By Elena Perez
Next Lesson - The Immunocompromised Host
- Understand the relevance of HIV
- Learn about the structure, replication and treatment of HIV
- Look at prevention and ethical dilemmas surrounding HIV
- In 2017, the estimated number of people living with HIV was of about 36.9 million, around 25% of them not being aware they have the virus.
- Human Immunodeficiency Virus is a single stranded enveloped virus, it replicates using the host’s machinery back into DNA and ssRNA again. It infects cells with CD4+ surface receptors.
- Treatment currently involves a combination of anti-retroviral drugs that target different stages of the HIV infection and replication processes.
- Important efforts to tackle the spread of the disease focus on prevention of transmission, but stigma is currently one of the main barriers to potential elimination of the disease.
Globally, HIV is a major public health concern and has proven to be a great challenge since it was first identified in the early 1980s. Despite estimated new cases decreasing (decrease in incidence), prevalence of HIV is increasing worldwide as life expectancy is steadily extended by current treatment therapies available. To have an idea of the magnitude of the problem, it is believed that 36.7 million people were living with HIV in 2016, of which 1.8 million were new cases and only 75% of people were aware of their status.
What is HIV?
HIV (Human Immunodeficiency Virus) is a retrovirus that belongs to the Retroviridae family, Lentivirus genus.
HIV specifically affects the immune system by destroying CD4 cells (a type of white blood cells) after hijacking their machinery to replicate. Extent of the infection is estimated by the CD4 T-cell count. To have an idea, a normal range of CD4 T-cell count would be between 500 and 2000 cells/μL. HIV progression can be divided into 4 different stages with regards to this parameter:
- Stage I corresponds to a ‘normal’ CD4 count >500 cells/μL and the patient is usually asymptomatic;
- Stage II is when the count drops <500 cells/μL and the patient starts to show mild symptoms;
- Stage III is described as a CD4 count <350 cells/μL and symptoms start to become more advanced;
- Stage IV is when the CD4 count goes <200 cells/μL and the presentation is more severe, also defined as AIDS.
AIDS (Acquired Immunodeficiency Syndrome) and is the term used to describe the more advanced stage of HIV infection when the patient has become ‘immunodeficient’ (or fully immunocompromised). What this means is that at this stage, the body is a lot more susceptible to previously harmless infections and opportunistic pathogens and malignancies.
Figure: Shows the changes in CD4 lymphocyte count over time in a patient with HIV
Creative Commons Source by Jurema Oliveira [CC BY 3.0 (https://creativecommons.org/licenses/by/3.0)]
Signs and symptoms of HIV
There is no specific physical sign relating to HIV infection itself, but these rather start presenting as a result of the immunodeficiency caused by progression of the infection. Acute seroconversion can manifest with flu-like symptoms: fever, malaise, weight loss and generalised rash. It can also present with generalised lymphadenopathy and further down the line, more recurrent and severe infections (one such example quite common in HIV is oral candidiasis). The first signs of HIV-related illness usually develop within 5 to 10 years, or sometimes even less.
Figure: Shows the main Signs and Symptoms of an Acute HIV infection
Creative Commons Source, by Mikael Häggström [CC BY 3.0 (https://creativecommons.org/licenses/by/3.0)]
Figure: Shows the main Signs and Symptoms of an AIDS infection
Creative Commons Source, by Mikael Häggström [CC BY 3.0 (https://creativecommons.org/licenses/by/3.0)]
The Life Cycle of HIV and Drug Targets
There are 7 steps of the HIV life cycle (i.e. how it hijacks and replicates in CD4 T-cell). These are important to understand as they are used as targets for treatment:
- Binding (or Attachment) – HIV binds to the receptors on the surface of the CD4 cell (either CCR5 or CXCR4). CCR5 antagonists/post-attachment inhibitors act here.
- Fusion – its envelope then fuses with the CD4+ cell membrane which allows the virus to penetrate the cell by emptying its contents inside the CD4+ host. These contents include HIV RNA and reverse transcriptase. Fusion inhibitors act here.
- Reverse transcription – inside the CD4+ cell, the emptied contents get to work and convert the HIV RNA into HIV DNA, which then enters the CD4+ cell nucleus. Non-nucleoside reverse transcriptase inhibitors (NNRTIs)/nucleoside reverse transcriptase inhibitors (NRTIs) act here.
- Integration – inside the nucleus, HIV integrases combine the viral DNA with the CD4+ cell’s own DNA. Integrase inhibitors act here.
- Replication (or Transcription) – when the infected cell divides, the DNA is ‘read’ and long chains of protein are made.
- Assembly – new HIV proteins and RNA move to the surface of the cell and assemble into ‘immature’ (non-infectious) HIV.
- Budding – newly formed immature HIV pushes itself out of the host CD4+ cell. The new HIV cell releases proteases which break up the long ‘immature’ protein chains into smaller ‘mature’ (infectious) HIV. Proteases inhibitors (PIs) act here.
Figure: Shows the Life Cycle of HIV
Creative Commons Source, by NIAID [CC BY 3.0 (https://creativecommons.org/licenses/by/3.0)]
As you can imagine, a lot of these HIV-specific enzymes are potential drug targets and by targeting different stages of the HIV life cycle simultaneously, we increase the chances to fight it off, avoiding the threat of resistance. This is why current treatment involves what is called ‘combined’ therapy: patients are prescribed a combination of 3 anti-retrovirals (ARVs) - known as triple drug therapy or highly active antiretroviral therapy (HAART) (if you are particularly interested in this topic it is worth visiting this webpage):
Figure: Drugs used to treat HIV
SimpleMed original by Elena Perez
Whatever the particular drug regimen someone is given, they will have to take the combination of medicines every day. It is important to point out that currently, these will not cure HIV but will increase life expectancy (slowing or halting progression) and prevent the spread of HIV by reducing the risk of transmission.
Prevention and Transmission
As we have just seen, despite some unique success story, there is currently no cure for HIV, just treatment which, if caught early, can help patients keep HIV at a low viral load and allow them to have an almost normal life expectancy. Although the treatment is helpful, it is also very expensive and only a portion of patients that are infected are being treated worldwide. Thus, important efforts are being placed in prevention.
These are some of WHO’s recommendations to help limit the risk of HIV transmission through sex:
- The correct use of male or female condoms for every sexual intercourse
- Taking antiretroviral drugs for pre-exposure prophylaxis of HIV (PrEP)
Being a blood borne virus, sexual contact is one mode of transmission - but not the only one. Any contact of infected bodily fluids with mucosal tissue, blood or broken skin can be a route of transmission. Thus, apart from sexual contact (that accounts for 95% of infections), HIV can also be transmitted through medical procedures such as blood transfusions, contaminated needles (mainly through needle exchange among IV drug users), or perinatal transmission (vertical transmission).
Not all these modes of transmission have an equal risk. There are certain factors that affect the risk of transmission: the type of exposure (type of sexual act/transfusion/needlestick (see article on hepatitis)/mucous membrane), the viral load in blood (if the viral load was undetectable in the first place, transmission is highly unlikely), etc.
Figure: Shows the risk of HIV transmission depending on the type of exposure
SimpleMed Original by Elena Perez
HIV Test and ethical dilemmas
The earlier HIV is diagnosed, the better the prognosis so anyone who suspects they might have become infected should attend their occupational health clinic or sexual health clinic for testing as soon as possible.
There are a few different tests that are used:
- Rapid Test (Point of Care (POC) test) – low cost, rapid test that can be done at home as a discreet postal testing and involves either blood testing through a finger-prick or saliva (taken as an oral swab). If negative, this test is pretty accurate, but it might sometimes result in a false positive result, so if positive, it needs to be confirmed with further serology testing.
- Serology – involves a full blood sample sent off to the labs and results are received within 7-10 days. This test looks for HIV antigen (viral protein) and HIV antibody (immune response to the antigen). It is slightly more accurate but might result in a false negative result.
- PCR (Polymerase Chain Reaction) – detects HIV nucleic acid. It is a highly sensitive test which can detect very early infection (few days) but it is expensive and results can take up to a week. This is not used for initial HIV testing but for follow-up and monitoring treatment response.
Who should be tested? Current guidelines state that anyone presenting with the following should be tested:
- Everyone in a population with a rate > 2/1000
- Bacterial pneumonia/TB [Resp]
- Meningitis/dementia [Neuro]
- Severe psoriasis; recurrent/multidermal shingles [Derm]
- Chronic diarrhoea/weight loss with unknown cause [Gastro]
- Any unexplained blood abnormality [Haem]
- Lymphoma, anal cancer [Onc]
- Cervical intraepithelial neoplasia (CIN) [Gynae]
- Any STI/HepB/HepC
In some cases, some patients (let’s say a nurse who undergoes a needlestick injury) might opt in to have post-exposure prophylaxis treatment given immediately to increase the chances of preventing infection. This is only given in certain emergency situations that need to meet the guidelines and must be started within 72 hours after the possible exposure to HIV.
Because of the infectious nature of HIV, there are some ethical dilemmas healthcare professionals might face. Ideally, testing should be done with consent from the patient who should be then trusted to disclose their status with their partner(s) or anyone they might put at risk of infection. However, in some situations, we might be asked for example, as GPs, not to tell a patients’ partner, in which case we should always make sure to talk the patient through the importance of the disclosure of such information as we are expected to weigh patient confidentiality against other people’s best interest and safety above all (i.e. the health of a mother, an unborn child, a sexual partner, colleagues at a workplace, etc.).
Another important aspect of HIV is the stigma that still prevails around the condition. When making a diagnosis of HIV, healthcare professionals must be aware of the impact this might have on their patients and provide them with the right support, medically but also psychologically.
Edited by: Thomas Burnell