CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21

Chen, Huabiao; Li, Chun; Huang, Jinghe; Cung, Thai; Seiss, Katherine; Beamon, Jill; Carrington, Mary; Porter, Lindsay C.; Burke, Patrick S.; Yang, Yue; Ryan, Bethany J.; Liu, Ruiwu; Weiss, Robert H.; Pereyra, Florencia; Cress, W. Douglas; Brass, Abraham L.; Rosenberg, Eric S.; Walker, Bruce D.; Yu, Xu G.; Lichterfeld, Mathias

doi:10.1172/jci44539

Cited by 159 publications

(165 citation statements)

References 46 publications

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“…The mechanisms by which Gal-9 acted in vitro are probably complex and involve down-regulation of HIV-1 coreceptors, such as CXCR4, CCR-5, and ␣4␤7, and up-regulation of p21 (Waf1/Cip1) in CD4 ϩ T cells, which has been reported to be associated with control of HIV-1 replication. 5 Therefore, our data suggest that Gal-9/Tim-3 interactions are beneficial in the context of HIV-1 acquisition (by inhibiting HIV-1 replication in activated CD4 ϩ T cells) but detrimental in the context of chronic infection (leading to HIVspecific CD8 ϩ T-cell suppression by Tregs, as we previously described 7 ). Taken together, influencing the function of the Tim-3/ Gal-9 pathway holds promise as a means to prevent HIV-1 infection in activated CD4 ϩ T cells.…”

Section: Introductionsupporting

confidence: 61%

“…3 More effective strategies that block initial HIV-1 acquisition at the site of exposure are required. Interestingly, deletion of 32 base pairs in the ccr5 gene 4 and selective up-regulation of p21 in CD4 ϩ T cells from elite controllers 5 render some individuals naturally resistant to HIV-1 infection. The mechanism(s) responsible for resistance of CD4 ϩ T cells to HIV-1 infection are not well known, but defining them is vital for designing prophylactic interventions.…”

Section: Introductionmentioning

confidence: 99%

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Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection

Elahi

Niki

Hirashima

et al. 2012

Blood

113

129

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Galectin-9 (Gal-9) is a tandem repeat-type member of the galectin family and is a ligand for T-cell immunoglobulin mucin domain 3 (Tim-3), a type-I glycoprotein that is persistently expressed on dysfunctional T cells during chronic infection. Studies in autoimmune diseases and chronic viral infections show that Tim-3 is a regulatory molecule that inhibits Th1 type immune responses. Here we show that soluble Gal-9 interacts with Tim-3 expressed on the surface of activated CD4 ؉ T cells and renders them less susceptible to HIV-1 infection and replication. The Gal-9/Tim-3 interaction on activated CD4 ؉ T cells, leads to down-regulation of HIV-1 coreceptors and up-regulation of the cyclin-dependent kinase inhibitor p21 (also known as cip-1 and waf-1). We suggest that higher expression of Tim-3 during chronic infection has evolved to limit persistent immune activation and associated tissue damage. These data demonstrate a novel mechanism for Gal-9/Tim-3 interactions to induce resistance of activated CD4 ؉ T cells to HIV-1 infection and suggest that Gal-9 may play a role in HIV-1 pathogenesis and could be used as a novel microbicide to prevent HIV-1 infection. (Blood. 2012;119(18):4192-4204) IntroductionProphylactic interventions against HIV-1 acquisition, such as vaccine and microbicide candidates, have not proved efficacious or even enhanced acquisition in previous human clinical trials. 1,2 Even the most promising vaccine to date, which involved a canarypox prime followed by a gp120 protein boost, only showed limited efficacy that waned over time. 3 More effective strategies that block initial HIV-1 acquisition at the site of exposure are required. Interestingly, deletion of 32 base pairs in the ccr5 gene 4 and selective up-regulation of p21 in CD4 ϩ T cells from elite controllers 5 render some individuals naturally resistant to HIV-1 infection. The mechanism(s) responsible for resistance of CD4 ϩ T cells to HIV-1 infection are not well known, but defining them is vital for designing prophylactic interventions.Galectin-9 (Gal-9), a member of the ␤-galactoside-binding animal lectin family, was originally characterized as an eosinophil chemoattractant. 6 Subsequent studies determined that it is a versatile immunomodulator involved in a wide range of biologic activities, such as cell adhesion and migration, proliferation and apoptosis, interaction of host cells with microbial pathogens, regulatory T-cell (Treg) differentiation and function, dendritic cell (DC) maturation, and antimicrobial immunity. 7-13 Gal-9 is expressed by eosinophils, endothelial cells, T lymphocytes, DCs, macrophages, lymphoid cells, Kupffer cells, intestinal epithelial cells, and vascular endothelial cells. 10,[14][15][16][17][18][19] Wide distribution of Gal-9 on host cells demonstrates an important but complex role for this lectin, whose biologic effects are exerted by 2 receptors with distinct, and often opposing effects: TIM-3 (T-cell immunoglobulin [Ig] and mucin domain-containing molecule 3) 20 and cell surface protein disulfide isomerase...

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Section: Introductionsupporting

confidence: 61%

Section: Introductionmentioning

confidence: 99%

Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection

Elahi

Niki

Hirashima

et al. 2012

Blood

113

129

View full text Add to dashboard Cite

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“…In particular, we did not detect p21 interactions with HIV-1 proteins involved in reverse transcription/integration, including Viral protein R, matrix, reverse transcriptase, and Integrase (28). Although p21 causes a preintegrative HIV-1 blockade in human hematopoietic stem cells (29), it has been reported to either inhibit or enhance HIV-1 transcription in MDMs and T cells (30)(31)(32). However, we did not observe a significant impact of FcγR-mediated activation on HIV-1 transcription in MDMs (33).…”

mentioning

confidence: 68%

p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway

Allouch

David

Amie

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Macrophages are a major target cell for HIV-1, and their infection contributes to HIV pathogenesis. We have previously shown that the cyclin-dependent kinase inhibitor p21 inhibits the replication of HIV-1 and other primate lentiviruses in human monocyte-derived macrophages by impairing reverse transcription of the viral genome. In the attempt to understand the p21-mediated restriction mechanisms, we found that p21 impairs HIV-1 and simian immunodeficiency virus (SIV)mac reverse transcription in macrophages by reducing the intracellular deoxyribonucleotide (dNTP) pool to levels below those required for viral cDNA synthesis by a SAM domain and HD domain-containing protein 1 (SAMHD1)-independent pathway. We found that p21 blocks dNTP biosynthesis by down-regulating the expression of the RNR2 subunit of ribonucleotide reductase, an enzyme essential for the reduction of ribonucleotides to dNTP. p21 inhibits RNR2 transcription by repressing E2F1 transcription factor, its transcriptional activator. Our findings unravel a cellular pathway that restricts HIV-1 and other primate lentiviruses by affecting dNTP synthesis, thereby pointing to new potential cellular targets for anti-HIV therapeutic strategies.

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“…Here, we used HIV-1 controllers, a group of patients widely used for investigation of HIV-1 immune defense mechanisms in previous studies (43)(44)(45) DCs in HIV-1 controllers seem to have a distinct functional and phenotypic profile that can contribute to the induction of highly functional HIV-1-specific T cell responses. These abilities have been associated with an altered expression profile of immunoregulatory receptors (46) and with enhanced abilities for HIV sensing and innate immune recognition (47).…”

Section: Cxcr3mentioning

confidence: 99%

Circulating CXCR5+CXCR3+PD-1lo Tfh-like cells in HIV-1 controllers with neutralizing antibody breadth

et al. 2017

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CD4+ T cells from elite controllers resist HIV-1 infection by selective upregulation of p21

Cited by 159 publications

References 46 publications

Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection

Galectin-9 binding to Tim-3 renders activated human CD4+ T cells less susceptible to HIV-1 infection

p21-mediated RNR2 repression restricts HIV-1 replication in macrophages by inhibiting dNTP biosynthesis pathway

Circulating CXCR5+CXCR3+PD-1lo Tfh-like cells in HIV-1 controllers with neutralizing antibody breadth

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