HIV escape from natural killer cytotoxicity: nef inhibits NKp44L expression on CD4+ T cells.
ABSTRACT HIV infection induces a progressive depletion of CD4 T cells. We showed that NKp44L, a cellular ligand for an activating natural killer (NK) receptor, is expressed on CD4 T cells during HIV infection and is correlated with both CD4 cell depletion and increase in viral load. NKp44LCD4 T cells are highly sensitive to the NK lysis activity. In contrast, HIV-infected CD4 T cells are resistant to NK killing, suggesting that HIV-1 developed strategies to avoid detection by the host cell immunity.
To assess whether viral protein can affect NKp44L expression, using Nef-deficient virus as well as a panel of recombinant vaccinia viruses expressing all HIV-1 viral proteins was tested. The involvement of Nef in the downmodulation of NKp44L was determined using defined mutants of Nef. Functional consequences of Nef on NK-cell recognition were evaluated by either 51Cr-release assays and degranulation assays in presence of anti-NKp44L mAb.
We observed that during HIV-1 infection, noninfected CD4 T cells exclusively expressed NKp44L, and demonstrate that Nef mediates NKp44L intracellular retention in HIV-infected cells. This has functional consequences on HIV-infected CD4 T cells recognition by NK cells, causing a decreased susceptibility to NK cytotoxicity. Furthermore, experiments in presence of neutralizing NKp44L mAb revealed that Nef inhibitory effect on NK cytotoxicity mainly depends on the NKp44L pathway.
This novel escape mechanism could explain the resistance of HIV-infected cells to NK lysis and as a result play a key role in maintaining the HIV reservoir by avoiding recognition by NK cells.
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ABSTRACT: Many aspects of HIV-1 pathogenesis are affected by Nef protein activity, and efforts have been made to study variation in the nef gene and how that variation relates to disease outcome. We studied the genetic diversity of the nef gene in distinct clones obtained from the same patient (intrahost) and in sequences obtained from different hosts (interhost). The set of sequences analyzed was obtained from HIV-1-infected Brazilian children and contained 112 clones from 25 children (intrahost samples), as well as 55 sequences from epidemiologically unlinked children (interhost samples). We found extensive site polymorphisms and amino acid length variations, mainly in the amino terminal region of the nef gene, between the myristoylation motif (MGxxxS) and the MHC-1 downregulation motif (Rxx). Analysis of the sequences deposited in the Los Alamos HIV sequences database ( www.hiv.lanl.gov ) indicated that the most frequent motif at the MHC-1 downregulation site in the subtype B strain is R(86%)A(64%)E(82%) (n = 1040) and R(78%)T(74%)E(56%) in the subtype C strain (n = 549). Conversely, the Brazilian subtype B isolates presented the motif R(81%)T(62%)E(67%) at this site (n = 64). A detailed analysis of selective pressures identified a concentration of codons under strong positive selection in the amino terminal region of the nef gene. We also determined that different sites are under positive selection in the subtype B and subtype C viruses. The amino acid composition in the MHC-1 downregulation motif of the nef gene in our sequences may indicate a distinct adaptive pattern of HIV-1 subtype B to the Brazilian host population.AIDS research and human retroviruses 11/2009; 25(11):1129-40. DOI:10.1089/aid.2009.0061 · 2.46 Impact Factor
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ABSTRACT: Natural killer (NK) cells are lymphoid effectors that are involved in the innate immune surveillance against infected and/or tumor cells. Their function is under the fine-tuning control of cell surface receptors that display either inhibitory or activating function and in healthy condition, mediate self-tolerance. It is known that inhibitory receptors are characterized by clonal and stochastic distribution and are extremely sensible to any modification, downregulation or loss of MHC class I surface expression that are induced in autologous cells upon viral infection or cancer transformation. This alteration of the MHC class I expression weakens the strength of the inhibitory receptor-induced interaction, thus resulting in a prompt triggering of NK cell function, which ends up in the inhibition of tumor progression and proliferation of pathogen-infected cells. Thus, the inhibitory function of NK cells is only one face of the coin, since NK-cell activation is controlled by different arrays of activating receptors that finally are involved in the induction of cytolysis and/or cytokine release. Interestingly, the inhibitory NK-cell receptors that are involved in dampening NK cell-mediated responses evolved during speciation in different, often structurally unrelated surface-expressed molecules, all using a conserved signaling pathway. In detail, during evolution, the inhibitory receptors that assure the recognition of MHC class I molecules, originate in, at least, three different ways. This ended up in multigene families showing marked structural divergences that coevolved in a convergent way with the availability of appropriate MHC ligand molecules.Self/Nonself - Immune Recognition and Signaling 01/2010; 1(2):103-113. DOI:10.4161/self.1.2.11717