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Loss of HIV-1–Specific Immunity During Treatment Interruption in 2 Chronically Infected Patients
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).
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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.
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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.
Joel N. Blankson, MD, PhD;
Joel E. Gallant, MD, MPH
Department of Medicine
Johns Hopkins University School of Medicine
Baltimore, Md
Thomas C. Quinn, MD
Johns Hopkins University School of Medicine and National Institute of
Allergy and Infectious Diseases
National Institutes of Health
Bethesda, Md
John G. Bartlett, MD
Department of Medicine
Johns Hopkins University School of Medicine
Robert F. Siliciano, MD, PhD
Department of Medicine
Johns Hopkins University School of Medicine and National Institute of
Allergy and Infectious Diseases
National Institutes of Health
1. Rosenberg ES, Billingsley JM, Caliendo AM, et al. Vigorous HIV-1-specific CD4+ T cell responses associated with control
of viremia. Science. 1997;278:1447-1450.
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2. Shwartz D, Sharma U, Busch M, et al. Absence of recoverable infectious virus and unique immune responses
in an asymptomatic HIV+ long-term survivor. AIDS Res Hum Retroviruses. 1994;10:1703-1711.
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3. deQuiros JC, Shupert WL, McNeil AC, et al. Resistance to replication of human immunodeficiency virus challenge
in SCID-Hu mice engrafted with peripheral blood mononuclear cells of nonprogressors
is mediated by CD8(+) T cells and associated with a proliferative response
to p24 antigen. J Virol. 2000;74:2023-2028.
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4. Rosenberg ES, Altfield M, Poon SH, et al. Immune control of HIV-1 after early treatment of acute infection. Nature. 2000;407:523-526.
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5. Blankson JN, Gallant JE, Siliciano RF. Proliferative responses to Human immunodeficiency virus type 1 (HIV-1)
antigens in HIV-1-infected patients with immune reconstitution. J Infect Dis. 2001;183:657-661.
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6. McNeil AC, Shupert WL, Iyasere CA, et al. High-level HIV-1 viremia suppresses viral antigen-specific CD4(+) T
cell proliferation. Proc Natl Acad Sci U S A. 2001;98:13878-13883.
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Letters Section Editor: Stephen J. Lurie,
MD, PhD, Senior Editor.
JAMA. 2002;288:162-164.
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