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Raised immunoglobulin levels in HIV infection reflect B-cell activation^^V The most commonly studied immunoglobulin is ig A ^ i , 232,331-334 although some authors have also

studied levels of IgG, IgM and IgD®'^’^^^. In the absence of HIV infection, haemophilic patients have been shown to have raised levels of immunoglobulins^^ and racial differences are thought to exist with blacks having higher IgG and IgA levels than whites^^®. The finding that IgM levels in pre-exposure samples were higher in men who subsequently became infected with HIV and who progressed rapidly to clinical disease than in both men who remained uninfected and in men who became infected but did not progress rapidly^^® suggests that rapid progressors may have a tendency to mount a prolonged IgM response to many antigens.

Levels of immunoglobulins are generally higher in HIV positive individuals than in healthy control subjects®°’^^®. During HIV infection IgA and IgG increase with disease progression, although this may be a response to the development of symptoms^^. There does not appear to be a similar increase in the levels of IgM throughout infection. Symptomatic patients have higher levels of IgA than asymptomatic HIV positive individuals®^ and thus IgA levels may be of some prognostic value in HIV infection®''®'®"''''®®'.

6.1.3 O ther non-specific m arkers o f im m une activation

Other commonly studied non-specific markers of immune activation include B2M, neopterin, soluble CD8, interleukin-2 levels (IL-2) and soluble IL-2 receptor levels.

B2M is part of the human leukocyte antigen (HLA) class I molecule which is found on the surface of most nucleated cells, including B and T lymphocytes. It is shed during cell turnover®®'®®® and, as levels of B2M are usually fairly stable, increases in B2M are thought to represent immune activation®®®. Raised levels are seen in autoimmune diseases, lymphoproliferative disorders, in renal transplant patients and during other viral infection®®®'®"'. Because of repeated exposure to antigenic stimulatory materials and other infectious agents®"', levels tend to be raised in IVDUs and haemophilic patients, irrespective of their HIV status. Levels have also been shown to be higher in children in Africa®"®, possibly due to the high background levels of bacterial and viral infections endemic to the country. No differences have been found according to either sex or race. Around the time of infection with HIV, B2M levels rise for a short time®"", before dropping almost to ‘normal’ levels'®'. Levels then rise during infection'®'®"’®"" and are a good indicator of an individual’s risk of disease progression®'''® '®' ®®"'®"". As they can be measured on stored serum and are less affected by measurement variability®"® their use has been favoured in developing countries where there is a lack of financial support for HIV care.

Neopterin is produced by macrophages when stimulated by T-cell generated gamma interferon'®'®"®. Increased levels of neopterin therefore, also reflect immune activation®"'. Elevated neopterin levels are often seen in conditions involving activation of cellular immunity and in patients undergoing immunomodulatory treatments®"'. Levels are increased in uninfected haemophilic patients®"®'®"®, homosexual men®"®, attenders at genito-urinary clinics®"® and IVDUs®"®. During HIV infection levels of neopterin tend to mirror those of B2M'®®'®"'®®® and the correlation between the two markers ranges from 0.33 to 0.74®' '®' ®®''®®®. As a result, whilst neopterin may be as

good a marker of progression as little additional benefit is obtained by measuring both markers^^^’^®^.

In vitro studies have suggested that soluble CD8 (sCD8) is released during activation and turnover of cytotoxic T cells^^^ and its measurement may therefore serve as an index of CD8 cell activity^®^. The few studies carried out on sCD8 suggest that levels are raised during HIV infection^^^’^^®’^®® and that levels are correlated with other immune activation markers, including B2M and neopterin. The sCD8 level has also been shown to be related to progression of HIV disease^^^'®®^'®®\

Interleukin-2 (IL-2) is essential for T-cell proliferation®®® and is released during T-cell activation. The presence of soluble IL-2 receptor (slL-2R) suggests an impairment in T cell function®®^ and therefore raised slL-2R levels would be expected in the presence of T cell activation®®®. slL-2R appears to have prognostic value for progression of HIV disease®®^,336.359,360,362 although significant correlations have been found between sIL-

2R and the other immune activation markers®®®’®®®. 6.1.4 HIV viral markers

HIV contains a core protein antigen, p24, which appears in culture supernatants of cells in which HIV is replicating. Hence the presence of p24 antigen in serum appears to be correlated with active HIV replication in v/vo®®®. p24 core antigen is usually detectable at the time of infection, but then becomes undetectable®®^’®®^, usually reappearing late in disease, although many individuals remain free of p24 antigen even during late stage disease^®®. Both progression to AIDS and the rate of CD4 decline appear to be more rapid in individuals who are p24 antigenaemic®^ ®®’®®’®®®’®®®’®®^'®®®.

Antibodies to p24 antigen appear soon after infection in almost all patients. Their loss may be one of the earliest markers of HIV progression®®, usually heralding a clinical deterioration®®. Progression to AIDS appears to be slowest in those with the highest titer of antibodies at infection®®®. Geographic differences exist in the levels of antibodies to p24 and of p24 antigen. In particular, patients from Africa have high levels of antibodies at all stages of HIV infection and rarely become p24 antigenaemic during infection®®^. Early in infection, the majority of individuals are infected with usually slow replicating non-syncytium-inducing (NSI) HIV variants®®®. At some stage in infection there may be a switch to faster replicating syncytium-inducing (SI) variants. This switch appears to be associated with a more rapid loss of CD4 cells and more rapid progression of HIV

present and the number of different viral strains present all appear to be related to disease progression^