PATHOGENESIS OF HIV-AIDS 

ABSTRACT 

The most chronic disease, HIV-AIDS acts against innate, adapted, and  intrinsic immunity, increasing the risk of infections and diseases.  Research on the pathogenesis of the virus has enabled us in developing  antiretroviral treatments and drugs but finding the cure or developing a  protective vaccine, still remains challenging. The Pathogenesis of this  virus is often obtained from the studies on subtype B viruses and non human primate studies. This article highlights the detailed pathogenesis  of the HIV virus and its ability to overcome the defensive webs. 

PATHOGENESIS 

The HIV-1 is composed of two positive-sense, single-stranded, identical  RNAs which are located inside the capsid surrounded by P24 proteins.  The outer coat of the HIV-1 is made up of a lipid bilayer on which the two  molecules- external glycoprotein, gp120, and the transmembrane  glycoprotein, gp41 are present. These form a spike on the surface of the  virion. Gp120 helps in the attachment of the virus to the target cell. During  the entry process, gp120 binds to the CD4+ receptors present in the cell. 

Along with CD4+, gp120 also attaches to some chemokine co-receptors.  CCR5 and CXCR4 are the two important chemokine co-receptors for HIV 1. Subsequent interactions between the virus and the chemokine co receptors lead to an irreversible conformational change in gp120. This  entry process can also stimulate the intercellular signal cascades which  facilitate viral replication. Mostly, the viral variants depend on CCR5  usage. It is in the later stages that CXCR4-tropic viruses appear. After  gp120 gets attached to the CD4+ and the chemokine receptors, gp41  helps in the fusion of the virus’s membrane and the targets cell’s  membrane. The viral core is released into the cell cytoplasm through pore  formation where it gets disassembled and then the RNA gets reverse  transcribed into DNA with the help of the reverse transcriptase enzyme. The virus has another enzyme known as integrase which helps the viral 

DNA to join with the target cell’s DNA. This process is facilitated by an  integrase binding host factor, lens epithelium-derived host factor  (LEDGF/p75). Now the cell gets transformed into a potential virus  producer. In the last steps, the viral proteins, produced by viral as well as  host-driven transcription, are assembled in proximity to the cell  membrane. For the process of viral escape from the cell, HIV-1 takes  advantage of the vesicular sorting pathway (ESCRT– I, II, III) by binding  TSG101 via its late domain, a short sequence motif in p6 of the Gag gene.  The virus has another important enzyme known as Protease which does  the function of cleavage of Gag-Pol poly-protein to produce mature  infectious virions. (Gag, Pol, and Env are three structural genes of the viral  genome). 

The most possible pathways through which the virus gets transmitted are Endocytosis (the cellular process through which substances are brought  into the cell by invagination of the cell membrane and forming a vesicle),  Transcytosis (the cellular process that transports macromolecules across  the interior of a cell), and attachment to mannose C-type lectin receptors located on dendritic cells and macrophages (example: DC-SIGN). C-type  lectin receptors are involved in the recognition and induction of adaptive  immunity to pathogens i.e., eliminating pathogens or preventing their  growth. The primary amplification of the virus takes place by replication in  the regional lymph nodes like draining lymph nodes. When the infected T lymphocytes or virions migrate into the bloodstream, secondary  amplification in the gastrointestinal tract, spleen, and bone marrow leads  to massive infection of susceptible cells. The virus population is mostly  homogenous after the early transmission but as the population of variant  genomes diversifies into distinct biological compartments, the mutant  viruses are generated. These mutant viruses are resistant to antibody  neutralization, antiviral drugs, and cytotoxic T cells which are responsible  for eliminating substances that the immune system identifies as harmful. 

HIV-1 destroys the CD4+ T lymphocytes, which are critical to our immune  system. This marks the hallmark of the infection with AIDS being the last  stage. Simian immunodeficiency virus (SIV) infection of rhesus  macaques- nonhuman primate model, suggests that vaginal transmission  results in the infection of a small number of CD4+ lymphocytes,  macrophages, and dendritic cells in the lamina propria.

Mammalian cells do have a defensive web against the virus. APOBEC3G/3F and TRIM5α are the intrinsic restriction factors that are  expressed in many cells. APOBEC3 enzymes of the superfamily cytidine  deaminases possess the ability to destroy and kill the retrovirus but HIV 1 avoids these by expressing “Vif”, a protein that disrupts the antiviral  activity of APOBEC3. The deaminases A3G, A3F, and A3B also have  potent antiviral activity. There is another protein named “Nef” which has  the ability to downregulate CD4 receptor expression on the cell surface of  infected cells. 

The ability of this virus to overcome the defensive webs proves AIDS to  be a life-threatening disease. Also, HIV mutates at a faster rate so  developing a vaccine is challenging. As of now, since we don’t have a  vaccine against HIV-1 and there is no cure, the only option is prevention  and access to antiviral treatments; as Prevention is always better than  cure.

HIV-1 is a retrovirus that encodes three structural genes (Gag, Pol, and Env) (A) Envelope glycoproteins gp120/41 form the spikes on the virion’s surface. During maturation the gag protein is cleaved and Gag p24 forms the core. The viral genome, viral reverse transcriptase (RT), integrase as well as a number of host proteins are encapsidated. (B) Dir erent steps of the viral life cycle on a cellular level and the potential targets for treatment interventions. (C) HIV-1 has evolved strategies to counteract the restriction factors 

TRIM5α and APOBEC3G/3F. If left unchecked by HIV-1 Vif, APOBEC3G/3F is encapsidated into the egressing virion, and on infection of a target cell leads to G-to-A hypermutations in the viral genome. Rhesus TRIM5α inhibits HIV-1 replication early after infection of the target cell before the step of reverse transcription.