Aetiology
The human immunodeficiency retroviruses can be broadly divided into two groups: HIV-1 and HIV-2, both of which cause AIDS. Infection with HIV-1 is associated with a progressive decrease in CD4 count and an increase in HIV viral load leading to clinical AIDS. The stage of infection can be determined by measuring the patient's CD4 count and correlating clinical findings, such as AIDS-defining illnesses. HIV-2 infection has a more indolent course and is largely limited to West Africa and countries with links to West Africa (e.g., Portugal, Spain, India).[16] Within the main types of HIV viruses there are many genetically distinct subgroups as the virus mutates and changes over time.
Human immunodeficiency retroviruses infect and replicate primarily in human CD4 T cells and macrophages. HIV can be transmitted via blood, blood products, sexual fluids, other fluids containing blood, and breast milk. Most adults are infected with HIV through sexual contact or injection drug use. Sexual intercourse is the most common, albeit inefficient, mode of HIV transmission. The risk of transmission per exposure is low; estimates are on the order of 0.1% per contact for heterosexual transmission, but this varies considerably and increases with concurrent ulcerative sexually transmitted infections (STIs), high HIV viral load, and lack of antiretroviral therapy (ART).[17][18]
Pathophysiology
The virus gains entry to the cells by attaching to the CD4 receptor and a co-receptor (CCR5 or CXCR4) via its envelope glycoproteins. It is called a retrovirus because it encodes the enzyme reverse transcriptase, allowing a DNA copy to be made from viral RNA. The reverse transcriptase enzyme is inherently error-prone, resulting in a high rate of HIV mutation, which can lead to viral diversity, selection of diverse variants, and ultimately to viral resistance in those on treatment.[19]
Once integrated into the cellular DNA the provirus resides in the nucleus of infected cells and can remain quiescent for extended periods of time. Alternatively it can become transcriptionally active (especially where immune activity is occurring) and can use the human host cell machinery to replicate itself. Viral RNA is then spliced singly or multiply to make a variety of structural and regulatory and accessory proteins. Viral proteases further process proteins and mature viral particles are formed when the virus buds through the host cell membrane.
Within a few weeks of infection there is a high level of viral replication in the blood that can exceed 10 million viral particles per microlitre of plasma. There is a concomitant decline in CD4 T cells. However, an immune response to HIV develops that curtails viral replication, resulting in a decrease in viral load and a return of CD4 T-cell numbers to near normal levels. The immune control is thought to be dependent on killer T cells and neutralising antibodies. Depending on how effective this control is, the viral load is known as the set point and this is thought to be prognostic of natural history outcomes for the person.[20]
Research suggests that the host's initial response to infection with HIV is critical and genetically determined. A small number of patients show unusually slow or no immune damage. These long-term controllers are being carefully studied with the hope of developing immune-based therapies for HIV.
Classification
HIV subtypes[3][4][5]
HIV belongs to the genus Lentivirus of the family Retroviridae and has been divided into two types.
HIV type 1 (HIV-1)
HIV-1 is the virus responsible for the global epidemic. There are three major groups within HIV-1:
Group M (major, which includes clades A, B, C, D, and L)
Group N (non-M and non-O)
Group O (outlier)
Clade B is the commonly occurring virus in Europe and the US. Clades A, C, and D predominate in Africa, clades B and AE (a circulating recombinant form) in Asia, and clade B in South America.[3]
Globally, subtype C accounted for 46.6% of all HIV cases between 2010 and 2015, followed by subtype B (12.1%), subtype A (10.3%), subtype CRF02_AG (7.7%), subtype CRF01_AE (5.3%), subtype G (4.6%), subtype D (2.7%), and subtypes F, H, J, and K (0.9% combined).[6]
Subtype L was discovered in 2019 from samples taken in the Democratic Republic of the Congo in 2001.[7]
Subtype VB (virulent subtype B) was discovered in the Netherlands in 2022.[8]
HIV type 2 (HIV-2)
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