Aetiology

HIV is a retrovirus that infects and replicates 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 individuals are infected with HIV through sexual contact, before birth or during delivery, during breastfeeding, or when sharing contaminated needles and syringes (intravenous drug users). 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 STIs, high HIV viral load in the host, and lack of antiretroviral therapy.[19]

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 rapidly lead to viral resistance in those on treatment.[20]

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 infected person.[21]

Research suggests that the host's initial response to HIV infection 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 2 types:

  • HIV type 1 (HIV 1) is the virus responsible for the global epidemic. There are 3 major groups within HIV 1: group M (major, which includes clades A, B, C, D, and L), N (non-M and non-O), and 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 infections 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]

  • HIV type 2 (HIV 2) is less pathogenic and restricted in the most part to West Africa.[3][8]

Primary HIV infection refers to the first 6 months following HIV acquisition and is associated with an evolving HIV antibody response and high-level plasma viraemia.[9]

AIDS occurs as a result of HIV infection, and usually develops over 10-15 years (median 11 years).[1][2] It is a syndrome of a constellation of infections, conditions, or malignancies (based on criteria set by the US Centers for Disease Control and Prevention and World Health Organization) that occur as a result of the increasing immune depletion that HIV infection incurs over time.[4]

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