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Human Immunodeficiency Virus (HIV) attacks the immune system. It has two main types HIV-1 and HIV-2 along with two forms, active and latent HIV. During latent HIV, HIV infected cells are in a resting state and do not replicate new HIV cells. HIV infects white blood cells such as lymphocytes e.g. CD4+ T cells. These cells trigger other immune cells like macrophages and B lymphocytes to activate an immune response. An assemblage of non-dividing immune cells is known as a latent HIV reservoir which can hide and hibernate in the body from months to years. Latent HIV can revert to active at any given time. Treatments such as antiretroviral therapy (ART) can decrease the levels of HIV in blood and body fluids, but cannot eradicate HIV due to HIV latent reservoirs.

The exact mechanism of how a latent HIV cell reservoir can become reactivated is not completely understood, nor is there a true effective strategy to target latent reservoirs. Protein kinase C (PKC) modulators are a potentially notable area because they have the ability to reactivate and induce viral protein production in latent HIV cell reservoirs in humanized BLT mice. In theory, while maintaining antiretroviral therapy, PKC will induce latent HIV cells to reactivate and become susceptible to therapy, and thus curing the individual. This study created a synthetically-accessible analog of bryostatin 1 (type of PKC), which displayed improvement of latent HIV cell inducibility and caused some of the newly HIV-expressing cells to die. This synthetic PKC exhibits a “kick and kill” response in latently-infected cells and exhibited improved tolerability.

Long Terminal Repeats (LTR) promoters and enhancers are required for HIV gene expression and are great targets for a CRISPR disruption and knockout. Without LTR, both active and latent forms of HIV will not express their genes. Ebina et al. discovered that utilizing a CRISPR knockout of HIV LTR could be a possible cure for HIV after targeting the latent form of HIV in Jurkat cells. Not only could this method knockout HIV gene expression, it was also able to remove internal viral genes from the host cell chromosome resulting in a promising step toward HIV eradication.

Recent studies show promising results for the eradication of proviral HIV by the genomic editing of CRISPR/Cas9 system. Studies conducted in 2014 by Liao et al involving genetically engineered human-induced pluripotent stem cells to utilize HIV-targeted CRISPR/Cas9 to disrupt HIV-1 latent reservoirs. Their results concluded in both circular or linear dsDNA, Cas9 could interrupt and inactivate viral gene expression before or after genomic integration into the host's genome. A threefold reduction of viral expression of HIV-1NL43-GFP in human primary T cells was observed when CRISPR/Cas9 targeted HIV-1 LTRs R region. HIV trans-activating response (TAR) is relatively common in HIV-1 subtypes; this element is located in the LTR R region of the HIV genome, which makes it a good target site for disruption in HIV-1 expression.

Adeno-Associated Virus (AAV) is part of the parovirus family, and can be modified and recombinated to lose its viral DNA and be utilized as a non-enveloped viral vector that can cross through the cell membrane and enter the nucleus to deliver a corrected DNA construct. AAV as a gene therapy vehicle for the delivery of CRISPR/saCas9 cells into HIV-1 latent reservoirs was explored by Yin and her team in 2017. Application of gene delivery through the AAV vector in HIV-1 excision in vitro and in vivo in HIV-1 Tg26 mice, EvoHIV –eLuc acutely infected mice, and HIV-1 infected humanized BLT mice. The "all-in-one" quadruplex AAV vector includes two sgRNA expressing cassetes and a saCas9 expressing cassette; this quadruplex sgRNA/saCas9 AAV-DJ/8 is about 5.716 kb. Yin et al 's studies proved that the quadruplex is capable of reducing potential HIV-1 escape by concomitantly targeting HIV proviral DNA, excision of HIV-1 despite the proviral mutation, and loss of function due to the removal of target gene. The quadruplex sgRNA/saCas9 AAV-DJ/8 was intravenously injected into Tg26 mice that resulted in excised HIV-1 proviral DNA and decreased viral RNA expression in several organs and tissues such as the liver, heart, lungs, spleen, vagina and colon.