Pathogenesis of HIV infection, Clinical staging,Natural history of untreated HIV infection,

HIV structure

HIV-1 and 2 are structurally similar (icosahedral) with the following components:

• 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, made up of viral protein p17.
• Core: it comprises
• RNA dimer. Two identical copies of single-stranded RNA linked together, each containing ~9500 nucleotides. Associated with a nucleocapsid and its precursor protein.
• Capsid protein encapsulates the ribonucleoprotein core which contains three enzymes; reverse transcriptase, integrase, and protease.

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 vpu instead of vpx.
• Both sides of the HIV provirus are flanked by a repeated sequence known as the long terminal repeat.

Staging, classification, and natural history of HIV disease

Clinical staging

Early in the epidemic, before HIV was discovered, diagnosis of AIDS was largely based on finding Pneumocystis jiroveci (previously carinii) pneumonia (PCP) or Kaposi's sarcoma. HIV antibody testing led to patients being identified as having asymptomatic infection, AIDS-related complex or AIDS. 

The CD4 count is a useful predictor for the development of opportunistic infections (OIs) and malignancies. 

CD4 (count/µL) A B C >500 A1 B1 C1 200 to 500 A2 B2 C2 <200 A3 B3 C3 * Those in categories A3, B3, C1, C2, C3 have AIDS under the 1993 surveillance case definition.

Category A

• Asymptomatic HIV infection
• Persistent generalized lymphadenopathy
• Acute retroviral syndrome

Category B

• Bacillary angiomatosis
• Candidiasis
  • Oral
  • Recurrent vaginal
• Cervical dysplasia
• Constitutional symptoms
• Oral hairy leukoplakia
• Herpes zoster
• Idiopathic thrombocytopenic purpura
• Listeriosis
• Pelvic inflammatory disease
• Peripheral neuropathy

Category C (AIDS defining conditions)

• CD4 count <200cells/mm³
• Candidiasis
  • Pulmonary
  • Oesophageal
• Cerebral toxoplasmosis
• Cervical cancer
• Coccidioidomycosis
• Cryptosporidiosis
• Cytomegalovirus
• Herpes simplex
  • Chronic (>1 month)
  • Oesophageal
• HIV encephalopathy
• Histoplasmosis
• Isosporiasis
• Lymphoma
• Mycobacterium avium complex
• Mycobacterium tuberculosis
• Pneumocystis jiroveci
• Pneumonia (recurrent)
• Progressive multifocal leukoencephalopathy
• Salmonellosis
• Wasting syndrome due to HIV

Natural history of untreated HIV infection 

Characterized by progressive loss of immune function allowing the development of some virulent bacterial infections, certain opportunistic infections, and malignancies that define AIDS. Progression rate varies depending on interactions between host, viral, and environmental factors. The average time between HIV acquisition and AIDS is ~10 years if untreated.

Course can be divided into 5 continuous stages: infection, early, middle, advanced, and late-stage disease. There is significant individual variation between patients in the same clinical stage.

• HIV infection: Disseminates widely in the body at seroconversion, usually with a very high VL and a rapid, spontaneously but not fully reversible CD4 cell count.
• Early stage: CD4 count >500cells/µL. After stage viraemia (rarely becoming undetectable). Usually asymptomatic apart from generalized lymphadenopathy and certain skin disorders (e.g. seborrhoeic dermatitis, aphthous ulcers, eosinophilic dermatitis, and psoriasis) which may deteriorate or appear for the first time.
• Middle stage: CD4 count 200 to 500cells/µL. Mostly asymptomatic/mildly symptomatic. Skin disorders of early stage may worsen. Recurrent herpes simplex infection, varicella zoster, diarrhoea, weight loss, and intermittent fever may develop. Lung infections caused by community acquired organisms such as Streptococcus pneumoniae, Haemophilus influenzae, and Mycobacterium tuberculosis become more common.
• Advanced stage: CD4 count 50 to 200cells/µL. Increased VL with classical manifestations of PCP, Kaposi's sarcoma, lymphomas, and Mycobacterium avium complex (MAC) infection.
• Late stage: CD4 count <50cells/µL. Very high levels of viraemia. Further development of conditions associated with severe immune deficiency e.g. CMV retinitis, disseminated MAC. Neurological manifestations increased due to primary brain lymphoma, multifocal leukoencephalopathy, and dementia. HIV wasting disease is commonly seen at this stage.