Human Immunodeficiency Virus Persistence and T-Cell Activation in Blood, Rectal, and Lymph Node Tissue in Human Immunodeficiency Virus–Infected Individuals Receiving Suppressive Antiretroviral Therapy

Khoury, Gabriela; Fromentin, Rémi; Solomon, Ajantha; Hartogensis, Wendy; Killian, M. Scott; Hoh, Rebecca; Somsouk, Ma; Hunt, Peter W.; Girling, Valerie; Sinclair, Elizabeth; Bacchetti, Peter; Anderson, Jenny L.; Hecht, Frederick M.; Deeks, Steven G.; Cameron, Paul; Chomont, Nicolas; Lewin, Sharon R.

doi:10.1093/infdis/jix039

Cited by 87 publications

(80 citation statements)

References 49 publications

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“…While we did not isolate Tfh cells, our analysis does allow direct comparisons of SIV infection of multiple populations of CD4 T cells isolated from the same animals but at different sites. Consistent with previous studies using samples from ARV-treated, HIV-infected individuals, we did not see higher levels of viral DNA within CD4 T cells isolated from lymphoid tissue, compared to those isolated from peripheral blood (28). These data might suggest that the circulation of memory CD4 T cells throughout peripheral blood and lymphatics leads to normalization of infection across these sites.…”

Section: Discussionsupporting

confidence: 92%

“…3D to F). Moreover, similar to previous analyses of HIV-infected humans, we did not see that populations of memory CD4 T cells in lymphoid tissues were more prone to harbor viral DNA than were those isolated from peripheral blood (28). Importantly, while preferential loss of Th17 cells is not routinely observed in peripheral blood and peripheral lymphoid tissues, these cells are consistently observed to be preferentially lost from MLN (which respond to antigens from the GI tract) (10,12,17,20,21,23,(29)(30)(31).…”

supporting

confidence: 86%

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Simian Immunodeficiency Virus Infects Functionally Polarized Memory CD4 T Cells Equivalently In Vivo

Lai

Starke

Flynn

et al. 2019

J Virol

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Among the numerous immunological abnormalities observed in chronically human immunodeficiency virus (HIV)-infected individuals, perturbations in memory CD4 T cells are thought to contribute specifically to disease pathogenesis. Among these, functional imbalances in the frequencies of T regulatory cells (Tregs) and interleukin 17 (IL-17)/IL-22-producing Th cells (Th17/Th22) from mucosal sites and T follicular helper (Tfh) cells in lymph nodes are thought to facilitate specific aspects of disease pathogenesis. However, while preferential infection of Tfh cells is widely thought to create an important viral reservoir in an immunologically privileged site in vivo, whether immunological perturbations among memory CD4 T cell populations are attributable to their relative infectivity by the virus in vivo is unclear.Here we studied peripheral blood and lymphoid tissues from antiretroviral (ARV)treated and ARV-naive Asian macaques and isolated functionally defined populations of memory CD4 T cells. We then assessed the degree to which these populations were infected by simian immunodeficiency virus (SIV) in vivo, to determine whether particular functionally identified populations of memory CD4 T cells were preferentially infected by the virus. We found that SIV did not preferentially infect Th17 cells, compared to Th1 cells, Th2 cells, or Tregs. Moreover, Th17 cells contributed proportionately to the total pool of infected cells. Taken together, our data suggest that, although Tfh cells are more prone to harbor viral DNA, other functionally polarized cells are equally infected by the virus in vivo and Th17 cells are not preferentially infected. IMPORTANCE Functional perturbations of memory CD4 T cells have been suggested to underlie important aspects of HIV disease progression. However, the mechanisms underlying these perturbations remain unclear. Using a nonhuman primate model of HIV, we show that SIV infects functionally defined populations of memory CD4 T cells equally in different anatomic sites. Thus, preferential infection by the virus is unlikely to cause functional perturbations.

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Section: Discussionsupporting

confidence: 92%

supporting

confidence: 86%

Simian Immunodeficiency Virus Infects Functionally Polarized Memory CD4 T Cells Equivalently In Vivo

Lai

Starke

Flynn

et al. 2019

J Virol

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“…In support of this finding, Khoury et al. also found that activated CD4 + T cells were significantly inversely correlated with current and nadir CD4 + T‐cell counts . It was reported that INRs showed increased levels of immune activation, mainly in CD4 + T cells; increased levels of proliferation; and increased rates of spontaneous CD4 + T‐cell death by apoptosis .…”

Section: Potential Mechanisms Of Incomplete Immune Reconstitutionmentioning

confidence: 74%

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

Yang

Zhang

et al. 2020

Journal of Leukocyte Biology

168

171

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The morbidity and mortality of HIV type‐1 (HIV‐1)‐related diseases were dramatically diminished by the grounds of the introduction of potent antiretroviral therapy, which induces persistent suppression of HIV‐1 replication and gradual recovery of CD4+ T‐cell counts. However, ∼10–40% of HIV‐1‐infected individuals fail to achieve normalization of CD4+ T‐cell counts despite persistent virological suppression. These patients are referred to as “inadequate immunological responders,” “immunodiscordant responders,” or “immunological non‐responders (INRs)” who show severe immunological dysfunction. Indeed, INRs are at an increased risk of clinical progression to AIDS and non‐AIDS events and present higher rates of mortality than HIV‐1‐infected individuals with adequate immune reconstitution. To date, the underlying mechanism of incomplete immune reconstitution in HIV‐1‐infected patients has not been fully elucidated. In light of this limitation, it is of substantial practical significance to deeply understand the mechanism of immune reconstitution and design effective individualized treatment strategies. Therefore, in this review, we aim to highlight the mechanism and risk factors of incomplete immune reconstitution and strategies to intervene.

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“…Many studies have shown a significant correlation between the frequency of PD-1 + CD4 + and CD8 + T cells with HIV persistence on ART in blood 63,65,66 , lymph node 67 and the gastrointestinal tract, which has almost three times the frequency of PD-1 + CD4 + T cells compared to lymph node or blood 68 . However, the most direct evidence of a clear relationship between HIV persistence and PD-1 expression comes from sorting CD4 + T cells from blood where a 10-fold enrichment of HIV in PD-1 high compared to PD-1 low CD4 + T cells was observed 63 .…”

Section: Introductionmentioning

confidence: 99%

Immune checkpoint blockade in infectious diseases

2017

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The up-regulation of immune checkpoint molecules, such as PD-1 and CTLA4 on immune cells occur during acute infections, such as malaria, as well as during chronic persistent viral infections, including HIV and hepatitis B virus (HBV). These pathways are important for preventing immune-driven pathology, but can also limit immune-mediated clearance of the infection. The recent success of immune checkpoint blockade in cancer therapy suggests that targeting these pathways could also be effective for preventing and treating a range of infectious diseases. Here, we review our current understanding of immune checkpoint pathways in the pathogenesis of infectious diseases and discuss the potential for therapeutically targeting these pathways in this setting.

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Human Immunodeficiency Virus Persistence and T-Cell Activation in Blood, Rectal, and Lymph Node Tissue in Human Immunodeficiency Virus–Infected Individuals Receiving Suppressive Antiretroviral Therapy

Abstract: During ART, rectal tissue is an important reservoir for HIV persistence with a high frequency of activated CD4+ and CD8+ T cells. PD-1 may represent a marker of HIV persistence in rectal tissue.

Cited by 87 publications

References 49 publications

Simian Immunodeficiency Virus Infects Functionally Polarized Memory CD4 T Cells Equivalently In Vivo

Simian Immunodeficiency Virus Infects Functionally Polarized Memory CD4 T Cells Equivalently In Vivo

Incomplete immune reconstitution in HIV/AIDS patients on antiretroviral therapy: Challenges of immunological non-responders

Immune checkpoint blockade in infectious diseases

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