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Novel HIV Antiretroviral Therapeutic Strategies
When the first cases of HIV infection appeared in the 1980s, AIDS was a deadly disease without any therapeutic alternatives. Currently, there is still no cure for most cases mainly due to the multiple tissues that act as a reservoir for this virus besides the high viral mutagenesis that leads to an antiretroviral drug resistance. Throughout the years, multiple drugs with specific mechanisms of action on distinct targets have been approved.
The human immunodeficiency virus (HIV) is still a very prominent disease worldwide. Acquired Immunodeficiency Syndrome (AIDS) can now be considered a chronic infection since patients are living longer due to the several options of antiretroviral therapy . The number of new cases has decreased, but nevertheless, according to the latest UNAIDS global statistics, 38.0 million people are living with HIV in 2019 and 1.7 million became newly infected with HIV in 2019 .
The initial step of HIV replication cycle involves SU binding to the host protein CD4, present in T helper lymphocytes, macrophages, and dendritic cells. The interaction between the CD4 binding site (CD4 bs) present in SU subunit with CD4 causes conformational changes in the SU glycoprotein that exposes the coreceptor binding site . Binding to coreceptor induces further conformational changes in the TM subunit, disclosing the fusion peptide which will connect to the target cell membrane due to its extremely hydrophobic nature, thereby enabling the fusion of both viral envelope and host cell membrane . Fusion of viral envelope could occur directly with plasma membrane or alternatively with endosome membrane after endocytosis. Following fusion, the viral capsid is then released in the cytosol forming the reverse transcriptase/pre-integration complex (RTC/PIC) that includes the two copies of gRNA, the viral proteins CA, NC, IN, RT, and Vpr as well as cellular proteins, namely cyclophilin A . Inside this structure, RT converts the single-stranded gRNA into a double stranded DNA (dsDNA). The RTC/PIC is transported through the cytoplasm into the host cell nucleus  via the nuclear pore, where RTC/PIC interacts with proteins of the nuclear pore complex, namely, Nucleoporin 358 and Nucleoporin153 . The structural integrity of RTC/PIC seems to be maintained until it enters the nucleus, minutes before the dsDNA integrates into host cell chromosome . The integration process is mediated by the integrase protein (IN) starting by removing nucleotides from the 3′ ends of the proviral DNA, and then, proceeding to catalyze a nucleophilic attack to the phosphodiester bonds of the DNA chains, thus forming a covalent bond between viral and host DNA. This is an essential step in viral replication allowing the establishment of latently infected cells . Some cell transcription factors enhancers bind to LTR and the regulatory proteins such as Tat, Rev, and Nef are produced. HIV-1 transcription from the LTR promoter is activated by the Tat protein through interaction with the nascent trans -acting-responsive RNA hairpin structure . The Env glycoproteins, after translation, processing, and cleavage by cellular furin protease migrate to the plasma membrane. Meanwhile the MA domain targets the Gag-Pol polypeptide to budding sites at the host cell membrane where it interacts with cytoplasmic tail of TM subunit of Env. This event allows virion assembly with gRNA and all the other structural and accessory viral proteins and budding of immature viral particles . During or soon after budding, the viral protease (PR) cleaves the Gag-Pol polypeptide which will allow the release of all structural proteins, such as MA, CA, and NC, as well as their reorganization into mature virions .
The period between the infection of the first host cell and the detection of the virus in the blood is called the eclipse phase and usually lasts from 7 to 21 days. After the infection of the first cell, the virus continues to replicate in the mucosa, submucosa, and adjacent lymphatic tissue. The replication concentrates in the gut-associated lymphatic tissue (GALT) quite early . Then, it follows an exponential rise of the viral loading in which the CD4+ cell counting rapidly decreases. This phase is characterized by flu-like and non-specific clinical signs that usually last between 7 to 10 days. After a few weeks, the immune system can generate a response . The cellular immune response starts with the activation of CD8+ cytotoxic lymphocytes. Their T-cell receptor (TCR) will bind to viral proteins, which are in turn connected to the antigen-presenting molecule (MHC I) to eliminate the infected cells . Generally, after 3 to 5 weeks, a humoral response starts to produce specific neutralizing antibodies that will destroy the virions via phagocytosis. The convergence of both types of immune responses leads to a decrease in viremia and a new rise in CD4+ cell count. The period, in which there is an infection but without antibodies, is called the “serological window period” . Even though this is an asymptomatic phase, and the viral loading is somewhat controlled, there is still a loss of immune cells since the virus continues to replicate in the lymphatic tissue (its reservoir), destroying its structure. Then, the viral loading becomes higher as the CD4+ cell count diminishes, leading to the beginning of the AIDS stage. In this stage, the patients are more susceptible to opportunistic infections .
Several aspects make it difficult to eradicate the virus once a patient is infected. One of them is related to the absence of proofreading activity in the viral RT, causing a great number of mutations and genetic diversity in the HIV genome. The other one is concerned with the ability of the virus to infect resting memory or naïve cells, leading to a latent viral state . The problem with viral latency is that it can occur even after patients have undergone antiretroviral therapy reducing viremia to an undetectable level .
2. Novel Therapeutic Strategies
2.1. New Transdermal Drug Delivery Systems
2.1.1. Transdermal Delivery System for Tenofovir Alafenamide
2.1.2. Transdermal Delivery of Enfuvirtide (T20) via Ultrasounds
2.2. Nanosystems for Drug Delivery
|Nanocarriers + ARV||Main Outcomes||References|
|Liposomes + Stavudine||Liposomes were revealed to be a promising alternative for stavudine delivery as these carriers can be easily absorbed by macrophages.|||
|Dendrimer + Zidovudine||The formulation reduced the AZT hemolytic effect and prolonged the drug release, decreasing the occurrence of side effects.|||
Carbosilane Dendrimers + Efavirenz
Carbosilane Dendrimers + Tenofovir
|An enlarged antiviral activity of all three drugs was observed when formulated with dendrimers.|||
|Nanodiamond Particles + Efavirenz||A suitable and slower release profile through a blood–brain barrier model was obtained impairing viral replication for a longer period.|||
|PGLA nanoparticles + Efavirenz
PGLA nanoparticles + Saquinavir
|An enlarged antiviral activity of all three drugs was obtained with PGLA nanoparticles.|||
|PGLA nanoparticles + Efavirenz + Raltegravir [thermosensitive gel]||A lower EC90 and a constant release of these loaded drugs were obtained being a promising option for pre-exposure HIV prophylaxis.|||
|CAP nanoparticles + Efavirenz
|High encapsulation efficacy and lower cytotoxicity in HeLa cells were observed besides enhanced prophylactic activity in TMZ-bl cells treated with EFV-CAP nanoparticles.|||
|CAP nanoparticles + Dolutegravir
|pH (4.2 and 7.4) influenced both the drug release and the cytotoxicity of this formulation.|||
This entry is adapted from 10.3390/molecules26175305
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