Oxford Handbook of Genitourinary Medicine, HIV, and Sexual
Health (2 edn)
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HIV structure
HIV-1 and HIV-2 are structurally similar (icosahedral) with the following components (Fig. 36.1).
Envelope: a lipid bilayer formed from host cell lipids and viral proteins. Embedded in the envelope is a complex protein (env) containing the viral surface glycoprotein (gp120) and a transmembrane glycoprotein (gp41). Both are derived from a precursor (gp160).
Matrix: encapsulated by the envelope and made up of viral protein p17.
Core: comprises
RNA dimer—two identical copies of single-stranded RNA linked together, each containing ~9500 nucleotides. Associated with nucleocapsid (p7 and p6).
Capsid protein p24 encapsulates the ribonucleoprotein core which contains three enzymes—reverse transcriptase (p66/51), integrase (p31), and protease (p15).
HIV structure: gp and p refer to glycoprotein and protein, respectively, and the numerical values (×103) indicate molecular weight.
Genetic organization of HIV
Genetic information is stored as RNA.
Gene maps for HIV-1 and HIV-2 are similar except that HIV-2 has vpx instead of vpu.
Both sides of the HIV provirus are flanked by a repeated sequence known as the long-terminal repeat.
Major structural proteins | gag | Encodes for capsid, matrix, and nucleocapsid |
pol | Encodes for viral enzymes | |
env | Encodes for envelope glycoproteins | |
Regulatory proteins | tat | Regulates HIV transcription |
rev | Induces transition from early to late genes | |
Accessory proteins | vpu | Enhances virus particle release |
vpr | Facilitates import of preintegration complex and cell growth arrest | |
vif | Maintains replication of HIV in lymphocytes and macrophages | |
nef | Downregulates CD4 receptors andstimulates HIV infectivity |
Major structural proteins | gag | Encodes for capsid, matrix, and nucleocapsid |
pol | Encodes for viral enzymes | |
env | Encodes for envelope glycoproteins | |
Regulatory proteins | tat | Regulates HIV transcription |
rev | Induces transition from early to late genes | |
Accessory proteins | vpu | Enhances virus particle release |
vpr | Facilitates import of preintegration complex and cell growth arrest | |
vif | Maintains replication of HIV in lymphocytes and macrophages | |
nef | Downregulates CD4 receptors andstimulates HIV infectivity |
HIV replicative cycle
Replication occurs in the following sequence: binding → fusion and entry → reverse transcription → integration → proviral transcription → cytoplasmic expression → assembly → budding and maturation.
Binding/attachment
Glycoprotein120 binds to the extracellular component of the CD4 receptor (expressed in helper T-cells, macrophages, monocytes, and microglial, dendritic, and Langerhans’ cells). A chemokine co-receptor (CCR5 or CXCR4) is also required for infection of helper T-cells or macrophages.
Fusion
Binding of gp120, CD4, and co-receptors produces a conformational change in gp41, leading to virion and cell membrane fusion and release of the viral core into the cell.
Reverse transcription
Viral reverse transcription complex includes viral RNA, transfer RNA (tRNALys), viral reverse transcriptase, integrase, matrix and nucleocapsid proteins, viral protein R (vpr), and various host proteins. Reverse transcription yields HIV pre-integration complex, composed of double-stranded viral cDNA, integrase, matrix, vpr, reverse transcriptase, and the high-mobility group DNA-binding cellular protein HMGI (Y). Pre-integration complex travels towards the nucleus using microtubules. Reverse transcription is error prone, producing a mistake every cycle and generating multiple mutations instrumental in both the development of drug resistance and escape from immune surveillance.
Integration
Integrase mediates the integration of the viral DNA into the host cell chromosome. It also removes terminal nucleotides from the proviral DNA, correcting the ragged ends generated by the terminal activity of reverse transcriptase.
Proviral transcription
Transcription is controlled by host factors. NF-κ B induced by T-cell receptor stimulation, IL-1, and TNF-α binds (NF-κ B) to DNA binding sites to activate transcription. Host factors regulate transcription of provirus. Transcription generates different multiple spliced HIV-specific transcripts, which are transported rapidly into the cytoplasm and encode nef, tat, and rev. Single-spliced or unspliced viral transcripts remain in the nucleus and encode the structural, enzymatic, and accessory proteins that are needed for the assembly of fully infectious virions.
rev-independent and rev-dependent cytoplasmic expression
During early HIV synthesis only multiple spliced mRNA transcripts are available for translation. Later on unspliced and singly spliced mRNAs diffuse into the cytoplasm where translation to structural protein synthesis starts.
Virion assembly
The HIV particles generated assemble at the host cell surface.
env proteins are synthesized in the endoplasmic reticulum and transported to the cell surface where gp41 anchors gp120 to the plasma membrane.
gag and gag–pol proteins are cleaved by viral proteases during budding to produce mature products.
Mature virions are released ready to infect new cells and begin the replication cycle once again. The entire process is extremely active, with 108–1010 viral particles produced each day.
HIV and its receptors
CD4 antigen is the principal receptor, and is mainly expressed on the surface of helper T lymphocytes. It is expressed to a lesser degree in CD4 dendritic cells, including Langerhans’ cells, CD4 monocytes, macrophages, and microglial cells.
Co-receptors: several chemokine receptors have been described, but CCR5 and CXCR4 are the most important co-receptors for HIV attachment in vivo. CCR5 is the co-receptor for NSI strains and CXCR4 is the co-receptor for SI strains.
gp120: contains hypervariable regions (V1–V5) which vary from one HIV isolate to another. V3 loop is not involved in CD4 binding but is important for HIV tropism for macrophages or T-lymphoid cell lines. It is also the target for neutralizing antibodies that block HIV-1 infectivity.
Factors influencing HIV disease progression
Host factors
Age: ↑ age is associated with ↑ progression.
Co-infection: may affect immune system resulting in ↑ progression (e.g. tuberculosis and hepatitis C). Cytomegalovirus is associated with ↑ progression in haemophiliacs.
Gender: ♂ appear to have higher viral loads at any CD4 level and may progress more rapidly.
Psychosocial factors: depression, impaired intellectual functioning, drug use, and social deprivation may be associated with ↑progression.
Genetic susceptibility:
Up to 20% of individuals of northern European descent have a deletion in the CCR5 gene resulting in a mutant (CCR5∆32). Homo-zygous individuals (1–2% of the Caucasian population) are almost resistant to HIV infection and heterozygotes are slow progressors. CCR2 (a minor co-receptor) deletion (CCR-V641) is widespread in all ethnic groups and results in slower progression to aids.
Certain HLA types are associated with ↓ or ↑ progression.
Possession or lack of certain genes: e.g. low copy number of CCL3L1 associated with ↑ susceptibility to HIV acquisition and progression.
Nutrition: poor premorbid state associated with ↑ progression.
Pharmacological variability: individual drug metabolism and elimination modifies response to therapy.
Viral factors
Changes in the phenotype and genotype of the virus enable it to ‘escape’ control by the immune system. In late HIV infection switching from CCR5 to CXCR4 (i.e. from NSI to SI) leads to infection of both active and resting immune cells, resulting in ↑ disease progression. Mutations may alter viral ‘fitness’ influencing pathogenicity. Gene mutation involving nef is associated with progression, and some drug-resistant mutations (e.g. M184V which induces lamivudine resistance) may ↓ viral fitness.
Drug susceptibility depends largely on HIV genotypic and phenotypic characteristics with genotype mutations rendering some drugs ineffective. Other factors such as efflux pumps may also be involved.
