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Secretion in Suppressed HIV-Infected Patients Despite Mature NK Cell Recovery: Evidence for a Defective Reconstitution of Innate Immunity1
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* Department of Microbiology and Immunology, Kimmel Cancer Center, Thomas Jefferson University, and
Philadelphia Field Initiating Group for HIV-1 Trials, Philadelphia, PA 19107;
HIV-1 Immunopathogensis Laboratory, The Wistar Institute, and
Division of Infections Diseases, University of Pennsylvania, Philadelphia, PA 19104
The impairment of NK cell functions in the course of HIV infection
contributes to a decreased resistance against HIV and other pathogens.
We analyzed the proportion of mature and immature NK cell subsets, and
measured subsets of IFN-
and TNF-
-producing NK and T cells in
viremic or therapy-suppressed HIV-infected subjects, and noninfected
control donors. Viremic HIV+ individuals had significantly
lower proportions of mature
CD3-/CD161+/CD56+ NK cells and of
IFN--producing NK cells compared with noninfected donors,
independent of CD4+ T cell counts. HIV-infected subjects
with undetectable viral load recovered mature
CD3-/CD161+/CD56+ NK cells and
cytotoxicity against tumor (K562) and HSV-infected target cells to
percentages comparable with those of uninfected individuals, but their
NK cells remained impaired in their ability to produce IFN-. In
parallel to these ex vivo findings, in vitro NK cell differentiation of
CD34-positive cord blood precursors in the presence of R5 or X4 HIV-1
resulted in the production of NK cells with a normal mature phenotype,
but lacking the ability to produce IFN-, whereas coculture of
uninfected PBMC with HIV failed to affect mature NK cell properties or
IFN- secretion. Altogether, our findings support the hypothesis that
mature NK cell phenotype may be uncoupled from some mature functions
following highly active antiretroviral therapy-mediated suppression of
HIV-1, and indicate that relevant innate immune functions of NK cell
subsets may remain altered despite effective viral suppression
following antiretroviral treatment.
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