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Ongoing Low-level Viral Replication and Polyfunctional CD8 T Cell Responses Detected in the HIV Elite Controllers
Florencia Pereyra*1, T Miura1, S Palmer2, B Block1, A Rothchild1, B Baker1, J Coffin2, and B Walker1
1Partners AIDS Res Ctr, Massachusetts Gen Hosp, Charlestown and Harvard Med Sch, Boston, US and 2NCI-Frederick, MD, US
Background:
HIV-1 elite controllers have been characterized as individuals who
spontaneously control viral replication to levels below the limits of detection
of standard polymerase chain reaction (PCR) and bDNA assays (<50 and 75
copies/mL, respectively), the actual level of viremia on these individuals is
largely unknown. To better understand the mechanisms of immune control of viral
replication, we used a real-time PCR (RT-PCR) assay with a sensitivity of 0.2 copies/mL to quantify plasma HIV-1 RNA and
compared HIV-specific immune responses between individuals with detectable and
undetectable viremia.
Methods:
Plasma samples from 45 elite controllers who had 3 viral RNA levels of
<50 copies/mL for at least a year without treatment were analyzed. High resolution
class I HLA typing was performed on all; HIV-specific antibodies and CD8 T cell
responses were measured by Western blot, interferon-gamma enzyme-linked
immunosorbent spot (ELISpot), and intracellular cytokine staining assays.
Results:
Of elite controllers, 75% had viremia that exceeded 0.2copies/mL (median
14 copies/mL), while the remaining 25% had viral loads that were undetectable.
Subjects with detectable viremia had a median of 9 bands positive on Western
blot (mean 8.6), whereas those with undetectable viral loads had a median of 7
bands positive (mean 6.3; p = 0.0360). Analysis of the HLA class-1
molecules expressed in these subjects showed similar expression of alleles that
has been associated with protection from HIV disease progression in both groups
(83 and 85%). Analysis of HIV specific CD8 T cell responses by interferon gamma
secretion showed a trend of higher breadth and magnitude of the responses (p
= 0.0622 and 0.0964), as well as a higher trend of HIV-specific CD8 T cells
that secrete interleukin (IL) -2 and multiple cytokines (polyfunctional cells)
(median 0.03 and 0.12, p = 0.24; median 0 and 0.04, p = 0.17) in
the group with detectable viremia
Conclusions:
Our data demonstrate that there is indeed ongoing viral replication in the
majority of elite controllers of HIV infection. We also show that even at this
low level of viremia, the presence of antigen seems to drive measurable HIV-specific
antibody and CD8 T cell responses, but does not negatively affect the ability
of CD8 T cells to secrete IL-2 or multiple cytokines.
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