HIV Epidemiology, Transmission, Structure & Course of Infection

Epidemiology:

38 million people worldwide currently live with HIV
Approx 2 million are newly infected annually
770,000 death from AIDs in 2018
In Western Europe, 2.2 million people live with HIV
Approx 100,000 people living with HIV in the UK

Subtype Epidemiology:

Subtype C is the most common globally (mainly affecting African continent)
Subtype B is the most common in the UK

WHO Target:

By 2020, the WHO wanted to achieve the 90/90/90 goal.
- 90% of people with HIV diagnosed
- 90% of those diagnosed with HIV on treatment
- 90% of those on treatment virally suppressed

Positive vs Negative Sense RNA Viruses:

Positive-sense viral RNA is similar to mRNA and thus can be immediately translated by the host cell.
Negative-sense viral RNA is complementary to mRNA and thus must be converted to positive-sense RNA by an RNA polymerase before translation.

HIV-1 Infection Process (Infection & Fusion):

Dendritic cells in epithelial or mucosal tissues typically capture the virus following sexual transmission and transport it to lymph nodes to be presented to immune cells, where infection then quickly spreads.
HIV is able to infect many types of immune cell (T helper cells, dendritic cells, macrophages, monocytes, etc) and thus displays viral tropism.
GP120 is the main glycoprotein allowing entry into the T Helper cell.
1. It binds to the CD4+ receptor on T cells leading to fusion of the viral and T cell membranes
2. GP120 must then bind to a co-receptor on the T-cell surfacein order to begin fusion. The most common co-receptors are the CXCR4 receptor (found mainly on T cells) and the CCR5 receptor (found on T cells, macrophages, monocytes and dendritic cells). Typically, the CCR5 receptor is used.
3. It should be noted that some people have homozygous mutations in their CCR5 receptors which means that they are immune to GP120 binding and thus resistant to HIV infection. This is the CCR5 Delta 32 mutation and those who are homozygous for this are resistant to HIV infection. It is interesting to note that this mutation is specific to European individuals and it is therefore theorised that the plagues of the middle ages may have played a part in bringing about this mutation. Around 10% of Europeans have this mutation.
4. Following binding, GP120 undergoes a conformational change to allow the binding of GP41.
Following GP120 binding and its conformational change, GP41 undergoes a structural change, exposing previously hidden hydrophobic gp41 fusion peptides that are inserted in the T Helper cell membrane allowing fusion to take place

HIV-1 Infection Process (After Fusion):

HIV is a single stranded positive sense RNA virus. It has two single strands of RNA, which are injected into the host cell following fusion alon with three enzymes:
1. Reverse Transcriptase
2. Integrase
3. Protease
Reverse transcriptase, injected with the ssRNA, then transcribes complementary double stranded proviral DNA
1. This enzyme has two main sites: the polymerase (generates cDNA) and the RNase H site which degrades the RNA strand, allowing the polymerase to form the second strand of DNA.
2. Reverse transcriptase makes 3-4 errors every time it replicates a HIV virion, thus makes every individual HIV virion unique. Thus, a collection of HIV cells is generally referred to as a 'quasi-species' as every virion behaves slightly differently but they are all related.
The integrase enzyme then splices the provirus into the host's genome (DNA).
1. It cleaves off the last two bases at either end of the newly generated HIV DNA
2. It then causes a nick in the host cell chromosome, before then integrating the viral DNA into the host genome
Whenever the immune cell then needs to replicate in response to an immune signal (e.g. infection), it also transcribes and translates HIV proteins, which are then spliced to be functional by the HIV protease that was originally injected into the cell.

Transmission:

Transmission is mainly by sexual intercourse
- Male to male transmission is the most common source
Intravenous drug abuse is another common source
Mother to child transmission can also occur
Blood transfusions are a less common source but do occur

Timeline of Infection:

The initial acute phase generally lasts approximately 4 weeks, in which time the individual will experience a flu like illness (fever, night sweats, malaise).
- Seroconversion occurs during this time, which is the period during which the body produces detectable levels of the HIV virus. This usually occurs at around 4 weeks.
At the point where the body has mounted a response to the virus and has suppressed it a bit, the virus enters the chronic phase (at around 12 weeks). During the chronic phase, an individual loses between 1-2 billion T cells per day. Despite this, during the chronic phase T cells usually remain >500 cells/mm3
- During the chronic phase an individual can develop a mutation within the HIV cells forming the X4 HIV strain which targets only the CXCR4 co-receptor (thus only T cells). If this strain is present, the T cells are more rapidly destroyed.
At 200-500 T cells/mm3, the body starts developing symptoms of chronic HIV infection:
- Swollen Lymph Nodes
- Oral Hairy Leukoplakia (white patch on tongue caused by Epstein Barr virus) - arises due to immunosuppression
- Oral candidiasis
At <200 T cells/mm3, the immune system is severely compromised and an individual is considered to have AIDS
- Patients will start experiencing extreme infections, persistent fever, fatigue, weight loss and diarrhoea
- Such infections include pneumocystis pneumonia and candidiasis of the eosophagus
- Tumours such as Kaposi sarcoma (red lesions on skin) are also common manifestations of AIDS

	Created by Matthew Coulson almost 5 years ago

Honours Degree Microbiology (Medical Virology) Note on HIV-1 Including Current and Future Treatment Strategies, created by Matthew Coulson on 09/03/2020.