion, and a high viral RNA load, all contributing to increasing the vulnerability of the liver, which subsequently inexorably develops a permissiveness to HBV. During the chronic phase of HIV infection, gut-associated dysbiosis and immune cell exhaustion, compounded by the hepatotoxic phenomena encountered during the acute phase, are two major consequences of HIV infection which are likely to enhance the probability of subsequent HBV invasion of the liver. The other possible facilitatory causes for HBV invasion of the liver in HIV-infected patients that we have discussed herein are the use of modern ART, and HIV-associated B-cell depletion. Finally, the AIDS phase of HIV infection is often defined by particularly low CD4+ T-cell counts, OIs (and OI-related drug treatments), and extraordinarily high viral RNA loads, all of which, as we have described herein, conspire to inflict further sustained injury to the liver, which also favors HBV establishment.

SZ and JO wrote the first draft of the manuscript. YLC, YJ, and HW provided critical revision of the manuscript. YKC conceived and designed the study. All authors read and approved the manuscript and its submission for publication.

This work was supported by the Chongqing Talent Cultivation Program (cstc2021ycjh-bgzxm0275), the Joint Medical Research Project (2020GDRC010) of Chongqing Science & Technology Bureau and Chongqing Health Commission, the Chinese Federation of Public Health foundation (GWLM202024), and the Chongqing Science & Technology Bureau project (cstc2020jscx-cylh0004).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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