In 1985, the US Food and Drug Administration  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 . 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 . 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  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  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 . According to United Nations Programme on HIV/AIDS  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.
We performed a literature review using the online search engine of the United States National Library of Medicine (http://www.ncbi.nlm.nih.gov/sites/entrez?db=pubmed) by searching for English language case reports and reviews under the medical subheading (MeSH term) ‘HIV seronegativity.’ Articles were screened to ensure that they reported a case or cases of HIV-positive patients whose plasma screening tests were negative at the time of diagnosis and remained antibody negative for prolonged periods or progressed to clinical AIDS and died without seroconversion. Data from these publications was reviewed and collated by the authors.
Twenty-five cases were identified that described patients with evidence of seronegative HIV-1 infection. All were confirmed to have seronegative HIV-1 infection by a combination of consistently negative results on two or more HIV-1 screening ELISA assays, and virologic evidence for HIV-1 infection by plasma HIV-1 RNA, p24 antigen assays, positive DNA PCR, recovery of virus from culture or all. These patients were found to be HIV-1 antibody negative at two or more time points (range 2–39) from independent samples. Patients that lacked evidence of serial antibody testing or definitive evidence of HIV-1 infection by any of the methods above were excluded, as were patients of HIV-2 infection.
Of the 25 seronegative patients who have been reported, the majority were in their third or fourth decade at the time of diagnosis. The mean age at diagnosis was 27 years. The youngest patient reported was an infant (age 2 months at the time of presentation); the oldest patient was 59 years old. Fourteen patients were male and 10 were female; in one patient, sex was not reported. None of the patients described had a medical condition that would predispose them to an attenuated immune response (Table 1).
The mode of virus acquisition was unknown or not reported in eight of 25 patients. Suspected parenteral exposure is described in one patient, and vertical transmission occurred in two patients. The remaining 14 patients were ascribed to sexual transmission. Pneumocystis jiroveci pneumonia, globally the most common AIDS-defining opportunistic infection , was present at the time of diagnosis in 12 of 25 patients. Other reported opportunistic infections at the time of diagnosis included esophageal candidiasis, tuberculosis, bacillary angiomatosis and cryptococcosis. Only four patients had CD4+ T-cell counts above 200 cells/μl (all of whom met criteria for AIDS through presentations with opportunistic infection), whereas 11 had counts below 50 cells/μl. Viral loads were not reported for seven patients. Among the remaining 18 patients, 16 had viral loads greater than 100 000 copies/ml. Six patients had viral loads that exceeded the upper limit of the assays used. Every patient met criteria for symptomatic AIDS.
In four patients, the time from primary infection to presentation could be determined; one patient was enrolled in a serodiscordant couples study  and received close serologic monitoring to identify incident HIV infection, one patient was followed closely because of high-risk behavior and had serial viral load and HIV-1 antibody testing  and two patients acquired HIV-1 infection as a result of vertical transmission [29,34]. All four of these patients progressed from primary infection to AIDS within 5 months. Although the exact time of primary infection could not be determined in the remainder of patients, there is clinical evidence for both high morbidity and rapid progression to AIDS (Table 1).
Viral clade or subtype was not reported for eight patients. Eleven patients had subtype B virus, one had subtype C, one had subtype A, one had subtype A2, two had a circulating recombinant form AG (CRF02-AG) and one had a circulating recombinant form BG (CRF14-BG). Of the eight patients reporting viral tropism, four were found to have dual-tropic virus (R5/X4) and four had R5-tropic virus. Eleven of 25 patients reported an evaluation for drug resistance mutations; all were negative, showing evidence of wild-type drug susceptible virus. Six cases reported phylogenetic analyses that linked the virus isolated from the index patient to virus from the HIV-infected source individual identified by history. In all of these cases, the source patient had a positive antibody response to HIV-1 (Table 2).
All patients by definition had multiple negative HIV-1 ELISAs. Western blot results were not reported for two patients. Fifteen patients had no bands present on western blot. Seven patients had a p24 band, four had a p17 band, one had p31 and p51 and one patient had faint gp160 and gp41 bands. All but two cases included an evaluation of humoral responses and quantitative immunoglobulin levels. Sixteen patients reported quantitative immunoglobulin levels, all of which were in the normal range. The two case reports of vertically infected infants describe normal immunoglobulin panels at 10 months of age. Several cases report antibody responses to common antigens or vaccines. Four patients were found to have immunoglobulin G (IgG) antibodies to hepatitis B and one to hepatitis C. Ten patients were reported to have antibodies to human herpesviruses (HHVs), including cytomegalovirus, Epstein–Barr virus, herpes simplex virus (HSV)-1, HSV-2 and HHV8.
The results from all patients demonstrate an inadequate humoral response that appears isolated to HIV-1 infection, as quantitative immunoglobulins and specific IgG responses to other pathogens or immunogens were normal in all patients. Although T-cell responses to HIV-1 infection appear to be central to the initial partial immune control of viral replication [43,44], comparatively little has been reported regarding the presence of cellular immunity in these patients. In a recent case report  describing two patients with rapid progression to AIDS (included here as patients #22 and 23), an interferon-gamma ELISPOT assay was used to detect cellular immune responses to HIV-1. No T-cell responses were found to HIV-1 in either patient. In patient number 25, our group demonstrated a reproducible T-cell response to two Gag epitopes . Despite the development of a broad antibody response to HIV-1 several months after the initiation of ART and immune reconstitution in this patient, the T-cell response remained limited to these two Gag epitopes.
Four case reports describe human leukocyte antigen (HLA) analysis. One patient was found to be homozygous for HLA class II alleles associated with high viral loads and rapid progression (HLA-DR1*0101 and HLA-DR1*0103) . HLA-B*3503, another allele associated with rapid progression , was identified in another patient. Our group identified the presence of the HLA-B*5802 allele in patient number 25, who has also been associated with rapid disease progression [47,48]. In one of the cases in which an HIV-1-positive source patient was identified by history and confirmed by viral phylogenetics, HLA typing was performed on both the index and source patients. This transmission pair was found to have matched HLA supertypes for 3 of 4 HLA-A and HLA-B alleles. Autologous viral epitopes did not induce a T-cell response in the index patient, suggesting that rapid progression in this patient may have occurred due to transmission of viral cytotoxic T-lymphocyte (CTL) escape mutants (Table 3).
Treatment and outcomes
There is high mortality among the reported cases of seronegative HIV-1 infection. Of the 17 patients reporting outcomes, there were 10 deaths occurring within a mean of 8 months of diagnosis (range = 2 days to 33 months). Eleven of 17 patients received some form of antiretroviral therapy, with nine receiving HAART. Three of these treated patients died, six seroconverted with positive ELISA and western blot assays after a mean of 3 months on treatment (range = 1–9 months), one patient had a viral load reported to be less than 1000 copies/ml without seroconversion at 16 months and one patient did not have an outcome reported after the initiation of HAART (Table 4).
The 25 patients discussed here indicate that seronegative HIV-1 infection is associated with high viral loads, rapid disease progression and significant mortality. It remains unclear whether this clinical presentation is a cause or an effect of the absence of a humoral response. The common causes of falsely negative HIV-1 antibody tests described above (‘window period’ testing, screening assays that do not detect nonclade-B virus, early ART and hypogammaglobulinemia) do not appear to be playing a role in these patients.
No patient is reported to have spontaneously seroconverted; however, several developed positive ELISAs and western blots after administration of ART and immune reconstitution. A similar phenomenon has been described in a patient coinfected with HIV and hepatitis C virus (HCV) . This patient had persistently detectable HCV viremia without hepatitis C antibodies (serosilent HCV infection) for a period of 13 months. Treatment with ART and anti-HCV therapy was followed shortly by the development of detectable HCV antibodies.
None of the patients reported here provide evidence of viral attenuation or mutation as a cause of the lack of antibody response. Case reports describing HIV-1-infected transmission pairs in which one partner exhibits an expected disease course (including positive HIV-1 antibody screening tests) and the other is HIV-1 seronegative with rapid disease progression (patients #5, 6, 7, 18 and 23) strengthen the conclusion that the host, not the virus, is responsible for this phenomenon.
It is tempting to ascribe a direct causal relationship between the lack of HIV-1-specific antibodies in this patient cohort and their rapid disease progression and high mortality. Scant immunologic evidence exists to support this concept however. In an SIV animal model, depletion of antibody-producing cells with the anti-CD20 mAb rituximab in SIV-infected primates did not significantly alter their viral loads or survival time when compared with SIV-infected primates who did not receive rituximab and retained SIV-specific neutralizing antibody titers [50,51]. In studies of elite suppressors (patients infected with HIV-1 with stable CD4+ T-cell counts who maintain viral loads <50 copies/ml without ART), low titers of neutralizing antibodies have been found and the highest levels of neutralizing antibodies to autologous virus were seen in patients with progressive disease [52,53].
Although the presence of HIV-1-specific neutralizing antibodies does not appear to be associated with control of viral replication, CTL response and the presences of specific major histocompatibility complex class I alleles do appear to correlate with viral load set points and the tempo of disease progression [43,44,54–56]. A subset of the patients described above underwent evaluation for T-cell function and HLA alleles. There appeared to be absent  or deficient T-cell responses to HIV-1 epitopes in these patients, which interestingly did not change after immune reconstitution and seroconversion . Several patients had HLA alleles known to be associated with rapid disease progression. In one case, the HLA supertypes between the seronegative patient described and the HIV-1-positive source patient were found to be identical, suggesting the possibility of transmission of viral species that had already mutated to evade the donor's cellular immunity.
The absence of an HIV-1-specific humoral response seen in the group of persistently seronegative patients described here may represent a downstream effect that begins with ineffective cellular immunity, leading to unimpeded viral replication and rapid CD4+ T-cell loss. As B cells require CD4+ T-cell signaling to become activated and produce antibodies in the setting of acute infection, profound and sudden CD4+ lymphopenia may lead to a lack of detectable antibody production. This inference is supported by the observation that in several of the patients described above, antibody production to HIV-1 antigens develops with restoration of CD4+ T cells after initiation of ART. The presence of normal immunoglobulin levels and detectable serum antibodies to common pathogens in the patients described here suggests that the defective humoral immune response may be unique to HIV-1 due to rapid depletion of HIV-1-specific CD4+ T-cell during primary infection .
If the clinical and immunologic responses of elite suppressors to HIV-1 infection exist at one end of a spectrum, seronegative HIV-1 patients such as the ones described here are at the other end. Further understanding of the interplay between the virus and development of adaptive immunity is needed to better understand the accelerated and dramatic clinical course among these patients, and has significant implications for diagnostics as well as therapeutic vaccine design.
All authors (A.M.S., E.R.M.S., J.N.B. and J.E.G.) contributed to evaluation, selection and data abstraction of the publications evaluated in this manuscript.
There are no conflicts of interest.
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