Loss of HIV-1–Specific Immunity During Treatment Interruption in 2 Chronically Infected Patients
- Joel N. Blankson, MD, PhD;
- Joel E. Gallant, MD, MPH
- Thomas C. Quinn, MD
- John G. Bartlett, MD
- Robert F. Siliciano, MD, PhD
To the Editor: Human immunodeficiency virus 1 (HIV-1) antigen-specific proliferative CD4+ T cell responses are typically absent in patients with chronic HIV-1 infection.1 However, these responses are present in so-called long-term nonprogressors who experience control of viremia even without treatment1-3 and in patients treated with highly active antiretroviral therapy (HAART) during acute seroconversion who are subsequently able to contain viremia after treatment interruptions.4 These findings suggest that the presence of CD4+ T cell proliferative responses to HIV-1 may be associated with protection against viral replication.
Methods
We studied 2 patients who were started on HAART during chronic infection and who were unusual in that they had strong and broad HIV-1–specific CD4+ T cell responses. Both patients experienced treatment interruptions, which allowed us to examine the relationship between strong proliferative responses to HIV-1 and the control of viremia. Blood was obtained from both patients at various times before and after the discontinuation of HAART. Viral loads were determined by reverse transcription polymerase chain reaction. Peripheral blood mononuclear cells were cultured at 106 cells/mL in the presence of 1 to 2 µg/mL of various HIV-1 antigens (p24, p66, gp160). The cells were pulsed with 3H thymidine on day 6 and were harvested on day 7. Proliferation response was estimated by dividing the counts per minute of each antigen by the counts per minute in the medium, yielding a stimulation index (SI).
Results
While on HAART, patient A maintained very low viral loads and at 3 different time points was found to have high (ie, 7-33) SIs of p24 and p66 antigens.5 Nevertheless, when HAART was discontinued, he experienced a rebound in viremia and a loss of this CD4+ proliferative response to both HIV-1 antigens (Figure 1, A).
Figure. Treatment Interruption, Viral Load, and HIV-1 Antigen–Specific CD4 T Cell Proliferative Response in 2 Patients With Chronic HIV Infection
Break in upper shaded bar indicates time of treatment interruption. HIV indicates human immunodeficiency virus.
Prior to treatment interruption, patient B had high levels of 3 different HIV-1 antigens. She experienced a significant decrease in these responses as early as 1 week after the discontinuation of therapy, prior to a rebound in viremia. Viremia was detected by day 21 and HAART was reinitiated at day 28, when her viral load reached 138 000 copies/mL (Figure 1, B). Following re-initiation of therapy, the patient eventually regained CD4+ T cell–mediated HIV-1–specific immunity.
Comment
These 2 chronically infected patients had strong and broad CD4+ T cell responses to HIV-1 while receiving HAART but were unable to suppress viremia after discontinuing therapy. In both cases, HIV-1-specific immunity was lost in the setting of recurrent viremia. Interestingly, a similar loss of HIV-1–specific proliferative responses during treatment interruption in chronically infected patients has been recently reported.6 In contrast, some persons with acute seroconversion and HIV-1–specific CD4+ T cell responses are able to experience control of viremia when therapy is interrupted once or twice.4 While it is possible that a second interruption of treatment would have resulted in better immune control of viral replication, the almost complete loss of proliferative responses during peak viremia makes this unlikely. The recovery of proliferative responses following the re-initiation of HAART in patient B suggests that T cell anergy rather than deletion is responsible for the loss of HIV-specific immunity. It is unclear why chronically infected patients with strong immune responses are unable to control viremia while not receiving therapy, but the reason may be related to the heterogeneous population of viruses found in chronic HIV infection. This diverse population may pose more of a challenge to the immune system than the relatively homogeneous isolates that are present shortly after seroconversion. These preliminary results may have implications for trials of therapeutic vaccination followed by treatment interruptions in chronically infected patients receiving HAART.
