There are two major variants of HIV — HIV-1 and HIV-2. HIV-1 is the most prevalent and virulent, as well as the best characterized. Therefore, in this essay the use of the term "HIV" will refer to HIV-1.

Genome and Virion Organization

The HIV-1 genome is encoded by a single-stranded RNA molecule approximately 9 kb (9,000 nucleotide bases) in length, and contains 9 open reading frames. Open reading frames are sections of a genome that encode for the production of a protein. The largest three reading frames transcribe the Gag, Pol, and Env polyproteins, which are proteolytically processed into proteins common to all members of the retrovirus family. Gag is processed into matrix (MA), capsid (CA), nucleocapsid (NC), and p6 — proteins that make up the inner core of the viral particle. Derived from the Env polyprotein, GP120 (surface, SU) and GP41 (transmembrane, TM) make up the virus’s outer membrane proteins. The polyprotein Pol includes the viral enzymes protease (PR), reverse transcriptase (RT), and integrase (IN), all of which are encapsulated in the core of the virion particle. Three other reading frames encode the accessory proteins Vif, Vpr, and Nef, also found in the virion core.

These 15 proteins, along with two strands of genomic RNA, make up the entire HIV viral particle. The remaining reading frames encode Vpu, Tat, and Rev, accessory proteins unnecessary for virion infectivity but important for the virus in its integrated state.

HIV Entry and Transport

After an infectious HIV-1 virion has entered the body of an individual, it will eventually find and bind to a suitable host cell such as a macrophage, dendritic cell, or helper T lymphocyte, all of which express a protein receptor named CD4 on their cell surface. Virion attachment to the CD4+ target cell membrane is through the cell surface binding of the HIV glycoprotein GP120 to the CD4 protein. The initial interaction of GP120 with CD4 is not sufficient for HIV-1 entry into the cell, yet causes a conformational shift (shape change) in the GP120 molecule to expose its chemokine co-receptor binding site. Once both the cell surface ligands are bound (CD4 and the co-receptor) by GP120, the viral transmembrane protein GP41 changes conformation to facilitate membrane fusion with subsequent viral entry into the cell. There are two major classes of HIV-1, distinguished by what kind of cell the virus will bind to and infect. This selectivity is governed by the co-receptor to which the GP120 protein binds. M-tropic virions preferentially bind to the CCR5 chemokine receptors found on macrophages, while T-tropic virus particles have an affinity for the chemokine receptor CXCR4, or fusin, found on T cells. Many other co-receptors have been identified besides the ones described, and probably even more will be discovered in the future.

Once inside the cell, the virion core is uncoated, exposing the HIV nucleoprotein complex, consisting of the RNA genome, reverse transcriptase (RT), integrase, the matrix protein, and Vpr. The nuclear localization sequence on Vpr then directs the nuclear transport of the nucleoprotein complex into the nucleus.

Reverse Transcription and Integration

Once inside the nucleus, RT reverse transcribes the RNA genome into a partially duplex DNA. RT first catalyzes the RNA-dependent DNA polymerization of the RNA genome into an RNA-DNA hybrid. The RNase H domain of RT then cleaves off the RNA, and RT subsequently becomes a DNA-dependent DNA polymerase to form the duplex DNA viral genome.

Following reverse transcription, the viral DNA genome is then integrated into a host chromosome of the infected cell, which can occur at many target sites within the host’s genome. Integration is the splicing of the viral DNA into the DNA genome of the host cell. HIV integrase performs a number of catalytic steps for this viral integration, presumably with the help of additional host cellular enzymes for the integration and DNA repair.

Viral Gene Expression

The HIV promoter is located in the 5’-long terminal repeat (LTR), and transcription of the integrated retroviral genes is performed by the host cell RNA polymerase II. However, inefficient transcription elongation limits the processivity of the polymerase to just a few hundred nucleotides without the essential help of Tat, an unconventional transcriptional activator.

After transcription from the integrated viral genes, the viral mRNAs are processed by splicing to differing lengths, then transported to the cytoplasm. HIV Rev regulates the transport of differently spliced viral mRNAs, and thus acts as a switch that turns on the production of infectious virions. Most mRNA products are doubly spliced to encode for the accessory proteins Tat, Rev, and Nef, and transported to the cytoplasm by default. These mRNAs are exported from the nucleus for use by the virus in its integrated, or latent, state. However, when the other structural viral components are later needed for virion packaging during the virion production stage, the singly spliced or unspliced transcripts that contain the Env coding region are bound by Rev at the Rev Response Element (RRE) and targeted for nuclear export.

Viral Particle Packaging and Maturation

Viral transcripts bound by Rev and exported to the cytoplasm are translated into protein for the formation of infectious virion particles. The polyproteins Gag and Gag-Pol are localized to the cell membrane by the N-terminal matrix section of the polyprotein. Env mRNA is translated at the endoplasmic reticulum into GP160. Because CD4 is also translated there and binds the viral Env protein, the complex can get retained, holding up GP120 from proceeding to the cell surface. However, Vpu intercedes to free the retarded GP160 by promoting CD4 degradation. Env is then transported to the cell surface, where again binding of cellular CD4 becomes a problem. To combat this, Nef promotes the endocytosis and degradation of surface CD4 at the cell surface.

Once the subunits are assembled at the inner surface of the cell membrane, the viral particles begin to bud from the cell surface, coated with GP120 and GP41 and containing an unrefined virus interior. These noninfectious particles are then released and undergo a maturation process involving processing of Gag and Gag-Pol by HIV protease and assembly of the core particle. Protease digests the polyproteins into MA, CA, NC, p6, PR, RT, and IN. This mature HIV virion is now ready to infect the next cell.

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