Re: Re: The predictions based upon the 'HIV/AIDS' hypothesis have been fulfilled 2 February 2005
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Nicholas Bennett,
Infectious Disease Postdoc/Clinician
Department of Pediatrics, University Hospital, Syracuse, NY

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Re: Re: Re: The predictions based upon the 'HIV/AIDS' hypothesis have been fulfilled

In response to Bruno Spagnoli's further question:

High non-specific antibody levels may give rise to false-positive HIV ELISAs, but there is no real evidence that this occurs from exposure to multiple pathogens or other antigens. The one case where this does happen is with EBV infection (infectious mononucleosis) due to widespread B cell activation (B cells produce antibodies), and as you might expect this is associated with transient false-positive HIV ELISAs in some individuals.

There is no reason to suspect that the AIDS-risk groups suffer from hypergammaglobulinemia (high antibody levels) and I can find no evidence for this in the literature, although antibody levels do rise slightly with age. Hypergammaglobulinemia can occur in some people post-HIV infection, as loss of CD4 T cells results in B cell dysregulation. The fact that the antibody dysfunction occurs _after_ seroconversion to HIV shows that it cannot be the cause of the positive HIV antibody tests.

As regards the specific examples requested, of course not all have been performed using PCR/culture controls, but it's a reasonable request to make. However, as stated above, there's no reason to suspect them to have hypergammaglobulinemia. There are some answers I can address though.

Hemophiliacs and homosexuals were used as controls in the papers of Jackson and Ho cited elsewhere on this thread. 0% detection by PCR or culture in seronegatives. Malaria is irrelevant since it isn't an AIDS- defining condition, but regardless there are plenty of studies directly addressing false-positive reactivity and showing malarial antibodies to have no effect on HIV reactivity [1,2] (ironically reference 1 is sometimes used in _support_ of malaria causing HIV false positives, highlighting a lack of reading ability). The only argument I've seen for TB reactivity is using anti-lipoarabionomanna (a constituent of TB bacteria) antibody cross-reacting with HIV tests. This may sometimes result in false-positive ELISA and negative or indeterminate WB, but such antibodies are actually less frequent in HIV+ people than HIV- controls, so low in fact that a standard TB diagnostic test using anti- lipoarabionomanna antibodies failed in nearly 90% of confirmed TB/HIV coinfections, in one study [3].

HIV negative people with immune dysfunction/suppression if anything have reduced antibody levels, for example if they suffer from a B cell deficiency. CD40 Ligand deficiency results in a specific rise in IgM antibodies (because the switch to IgG and other mature subclasses cannot occur) but that's the only example I know of with raised antibodies of any kind.

More generally, HIV tests are usually validated against a panel of known or potential false-positive conditions. E.g. the Vironostika kit mentioned in my previous post [4] was tested against 19 possible conditions, usually 10 samples of each for a total of 185, and gave a single false-positive result in one specimen of raised bilirubin (greater than 6.3 g/dl, more than twice the upper limit of normal) which was actually due to weak false-positive reactivity to gp160, as shown by WB. The specific conditions used in the Vironostika test were:

Antinuclear antibody positive, CMV antibody positive, EBV antibody positive, Rubella antibody positive, Elevated bilirubin, Hemolysed specimens, HSV-1 or HSV-2 antibody positive, HTLV-I or HTLV-II antibody positive, Lipemic Multiple transfusion, Multiparous females, Rhematoid factor positive, SLE positive, Syphilis antibody positive, Toxaplasmosis gondii positive, HBV antigen positive, HCV antibody positive, Hypergammaglobulinemia, Influenza vaccinated.

The Reveal Rapid HIV test kit [5] was tested against serum specimens from over 3700 people from three high-risk populations (unspecified). Of the high risk population the kit gave 31 false positive results as judged by a second set of tests (ELISA and WB). There were 125 true positives in the cohort.

When tested against plasma specimens from a low-risk population it gave 41 false positives from a cohort of 3011 (so the combined ELISA/WB protocol used as a control gave zero of 3011 positive results). Again, several potential false-positive reactions were tested, with no effect (Hep B and C antibodies and proteins, EBV, mycoplasma, syphilis reagin antibodies etc).

The Cambridge Western Blot (urine testing version) [6] was tested against 281 specimens from potentially reactive conditions and gave 2 potentially false positive results, both of which turned out to be true positives. They looked at autoimmune diseases, kidney and liver diseases, STDs, urine conditions, pregnancy, cancers, multiple transfusions and women who have had multiple pregnancies. It was also tested against 515 specimens from low-risk groups and showed no bands whatsoever.

In summary, it seems to me that there is neither an expectation that the high-risk individuals should get false-positive HIV tests due to hypergammaglobulinaemia, nor any evidence that the HIV tests are commonly going to give false-positive results due to the known false-positive conditions.

Nick Bennett njb35@cantab.net

1. Biggar et al Lancet. 1985 Sep 7;2(8454):520-3. "ELISA HTLV retrovirus antibody reactivity associated with malaria and immune complexes in healthy Africans."

2. Greenberg et al Lancet. 1986 Aug 2;2(8501):247-9. "Evaluation of serological cross-reactivity between antibodies to Plasmodium and HTLV- III/LAV."

3. Boggian et al J Clin Microbiol. 1996 Jul;34(7):1854-5. "Infrequent detection of lipoarabinomannan antibodies in human immunodeficiency virus- associated mycobacterial disease. Swiss HIV Cohort Study."

4. http://www.fda.gov/cber/pmalabel/P020066LB.pdf

5. http://www.fda.gov/cber/pmalabel/P000023LB.pdf

6. http://www.fda.gov/cber/sba/hiv1cam052898S.pdf

Competing interests: None declared