Iranian Journal of Medical Microbiology

.

Acquired Immune Deficiency Syndrome (AIDS) is one of the basic public health issues in different societies. Unfortunately, the lack of awareness, equipment, and education has augmented the number of people suffering from this disease. Studies have shown that most individuals have this disease from adolescence. AIDS epidemics have significantly affected its side effects and mortality. It is estimated that 33.4 million people worldwide have HIV (1), and 25 million people have died because of this disease (2). It has been reported that more than 95% of individuals having HIV live in developing countries and more than 7 million are in Asia and the Pacific Ocean (3). HIV is still an important problem for the public health, with about 1.8 million new cases of infection annually. It was reported that about 38 million people lived with HIV in 2018 (4). New cases of HIV infection are decreasing annually; however, this decrease is not rapid enough to meet 90-90-90 target (90% diagnosis, 90% treatment, 90% virus surpass) until 2020 which has been determined by the shared program of the United Nations on HIV and AIDS to end this disease (5). To achieve the current target, which decreases the new cases of HIV infection to less than 500000 cases in 2020 throughout the world, producing durable, safe, effective, and acceptable products to decrease HIV sexual transmission is one of the most important priorities in preventing HIV (6). The world program to remove AIDS infection among children until 2015 and keep their mothers alive include four items: 1) preventing AIDS transition to women of pregnancy age; 2) preventing unwanted pregnancies among women with AIDS; 3) inhibiting AIDS transmission using antiviral drugs during pregnancy and breastfeeding; and 4) providing care, therapy, and support for mothers, children, partners, and families that live with AIDS (7). The service coverage for preventing HIV transmission from mother to child has been increased significantly since the beginning of world programs and reached 77% in 2015. As a result, new cases of HIV infection among children (0-14 years old) decreased by 51% from 2010. Moreover, the number of children receiving antiviral treatment has increased from 452000 in 2010 to 910000 in 2016, which decreased AIDS mortality among children by 44% (8). Remarkable development has been made in recognition of people with HIV: 21.7 million of the guesstimated 36.9 million people living with HIV worldwide are now on therapy (9). The amount of AIDS-linked fatalities in 2017 was the lowest ever in the 21^st century, and the occurrence of HIV infections has been lessening (9). The limited access to treatment, especially for the people at risk, are barriers that need to be addressed (10). The antiretroviral therapy is a treatment that does not cure the illness but is in high demand for the patients (11). According to the World Health Organization (WHO), the instant action is required to control the disease (12). The HIV vaccine will presumably be needed to finish the HIV epidemics (13). One of the most important features of HIV epidemics is the wonderful global genetic variety (14). HIV variety influences the HIV diagnosis measurements, viral load evaluations (15), expansion of drug resistance, and response to the antiretroviral therapy (16, 17).
The goal of nanotechnology is to control substances at the atomic and molecular levels (18). The utilization of nanotechnology in medicine, referred to as nanomedicine, necessitates the application of nanoparticles for preventive, therapeutic, and diagnostic purposes (19). Nanomedicine has made a considerable effect on the patients universally across different illness situations confining from hypercholesterolemia to macular degeneration and different cancers; present treatments Myocet for the breast cancer, Visudyne for macular degeneration and Tricor for cholesterol controlling (20-22). The principal utilization of nanotechnology in the targeted drug delivery has been performed by nanoparticles that are particularly beneficial in the treatment of tumors (23). Nanoparticles play a significant role in the society via a diversity of applications ranging from electronics to medicine. Nano-compounds have been extensively exploited in biomedicine in various ways (24-27). Nano-based delivery systems can be attuned to regulate medication release, lessen drug-related poisonousness, and protect medicines from metabolism (28-31). Nanotechnology requires the synthesis and manipulation of the substances or systems where at least one dimension is in the nm size (32-38). Particles in this size range have unrivaled physicochemical attributes, which are distinguished from those of bulk substances or single atoms or molecules (33, 35, 36, 38, 39). The essential meaning of the application of nanotechnology-based systems for the antiretroviral medicine transfer is linked to the pharmacokinetics modulation of the synthetic molecules. The absorption, dissemination, and deletion in the human body are distinguished not by the medicine attributes, but the nanosystems physical and chemical attributes, especially surface-displayed molecules, electric charge, and the size (40). The general attributes of nanosystems that are served in the antiretroviral medicine transfer contain adaptation, good toxicity characteristics, ability to modulate drug-dissemination, high drug payloads, and low expense (41, 42). Some studies have demonstrated that nanomaterials can have a positive influence on the tissue repair (43, 44, 45). Nanotechnology-based methods can be utilized to construct nanofibers and controlled-release nanoparticles to guide cell behavior. Nanoparticles have a high capability as carriers for the delivery of different molecules, including RNA, DNA, etc. The attributes and performance of nanomaterials have led to their application in the gene delivery programs (46). Nanoparticles have been used as carriers for the drug delivery. Nanocarriers improve drug performance and reduce its side effects by altering the pharmacokinetic properties of the drug. In the manufacture of nanoparticles to transfer drugs, different materials such as polymers, metal particles, lipids, etc. are utilized, which can be produced depending on their production method, and disparate shapes and sizes. The future of research is on the development of multifunctional drug nanoparticles, such as particles with the targeted drug delivery capabilities.
 

.

HIV is a member of the Lentivirus genus and the Retroviridae family (47). Lentiviruses share most of the morphological and biological characteristics. Most mammals are infected with Lentivirus, which is the cause of many long-term diseases with long latency (48). Two types of HIV have been determined: HIV-1 and HIV-2. HIV-1 is the virus that was detected first. This has more viral load with more infectivity (49), and is the main cause of HIV infections all over the world. Milder infection of HIV-2 compared to the HIV-1 reveals that few people are exposed to HIV-2 infection. Due to low transmission capacity, HIV-2 is limited to some regions in the Western Africa (50). HIV-2 is transmitted through sexual contact and blood and is rarely transmitted from mother to child (51). Although HIV-2 causes AIDS, disease progress is slower than HIV-1 (52-54) and is generally less transmitted (55). Molecular epidemiology studies have presented insights on the origin and patterns of wide geographical transmission of HIV-1 (56). Young people between 15 and 24 years old are more exposed to this disease, and it is estimated that 6000 to 7000 individuals are infected daily (57) which 95% of them are in developing countries (58). Young men form one-fourth of the HIV patients and are exposed to HIV due to involving in high-risk behaviors (59). After primary infection and local augmentation in the mucosa, the infected cells migrate to the local lymph nodes resulting in a slight primary viral reinforcement in the naïve T cells (60). The viral infection is then rapidly disseminated by T cells to lymphoid organs, exclusively the lymphoid tissues related to the intestine, spleen, and bone marrow, being companioned by a burst in the viral load (61). During the acute and early phases of the digestive system infection, it is exclusively affected by the virus, resulting in the considerable loss of CD4+ and CD8+ T cells, which is never fully ameliorated entirely and persist notwithstanding antiretroviral therapy (62, 63). People in the acute phase of infection are in the enhanced risk for the sexual transition as a consequence of high viral load in blood and reproductive tract (64). In this case, the CD4+ T cell levels ameliorate soon after andCD8+ T cells ascend by a quick recovery of usual rates. The virus load is then decreased in the answer to the immune response, but is never entirely evacuated, eventuating in a latent, asymptomatic infection (65). During latency, the virus insists on the extravascular tissues, dendritic cells, and resting CD4+ memory cells. This condition can be developed by diminished CD4+ T cell counts and escalating viral load (66). By the development of infection, HIV genetic variety is enhanced dramatically owing to severe error-prone reverse transcription which helps to escape the immune system (67).
  

.

2.1. Effects of Antiretroviral Drugs

2.1.1 Before Exposure

Initial treatment of individuals who are in contact with infected persons prevents AIDS transmission up to 96% (68, 69). Prevention before exposure with certain doses of tenofovir with or without emtricitabine was effective in some groups which include gays or couples that one of them is infected (70).
 

2.1.2 After Exposure

Prevention after exposure is the period of using antivirus, which is described as 48-72 hours after exposure to the infected blood or genital discharge (71). Using zidovudine decreases HIV infection up to five times (71). Current treatment programs generally use zidovudine or tenofovir/emtricitabine, and they can decrease the infection risk significantly (71).
 

2.1.3 Mother to Child

If breastfeeding is only done by mother, long-term antivirus prevention period decreases the transmission risk (72). This period includes using antivirus drugs during pregnancy, and after giving birth, and a special baby bottle should be used instead of breastfeeding (73, 74).
 

2.2. Macromolecular Inhibitors

Various anionic macromolecules prevent HIV-1 from binding to CD4 via interactions with glycoproteins (75). Therefore, their capability as a preventive method has been investigated in several clinical trials. However, macromolecular inhibitors demonstrated a supreme assurance in animal models; clinical trials in humans have shown no significant resistance to placebo (75-77). Some inhibitors, for example, cellulose sulfate, have shown an augmented danger of HIV owing to the demolition of the vaginal epithelium (77). Currently, nanotechnology-based macromolecular inhibitors are being evaluated in the clinical trials (78-81). There is remarkable interest in expanding new vaginal ring designs for the continued release of large molecular weight, and particularly remedial peptides, and proteins. Much of the initiative in vaginal ring scheme has been driven by endeavors to extend microbicidal vaginal rings for the prophylaxis of sexual transmission of the HIV, and general-purpose prophylaxis technology rings for contemporary prophylaxis of HIV transferred infections (82-84). Histone deacetylase inhibitors have been demonstrated to restrain HIV-1 infection in monocyte-isolated macrophages by activating SAMHD1 (85). The HJ16 is a monoclonal antibody isolated from memory B cells from HIV-infected persons that can neutralize nearly 40% of HIV isolates (86). The retrocyclins have been demonstrated to prevent the six-helix bundle formation of HIV, which is needed for the viral fusion (87, 88). The M9 is an instance of single-chain antibody fragments efficacious against primary HIV in vitro (89). The M36 molecule is an example of a heavy chain domain antibody that demonstrates higher neutralizing activity against primary HIV isolates in comparison with single-chain antibody fragments (90).
 

2.3. Nucleic Acid Therapy (siRNA)

Detection of the RNA interference (RNAi) mechanism has revolutionized various bases, such as medicine. The RNAi uses an RNA structure to persuade mRNA degradation in a particular sequence (91-94). In recent years, remarkable endeavors have been made to establish the RNAi structures for the HIV prevention with topical administration. It contains several HIV-1 encoded siRNAs such as tat, rev, pol, vif, env, vpr, and LTR that can prevent HIV-1 in the cells. The HIV transmission occurs through the use of different cellular recipients from the host (92-94). Thus, siRNAs targeting the expression of these recipients can prevent HIV. However, RNAi therapy can prevent HIV; although, there are different challenges with RNAi drug delivery. Severe hydrophilicity and an anionic load of siRNA substantially inhibit their cellular uptake (93-95). The advances in chemistry and drug delivery for remedial siRNAs have helped to prevail various obstacles to their clinical progress (96). The transfection efficiency and cytotoxicity of the nanoparticles are the most significant parameters to be assumed for the siRNA delivery (97). Among different nanocarriers utilized for in vitro and in vivo siRNA transfection, chitosan and its derivatives have attracted more attention for the treatment in the specific tissues such as lungs and colon (98-100).
 

2.4. Nanotechnology for Prevention of HIV

According to the National Nanotechnology Improvisation, nanotechnology contains research of nm-sized substances in at least one dimension (31, 101-104). However, materials over 100 nm in size are also included under nanotechnology field. Currently, various nanotechnology-based products are being applied in the clinical trial. In recent years, various studies have focused basically on the use of nanotechnology to improve the therapeutic efficacy and target antiretroviral methods (31, 101-107). Their ability to combine, defend, and absorption of the non-orally prescriptible anti-HIV medicines, namely oligonucleotides (108, 109), significantly ameliorates the bioavailability of the various molecules (110-112). The application of nanoparticulate systems for the antiretroviral medication delivery can be especially beneficial for the targeted delivery, specifically to the cells that are straightly involved in Human Immunodeficiency Virus (HIV) (41, 42). The application of nanotechnology in medicine prepares innumerable facilities in the treatment of HIV (113). Nanotechnology-based systems can influence drug delivery systems and ameliorate drug characteristics. They can also augment the effectiveness of treatment and lessen drug toxicity (114). In HIV infection, CD4+ T cells are  critical targets for the virus. This has stimulated a number of nanoparticle-based strategies to aim remedial factors like antiviral siRNA or antiretroviral drugs to CD4+ T cells to prevent HIV replication. Lipid nanoparticles enclosing the antiretroviral drug indinavir were aimed at CD4+ T cells using peptides that identify the CD4 co-receptor. Pre-treatment of CD4+ T cells with the targeted lipid nanoparticles resulted in a lessened number of the infected cells contrasted to the non-targeted lipid nanoparticles in vitro (115). The NCT02549040 trial (phase 1) registered 16 patients and evaluated and compared the relative bioavailability of different MK-1439 experimental nano-formulations (NFs) with that of a MK-1439 film-coated tablet, in the patients with HIV-1 infection.
 

2.5. Nanotechnology and Gene Therapy

Nanotechnology-based gene therapy is a method of treating HIV by incorporating a gene into a cell that is associated with a viral infection or replication. Other compounds based on the nucleic acid can be used to interfere with viral replication (116). Weber et al. have utilized carbosilane dendrimers to deliver siRNAs targeting HIV p24 (117). The dendrimer siRNA collection demonstrated the best efficiency in HIV-infected peripheral blood mononuclear cells without any cytotoxicity, and maintained siRNA from degradation in the presentment of RNase. The dendrimer was examined in mice, and the efficient siRNA forwarding via blood-brain barrier was noticed (118). The scientists in the University of California, Los Angeles have demonstrated that cell-derivative gene transmission is secure and active in people living with HIV. Delivery of particular CD4 siRNAs led to the RNA responses without side effects such as cell toxicity or immune stimulation. Antibody-based siRNA delivery displayed that the gag gene could suppress HIV proliferation in the initial T cells (119). Another gene therapy method is to constantly inactivate CCR5 by the zinc finger nucleases. Zinc finger nucleases are genomic scissors containing DNA binding and cleaving domains (120).
 

2.6. Nanotechnology and Vaccine

Nanoparticles not only prepare the ameliorated antigen delivery but also play a significant role in the starting immunity (121-123). There are advantages in using nanoparticles in a vaccine structure. Nanoparticles can strengthen the absorbed antigens and act as an antigen (121, 124). They can also imitate the characteristics of pathogens, such as viruses (125). Nanoparticles can induce the adaptive and innate immune responses. They are applied as antigen carriers to augment the antigen processing and presenting, due to their high particular surface area and performance. These specifications of nanoparticles have led to the efficacious cell targeting and controlled release of the antigens (126). Nanoparticles can enhance the half-life of most vaccines (127). The first effort to obtain HIV antigens using liposomes was reported nearly two decades ago (128). Since then, the impact of various features including liposome components, ways of construction, HIV antigen, the path of prescription, and the sort of adjuvant for the expansion of liposomal HIV vaccines have been investigated, and research is still in progress. Phillips et al. estimated the effect of liposome ingredients on the immune responses to HIV envelope glycoprotein gp120 after percutaneous prescription (129). Polymeric nanoparticles are of immense interest in vaccine delivery because of having some attractive attributes, including biocompatibility, predictability, biodegradation, stability, easy surface modification, and the safety (130). Polymer-based delivery systems demonstrated some advantages such as stable release, protection of the enclosed antigen against enzymatic degradation, targeted delivery, and adjuvant influences. Some polymer nanoparticles have been pursued for the development of mucosal vaccines to deliver antigens (131-133). Carbon nanoparticles are utilized as another compound for the drug and vaccine delivery owing to their high biocompatibility. They can augment the level of IgG response by the protein antigen presentation (134).
 

2.7. Nanomaterials for Prophylaxis and Treatment of HIV

2.7.1. Liposomes

Liposomes are vesicular carriers contained of two phospholipid layers and an aqueous nucleus. They are appropriate as drug carriers. It is worth noting that the aqueous nucleus is best to maintain hydrophilic drugs, while the two phospholipid layers maintain the hydrophobic and amphiphilic medicines. In addition, they are very useful for antiviral factors because of their native form that are taken up by the reticuloendothelial system and is rapidly removed from the bloodstream (135). Liposomes were the first to be developed and also have the longest research history among all the commercial nanocarriers. The size of liposomes can be in the range of 80 nm-10 µm depend on the procurement way and combination. Many studies are providing detailed descriptions of liposome ingredients, ways of construction, types of liposomes, biophysical attributes, properties, and their usages (136-138). The characteristic of liposomes to get quickly identified by the phagocytic cells of liver and spleen after intravenous prescription and get somewhat concentrated in lysosomes has been used for enhancing the prevention and treatment of different infectious illnesses (137-141). The first liposomal formulation introduced to the world pharmaceutical market was the liposome containing doxorubicin called Doxil®. The presence of polyethylene glycol (PEG) on the surface of this liposome enhanced the half-life of doxorubicin (142, 143). Malavia et al. formulated different liposomes, comprising cardiolipin and synthetic phospholipids by simple ethanol injection procedure. The combination of liposomes had a significant influence on the anti-HIV activity and the elective indicator of cardiolipin. Cardiolipin-tagged fluorescence liposomes were found to be maintained in the vaginal cavity of mice for almost 24hours after intrauterine prescription, and liposomal formulation had no side effects (144, 145). The MC-1220, a hydrophobic reverse transcriptase suppressor, was encapsulated in liposome and they were surrounded in Carbopol gel (146). Liposomes have been utilized for the intravaginal transfer of siRNA targeting HIV-1 or HSV-2 (147-149). Wu et al. expanded alginate-based scaffolds for the transfer of inert mucosal PEGylated cationic liposomes comprising fluorescently tagged siRNA (148). It was perceived that liposomal siRNA could attain the vaginal epithelium and reticence gene expression (148). The use of liposomes has also been presented in self-amplifying RNA vaccines transfer (150). The liposomes used for this objective had significant countenances such as attendance of cationic lipid, ionizable lipid, and PEGylated lipids (150). The liposomal AAR029b had the advantage of slower clearance rate, higher whole medicine exposure over time, and increasing serum half‐life, resulting in the expansion of permanent proteolytic peptide triazoles for the HIV-1 treatment capability (151). Surface‐rectified liposomal nanocarriers have been used for the transfer of anti‐HIV‐1 drugs to provide access to lymphoid tissues (152, 153). Liposomes are divided into cationic, anionic, and neutral types. Liposomes can retain the antigens from degradation, and increase their absorption by antigen-presenting cells. The cationic liposomes are usually applied in the adjuvant delivery system in DNA vaccines (154). The following Tables highlight the clinical trials on the effects of nanoparticles, especially liposomes, in the treatment and prevention of HIV-related diseases (Tables 1 and 2) (155). The hydrophobic and hydrophilic nature, biocompatibility, and ease of surface changes are among the factors that introduce liposomes as a suitable option for the drug delivery.
 

Table 1.  Ongoing clinical studies exploring the contribution of liposomes

Table 2.  Completed clinical studies exploring the contribution of liposomes

2.7.2. Dendrimers

Table 3.  Completed clinical studies exploring the contribution of dendrimer

The authors thank all those who helped them writing this article.

 

The authors declared no conflict of interests.