An introduction to HIV/AIDS

Introduction 

HIV (Human Immunodeficiency Virus) is a retrovirus that currently infects ~38 million people worldwide. Its end-stage disease, AIDS (acquired immunodeficiency syndrome), is estimated to cause 1.6 million deaths per year. HIV appears to have originated in Cameroon in the 1920s through the evolution of SIVcpz, a Simian Immunodeficiency Virus (SIV) that infects wild chimpanzees. 

HIV spread to the United States between 1966 and 1972 and came to public attention in the early 1980s when several Americans (particularly gay men) began to suffer and die from a previously undiscovered disease, first described as a ‘rare cancer’. This disease was given the name AIDS in 1982. The following year, the infecting virus was first isolated from a patient's blood sample. It soon became apparent that HIV was transmitted through bodily fluids, primarily by sexual transmission or through the act of sharing needles. The global incidence of HIV infection peaked in 1997, at 3.3 million new infections per year. Effective education about safer sexual practises, as well as the use of antiretroviral therapy (ART), have since helped slow down infection rates. Nonetheless, there is still no specific cure for HIV/AIDS and it thus remains a global pandemic.

The HIV infection cycle

During sexual transmission of HIV, the virus enters the body through mucous surfaces, initially targeting cells in the rectum or genital tract. Once it has entered the blood stream, the virus can invade white blood cells that have CD4 cell surface receptors, namely CD4+ T-lymphocytes and macrophages. CD4+ T lymphocytes (T-helper cells) assist in the killing of a pathogen through the activation of cytotoxic T cells, while macrophages detect, engulf and destroy invading pathogens. HIV infection results in the gradual loss of these immune cells, hence suppressing the immune system and causing AIDS. In fact, patients who die from AIDS aren't killed by the HIV infection itself, but rather by complications in a secondary infection, such as pneumonia.  

The outer envelope of the HIV viral particle contains two glycoproteins, gp120 and gp41. The interaction of gp120 with the CD4 receptor induces a conformational change that brings the envelope glycoproteins closer to the host cell membrane, allowing gp120 to also interact with CCR5, the major CD4 co-receptor. Next, gp41 inserts itself into the host cell outer membrane, which initiates the fusion of the host membrane with the viral particle envelope, releasing the viral RNA genome and viral proteins into the host cell cytoplasm. Here, viral RNA is reverse transcribed by the viral protein reverse transcriptase (RT) to yield DNA. The RNA is then degraded to ensure that the virus isn’t detected by the host immune system. The viral DNA, along with the HIV protein integrase and other accessory proteins collectively form the pre-integration complex (PIC), which is imported into the host cell nucleus via the nuclear pore complex (NPC). Inside the nucleus, integrase catalyses the insertion of the viral DNA into the host cell genome. Once integrated, HIV uses the host cell machinery (RNA Polymerase II and transcription factors) to transcribe the viral DNA. The resulting transcripts are exported to the cytoplasm, where they are translated into long chains of HIV proteins. These protein chains are the building blocks for the production of more HIV. The newly synthesised HIV proteins and RNA assemble into an immature (non-infectious) HIV particle at the surface of the cell. This immature HIV particle pushes itself out of the host CD4 cell and releases HIV protease (PR), a protein that breaks up the long polyprotein chains, forming a mature, infectious HIV that can go on to infect another CD4+ T cell.

Treatments

There is no specific cure for AIDS, however, multiple stages of the HIV life cycle can be inhibited with antiretroviral treatments, which help patients manage the disease progression:

1) Fusion inhibitors such as CCL3 and CCL5 (Chemokine C-C Motif Ligand 3/5) bind to the CCR5 co-receptor and inhibit the fusion of the viral particle with the host cell membrane.

2) Nucleoside/non-nucleoside reverse transcriptase inhibitors (NRTI/NNRTI) bind competitively/non-competitively to HIV reverse transcriptase resulting in premature termination of reverse transcription. The drug APOBEC3G inhibits reverse transcription by binding to the modified Lysine-tRNA nucleotide that mediates the initiation of reverse transcription.

3) Integrase strand transfer inhibitors (INSTIs) block HIV integrase to inhibit integration of the viral DNA into the host genome.

4) Tetherin is a drug that inhibits the release of immature viral particles from the host cell.

5) Protease inhibitors inhibit proteolysis of the long polyprotein chain, thus preventing viral particle maturation. 

Highly active anti-retroviral treatments (HAART) usually combine drugs that inhibit three or more of these viral processes. Potential side effects of HAART include muscle pain, headaches, nausea, fatigue, diarrhoea and sleeping difficulties. Treatments for AIDS are complicated by the high mutation rate exhibited by HIV. Antigenic drift is the process by which an accumulation of mutations in the genes that code for antibody-binding sites results in the generation of a new strain of the virus. This strain cannot be inhibited effectively by the original antibodies, making it easier for the virus to spread through a population and ‘escape’ antiviral treatments. Additionally, the HIV envelope glycoproteins coat the entire surface of the envelope, posing a significant barrier to the induction of protective antibody responses. This is known as antigenic shielding. The next generation of HIV vaccines will likely involve recombinant viral vectors. However, there are still concerns with the safety of generating these. Vaccines containing DNA sequences have been contemplated, nevertheless, these provide a lesser degree of protection and are strain specific.