Transmission of HIV infection

HIV-1 and HIV-2, the major and minor human AIDS viruses,are transmitted in ways that are typical for all retroviruses –“vertically” – that is from mother to infant, and “horizontally”through sexual intercourse and through infected blood. Thelymphocytes of a healthy carrier of HIV replicate, andeliminate, over one billion virions each day and the circulatingvirus “load” may exceed ten million virions per millilitre. Atthese times viraemia can be recognised by measuring the p24antigen of HIV in blood and quantifying viral DNA or RNA(see below). Transmission also depends on other factors,including the concentration of HIV secreted into body fluidssuch as semen, secondary infection of the genital tract, theefficiency of epithelial barriers, the presence or absence of cellswith receptors for HIV, and perhaps the immune competence ofthe exposed person. All infections with HIV appear to becomechronic and many are continuously productive of virus. Theultimate risk of spread to those repeatedly exposed is thereforehigh.The stage of infection is an important determinant ofinfectivity. High titres of virus are reached early in infection,though this phase is difficult to study because symptoms may bemild or absent and any anti-HIV response undetectable; it isnevertheless a time when an individual is likely to infectcontacts. When, much later, the cellular immune response toHIV begins to fail and AIDS supervenes the individual mayagain become highly infectious. In the interval between, theremay be periods when except through massive exposures – forexample blood donation – infected individuals are much lessinfectious. Nevertheless, in the absence of reliable markers ofinfectivity, all seropositive individuals must be seen aspotentially infectious, even those under successful treatment.Effective ways are constantly being sought to protect theircontacts and this has led to the development of the concept of“safe sex”. Ideally, this should inform sexual contact between allindividuals regardless of whether they are known to be infectedwith HIV.

Strategies for HIV vaccine development

• A good vaccine should induce neutralising antibody, helperT-cells and cytotoxic T-cells.

• Since antibodies bind to three dimensional structures,induction of neutralising antibody requires native envelope.Problem: Native envelope is trimeric.

• T-cells recognise 8–15 amino acid-long peptides bound toMajor Histocompatibility Complex (MHC) class I and IImolecules.Problem: Antigen needs to enter antigen presenting cells,usually dendritic cells, to be broken down to peptides.

• Peptides with novel adjuvants can generate good T-cellresponses.Problem: Different peptides bind to each MHC allele so alarge cocktail of different peptides may be needed.

• Adjuvants are needed to induce large responses.Problem: There are very few adjuvants available forunrestricted use in humans. Alum is mainly good for inductionof antibody responses.

• DNA immunisation can generate antibody, helper andcytotoxic responses and allows incorporation of adjuvantmolecules into the vaccine.Problem: So far DNA vaccination has not proved as effectivein man as in experimental animals.

• HIV is very variable and escape variants arise rapidly ininfected individuals. Prophylactic immunisation may tip thebalance in favour of the host and prevent escape. Some partsof the virus sequence are relatively invariant, these should betargeted if possible.

• In experimental animals immunisation with differentimmunogens appears promising. DNA vaccination followed byimmunisation with antigen in a recombinant viral vector seemsparticularly effective. This is now under trial in man.

History of the AIDS

The first recognised cases of the acquired immune deficiencysyndrome (AIDS) occurred in the summer of 1981 in America.Reports began to appear of Pneumocystis carinii pneumonia andKaposi’s sarcoma in young men, who it was subsequentlyrealised were both homosexual and immunocompromised. Eventhough the condition became known early on as AIDS, itscause and modes of transmission were not immediatelyobvious. The virus now known to cause AIDS in a proportionof those infected was discovered in 1983 and given variousnames. The internationally accepted term is now the humanimmunodeficiency virus (HIV). Subsequently a new variant hasbeen isolated in patients with West African connections –HIV-2.The definition of AIDS has changed over the years as aresult of an increasing appreciation of the wide spectrum ofclinical manifestations of infection with HIV. Currently, AIDSis defined as an illness characterised by one or more indicatordiseases. In the absence of another cause of immune deficiencyand without laboratory evidence of HIV infection (if thepatient has not been tested or the results are inconclusive),certain diseases when definitively diagnosed are indicative ofAIDS. Also, regardless of the presence of other causes ofimmune deficiency, if there is laboratory evidence of HIVinfection, other indicator diseases that require a definitive, orin some cases only a presumptive, diagnosis also constitute adiagnosis of AIDS.In 1993 the Centers for Disease Control (CDC) in the USAextended the definition of AIDS to include all persons who areseverely immunosuppressed (a CD4 count <200>

AIDS-defining conditions with laboratory evidence of HIV

• Diseases diagnosed definitively

• Recurrent/multiple bacterial infections in child <13>

• Coccidiomycosis – disseminated

• HIV encephalopathy• Histoplasmosis – disseminated

• Isosporiasis with diarrhoea persisting >1 month

• Kaposi’s sarcoma at any age

• Primary cerebral lymphoma at any age

• Non-Hodgkin’s lymphoma: diffuse, undifferentiated B cell type, or unknown phenotype

• Any disseminated mycobacterial disease other than M.tuberculosis

• Mycobacterial tuberculosis at any site

• Salmonella septicaemia: recurrent

• HIV wasting syndrome

• Recurrent pneumonia within 1 year

• Invasive cervical cancer

• Diseases diagnosed presumptively

• Candidiasis: oesophagus

• Cytomegalovirus retinitis with visual loss

• Kaposi’s sarcoma

• Mycobacterial disease (acid-fast bacilli; species not identified by culture): disseminated

• Pneumocystis carinii pneumonia

• Cerebral toxoplasmosis