Seronegative HIV-1 Infection: a Review of the Literature

Spivak, Adam M; Sydnor, Emily RM; Blankson, Joel N; Gallant, Joel E


AIDS. 2010;24(10):1407-1414. 

In This Article

Abstract and Introduction


HIV-1-specific antibodies can be detected in HIV-1-positive patients within weeks of primary infection. Rare cases have been reported of patients who are persistently seronegative despite evidence of HIV-1 infection. We present a retrospective review of the clinical, virologic and immunologic characteristics of 25 persistently seronegative patients whose cases have been published to date and postulate a biologic mechanism for this phenomenon.


In 1985, the US Food and Drug Administration[1] approved the first diagnostic test for HIV-1, an ELISA that detected the presence of antibodies to viral antigens in the serum. Fourth-generation ELISAs that simultaneously detect HIV-1 antibodies and p24 antigen have been developed over the last decade and are now in clinical use for HIV-1 screening in most countries.[2–4] Specimens deemed positive by ELISA should be confirmed by supplemental testing algorithms employing either alternative format screening assays, western blot, immunofloresence assays or a test to detect HIV RNA according to current Centers for Disease Control and Prevention recommendations.[5] The performance characteristics of this testing strategy have been extensively evaluated,[6,7] and with a sensitivity and specificity greater than 99%,[8–10] it has proven to be one of the most reliable and accurate diagnostic tests in clinical medicine.

Patients exposed to HIV-1 typically develop HIV-1-specific antibodies within several weeks of primary infection.[11] Falsely negative screening HIV-1 antibody tests have most often been attributed to a 'window period' prior to the development of an HIV-1-specific antibody response or infection with HIV-2 or nonclade B HIV-1.[12–17] Several other less common phenomena can lead to falsely negative HIV-1 screening tests. In several case reports, patients treated with HAART very early in the course of disease did not develop a full HIV-1 antibody response, possibly due to HAART-induced virologic suppression and subsequent lack of antigen.[18,19] Another case report[20] describes a patient whose HIV-1 antibodies became undetectable after treatment with HAART and mycophenolate mofetil and returned once these treatments were stopped. In 2005, a case report[21] was published describing a patient with common variable immunodeficiency who lacked HIV antibodies over a 10-month period but had repeatedly detectable HIV-1 viral loads as high as 300 000 copies per milliliter. In rare cases, HIV-1-infected patients who are not receiving antiretroviral therapy (ART) or immunosuppressive medications have demonstrated persistent lack of humoral immunity to HIV-1.[22–41] These patients tend to present with severe immunodeficiency, likely due to a combination of negative antibody-based screening tests that delay diagnosis as well as a tendency toward rapid disease progression.

Over one million people are estimated to be living with HIV-1 in the United States, and more than 16 million people are tested for HIV-1 annually.[5] According to United Nations Programme on HIV/AIDS[2] epidemiologic data, in 2008, there were 33.4 million people living with HIV/AIDS worldwide and 2.7 million incident infections. Since HIV-1 was first recognized, however, there have been only 25 published case reports of patients with confirmed HIV-1 infection who do not have detectable HIV-1 antibodies. We describe here the clinical, virologic and immunologic characteristics of these patients with seronegative HIV-1 infection.


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