This case demonstrates a massive CD8 expansion in the setting of acute HIV infection that was associated with a severe symptomatic infection and a rapid decline in peripheral CD4 count. In the absence of any evidence of malignancy, the strong CD8 cell expansion observed likely reflects the rapid expansion of HIV-1-specific CD8 T cells following infection. We cannot exclude activation and cytokine-driven expansion of non-HIV-1-specific T cells or significant immune system dysfunction, but if non-HIV-1-specific expansion of T cells did occur, it was not reflected in the CMV T cell response to the pp65 TPRVTGGGAM epitope, which was detectable but 50- to 79-fold lower in magnitude than the mapped HIV-1-specific responses (). In addition, assuming a relationship between specific IFN-γ secretion as measured by ELISpot and tetramer frequency,11
as many as 20% of CD8 T cells in this patient were directed at the four epitopes identified. High frequencies of HIV-1-specific T cells have been reported in other studies, with studies by Wilson et al.3
reporting HIV-1 tetramer-specific frequencies approaching 4% in acute infection and Papagno et al.12
reporting frequencies of 10% tetramer-positive CD8 T cells in chronic HIV-1 infection. More recently, Ferrari et al.
employing intracellular cytokine and degranulation (IFN-γ, IL-2, TNF-α, MIP-β, CD107) flow cytometry techniques, reported frequencies of acute HIV-1epitope-specific CD8 T cells in the range of from 0.65 to 7.29% of the total CD8 population within the first 4 weeks of infection. The capacity of the T cell response to expand rapidly in acute viral infections is best demonstrated by studies of acute EBV infection where EBV-specific CD8 T cells comprised up to 44% of the total CD8 T cell response.14
The 40% contraction of absolute CD8 cells within 5 days and results from in vitro
assays suggested that cells were functional but highly apoptopic and poorly replicative. These observations are consistent with primary T cell responses and kinetics to live attenuated yellow fever vaccines15
and mouse models of virus infection16
that describe strong activation and expansion of virus-specific primarily effector T cells within weeks of infection followed by a contraction phase limiting the duration of the primary T cell response preventing immunopathology that would no doubt result if T cell expansion remained unchecked.
Recent studies have shown that primary T cell responses make a significant contribution to killing of virus-infected cells but may also select for rapid viral escape during acute viremia.8
Because this patient went on antiretroviral therapy within weeks of admission we have insufficient data on whether these primary HIV-1-specific T cell responses selected for viral escape. It is notable, however, that there was a 1.5 log drop in viremia over a 10-day period coincident to the detection of HIV-1-specific T cell responses. Previous studies on CD8 expansion during AHI have demonstrated that HIV-1-specific expansion may represent a limited T cell repertoire, and may be associated with more rapid progression. Conversely, Ferrari et al.13
described the CD8+
T cell response to acute HIV infection in symptomatic patients. They did not see an association with the magnitude of CD8+
T cell response and the appearance of escape mutants. In this individual, the height of the CD8 T cell response, the systemic symptoms, and elevated LFT in the setting of clonality by TCR gene rearrangement raised concerns that the patient may have presented with a malignant or premalignant syndrome. The rapid decline in CD8 count and the subsequent epitope analysis were not consistent with malignancy.
The question of whether this CD8 cell response was targeted entirely or predominantly against HIV is difficult to answer, but the HIV-specific response was robust, the proportion of activated CD8 cells was remarkably high,and despite the level of immune activation levels of other common viral pathogens (CMV and EBV) were either not detected or below quantification. Certainly the magnitude of the CD8 T cell response contributed to the patient's clinical illness, but whether the response was ineffectual is not certain. We note that the CD4 cell count was rising and the CD8 count and plasma HIV RNA were falling prior to the institution of antiretroviral therapy, which his clinicians believed was indicated based on the symptoms, CD4 decline, and CD8 expansion data at the time.
In conclusion, this case demonstrates that the magnitude of immune activation accompanying AHI can extend beyond what has been described to the point of mimicking malignancy. This massive expansion of CD8 T cells could have contributed to the severe symptoms seen in this individual and may reflect a profound disregulation of the T cell compartment. These results provide insights into the diversity of response to acute HIV infection.