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Natural killer cells that respond to human immunodeficiency virus type 1 (HIV?1) peptides are associated with control of HIV?1 infection.

ABSTRACT: Human immunodeficiency virus (HIV)-specific natural killer (CD3- cells), CD4, and CD8 T cellular responses were determined in 79 HIV?1-infected women in response to HIV?1 peptide pools (Gag, Pol, Nef, Reg, and Env) with use of a whole?blood intracellular cytokine staining assay that measures interferon-? and/or interleukin-2. HIV?specific CD3- cell responses to any region (Env and Reg predominantly targeted) were associated with lower viral load (P = .031) and higher CD4 T cell count (P = .015). Env?specific CD3- cell responses were stronger in women who had both Gag CD4 and CD8 T cell responses and, in turn, was associated with lower viral load (P = .005). CD3- cell responders had significantly higher representation of CD4 T cell responses to Env and Reg (P = .012 and P = .015, respectively) and higher magnitudes of CD4 T cell responses (P = .017 and P = .037, respectively) than did nonresponders. Peptide?specific natural killer cells are associated with markers of less severe disease progression among HIV?1-infected women (lower viral load and higher CD4 T cell count) and with stronger HIV?specific T cell responses.

SUBMITTER: Tiemessen CT

PROVIDER: S-EPMC3060333 | biostudies-literature | 2010 Nov

REPOSITORIES: biostudies-literature

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Natural killer cells that respond to human immunodeficiency virus type 1 (HIV‐1) peptides are associated with control of HIV‐1 infection.

Tiemessen Caroline T CT Shalekoff Sharon S Meddows-Taylor Stephen S Schramm Diana B DB Papathanasopoulos Maria A M Gray Glenda E G Sherman Gayle G G Coovadia Ashraf H A Kuhn Louise L

The Journal of infectious diseases 20101101 9

Human immunodeficiency virus (HIV)-specific natural killer (CD3- cells), CD4, and CD8 T cellular responses were determined in 79 HIV‐1-infected women in response to HIV‐1 peptide pools (Gag, Pol, Nef, Reg, and Env) with use of a whole‐blood intracellular cytokine staining assay that measures interferon-γ and/or interleukin-2. HIV‐specific CD3- cell responses to any region (Env and Reg predominantly targeted) were associated with lower viral load (P = .031) and higher CD4 T cell count (P = .015). ...[more]

PMID: 20874516

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Project description:The goal of this project is todetermine if natural killer (NK) cells could be able to control HIV replication and reduce or eliminate viral reservoirs leading to HIV cure or a functional cure. Despite thirty years of work and significant progress, HIV infection continues to be an incurable disease. Antiretroviral therapy (ART) has significantly decreased the morbidity and mortality, but lifelong treatment is merely suppressive and does not cure HIV/AIDS. This is because of the existence of a reservoir of viral DNA+ (vDNA+) in cells of the lymphoid tissues with an intact provirus that is thought capable of initiating new rounds of HIV replication (i.e. latency). In addition to this inducible reservoir data suggest ongoing low-level virus replication and persistence in lymphatic tissues of some patients that is related to suboptimal drug levels in these tissues. Strategies are needed that can address both issues. NK cells are innate immune effectors that recognize virally infected targets through a cadre of activating and inhibitory receptors but become dysfunctional in HIV infected people. Strikingly, African green monkeys (AGM) and sooty mangabeys mount a strong control of viral replication in lymph node follicles shortly after the viremia peak that lasts throughout infection. Several mechanisms have been proposed to be implicated in the strong control of viral replication in natural host’s lymph nodes, such as NK cell-mediated control. Indeed, we have recently shown that NK cells could migrate into the b cells follicles in a CXCR5 dependent manner and thus participate to the elimination of viral replication. Thus the purpose of this study is too compare at the transcriptomic level different subset of NK cell isolated from blood and peripheral lymph node of chronically infected AGM to identify a transcriptomic signature which could be linked to an efficient control of SIV replication. This results could then provide a new aproche which could be exploited to generate functional NK cells against HIV in infected patients.

Project description:Targeted HIV cure strategies require definition of the mechanisms that maintain the virus. Here, we tracked HIV replication and the persistence of infected CD4 T cells in individuals with natural virologic control by sequencing viruses, T cell receptor genes, HIV integration sites and cellular transcriptomes. Our results revealed three mechanisms of HIV persistence operating within distinct anatomic and functional compartments. In lymph node, we detected viruses with genetic and transcriptional attributes of active replication in both T follicular helper (TFH) cells and non-TFH memory cells. In blood, we detected inducible proviruses of archival origin among highly differentiated, clonally expanded cells. Linking the lymph node and blood was a small population of circulating cells harboring inducible proviruses of recent origin. Thus, HIV replication in lymphoid tissue, clonal expansion of infected cells, and recirculation of recently infected cells act together to maintain the virus in HIV controllers despite effective antiviral immunity. Fluorescence-activated cell sorting (FACS) was used to sort subsets of CD4 T cells from blood (peripheral blood mononuclear cells; PBMC) and lymph node from a cohort of HIV-infected people with natural control of the virus (termed HIV controllers). Subsets of CD4 T cells that were sorted are as follows: from blood, (1) naÃ¯ve (N), (2) central memory (CM), (3) transitional memory (TM), and (4) effector memory (EM); from lymph node, (1) naÃ¯ve (N), (2) non-germinal center T-follicular helpers (nGC), (3) germinal center T-follicular helpers (Tfh), (4) effector memory (EM), and (5) other central memory-like subsets (CMPD1lo57lo, CMPD1lo57hi, and/or CMPD1lo). Total RNA and total DNA were extracted from these sorted subsets in separate fractions using RNAzol RT and DNAzol. Total cellular DNA was used for HIV quantification and sequence analysis as describe in the publication. Total RNA used for mRNA library construction by oligo-dT purification (Dynabeads), random fragmentation by heating in the presence of Magnesium (in form of 5x first-strand buffer, LifeTech), reverse transcription (SuperScript III), and then second-strand synthesis, end repair, a-tailing, and adaptor ligation using NEBNext enzyme master mixes and oligonucleotides. Libraries were sequenced on an Illumina HiSeq2000. Please note that each 'source name' value represent individual who havs HIV infection with natural control of the virus.

Dataset Information

Natural killer cells that respond to human immunodeficiency virus type 1 (HIV?1) peptides are associated with control of HIV?1 infection.

Publications

Natural killer cells that respond to human immunodeficiency virus type 1 (HIV‐1) peptides are associated with control of HIV‐1 infection.

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