The patient had clinical and laboratory evidence of AIDS despite HIV-1 antibody tests that remained persistently negative until after he had achieved immune reconstitution with highly active antiretroviral therapy (HAART). False negative HIV-1 screening tests are rare and are usually attributed to testing within several weeks of primary infection, before a detectable humoral response develops [12
]. Little evidence exists to support the phenomenon of “seroreversion,” in which patients with HIV-1 infection lose their antibody response over time [13
]. The patient described here, who presented with symptomatic AIDS and was persistently seronegative over a five month period, does not fall into either of these categories, and was diagnosed with seronegative HIV-1 infection. Making this diagnosis often involves a combination of repeatedly negative serum HIV-1 ELISA and Western blot tests without prior positive testing, clinical evidence of AIDS or HIV-related symptoms, and evidence of HIV infection based on a positive p24 antigen, positive HIV-1 DNA or RNA polymerase chain reaction or HIV-1 viral culture. Previously described cases of seronegative HIV-1 infection have not documented spontaneous seroconversion; patients who were not treated for HIV-1 with antiretroviral therapy died or were lost to follow up while several of those treated with HAART, including our patient, developed HIV-1 antibodies after immune reconstitution [4
In sequencing gag
genes from this patient's virus, we were unable to identify any large deletions that could have explained the lack of an HIV-specific antibody response. Both clinical evidence and viral culture assays suggested that he was infected with a replication competent virus. This is in keeping with prior descriptions of seronegative HIV-1 infection [4
], in which a host immune defect appears to be responsible for seronegativity rather than infection with an attenuated or mutated virus.
The role of antibodies in the control of untreated HIV-1 infection is not well understood. Several lines of evidence suggest that neutralizing antibodies do not have a major role in controlling viral replication. In elite suppressors, HIV-1 infected patients with stable CD4 counts who maintain viral loads below 50 copies/mL without antiretroviral therapy, a recent report demonstrated minimal neutralizing antibody titers to autologous virus despite their lack of disease progression. Conversely, untreated patients with progressive disease were found to have the highest antibody titers to autologous virus [14
]. Given a lack of evidence that HIV-1 antibodies can slow progression of disease, it seems unlikely that seronegativity alone is responsible for what appears to be the rapid disease progression seen in the patient described here.
In contrast to neutralizing antibodies, cytotoxic T cells (CTLs) appear to be central to host defense against HIV-1 infection. This is evident in SIV models in which CD8+
cell depletion leads to increased viral loads that are suppressed with recovery of these cells [15
]. It is intriguing that one of the HLA alleles present in this patient, HLA-B*5802, is associated with rapid progression. This allele differs by only three amino acids from HLA-B*5801, an allele associated with low viral loads and good disease prognosis [11
This patient did have weak but reproducible T cell response to two Gag epitopes while he was seronegative, something that has not been demonstrated previously in these patients. The only other case report to describe HIV-1- specific T cell immunity in seronegative patients found no T cell responses to the entire HIV-1 proteome in two patients [6
]. Interestingly, once he achieved immune reconstitution, his antibody response expanded dramatically (), but his T cell responses remained unchanged.
We cannot draw definitive conclusions regarding the pathophysiology of seronegative HIV-1 infection from a single case report; however some intriguing clues are present. It has been previously demonstrated that CTLs usually appear within weeks of primary infection, and are largely responsible for controlling both viremia and the tempo of disease progression. One explanation of the pathophysiology of seronegative HIV-1 infection is that transmitted virus, replicating without significant immune pressure due to an absent [6
] or narrow CTL response such as the one seen in the patient described here, leads to overwhelming immune suppression and symptomatic AIDS. Thus the hallmark of seronegative HIV-1 infection, lack of detectable HIV-1 antibodies, may represent a marker for deficient HIV-specific cellular immunity in these patients, which in turn may be the underlying etiology of their unique and dramatic clinical course. This hypothesis needs to be tested in a larger number of patients in order to better understand the interaction between cellular and humoral immunity in the control of HIV-1 infection, which could have major implications for HIV-1 vaccine design.