CD4 downregulation by memory CD4+ T cells in vivo renders African green monkeys resistant to progressive SIVagm infection

Beaumier, Coreen M.; Harris, Levelle D.; Goldstein, Simoy; Klatt, Nichole R.; Whitted, Sonya; McGinty, John W.; Apetrei, Cristian; Pandrea, Ivona; Hirsch, Vanessa M.; Brenchley, Jason M.

doi:10.1038/nm.1970

Cited by 129 publications

(176 citation statements)

References 54 publications

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“…CD4 down-regulation by memory CD4 þ T cells was recently proposed as a key mechanism by which African green monkeys survive SIVagm infection without developing AIDS. 42 These data might contrast with our findings of increased CD4 down-regulation in progressive HIV disease. However, they might also indicate that CD4-downregulation is not the pathway leading to CD4 depletion.…”

Section: Discussioncontrasting

confidence: 95%

210 Low Post-Seroconversion CD4 Count and Rapid Decrease of CD4 Density Identify HIV+ Fast Progressors

Audigé

Taff

Rickenbach

et al. 2011

JAIDS Journal of Acquired Immune Deficiency Syndromes

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R (2010). Low postseroconversion CD4 count and rapid decrease of CD4 density identify HIV+ fast progressors. AIDS Research and Human Retroviruses, 26(9) CD4 expression in HIV replication is paradoxical: HIV entry requires high cell-surface CD4 densities, but replication requires CD4 down-modulation. However, is CD4 density in HIV þ patients affected over time? Do changes in CD4 density correlate with disease progression? Here, we examined the role of CD4 density for HIV disease progression by longitudinally quantifying CD4 densities on CD4þ T cells and monocytes of ARTnaive HIV þ patients with different disease progression rates. This was a retrospective study. We defined three groups of HIV þ patients by their rate of CD4 þ T cell loss, calculated by the time between infection and reaching a CD4 level of 200 cells/ml: fast (<7.5 years), intermediate (7.5-12 years), and slow progressors (>12 years). Mathematical modeling permitted us to determine the maximum CD4 þ T cell count after HIV seroconversion (defined as ''postseroconversion CD4 count'') and longitudinal profiles of CD4 count and density. CD4 densities were quantified on CD4 þ T cells and monocytes from these patients and from healthy individuals by flow cytometry. Fast progressors had significantly lower postseroconversion CD4 counts than other progressors. CD4 density on T cells was lower in HIV þ patients than in healthy individuals and decreased more rapidly in fast than in slow progressors. Antiretroviral therapy (ART) did not normalize CD4 density. Thus, postseroconversion CD4 counts define individual HIV disease progression rates that may help to identify patients who might benefit most from early ART. Early discrimination of slow and fast progressors suggests that critical events during primary infection define long-term outcome. A more rapid CD4 density decrease in fast progressors might contribute to progressive functional impairments of the immune response in advanced HIV infection. The lack of an effect of ART on CD4 density implies a persistent dysfunctional immune response by uncontrolled HIV infection.

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Section: Discussioncontrasting

confidence: 95%

210 Low Post-Seroconversion CD4 Count and Rapid Decrease of CD4 Density Identify HIV+ Fast Progressors

Audigé

Taff

Rickenbach

et al. 2011

JAIDS Journal of Acquired Immune Deficiency Syndromes

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“…Although downregulation of CD8 coreceptor is often subsequent to TCR-mediated signaling (46), a significantly high proportion of CD8 dim T cells has been observed in African green monkeys (AGM) and was protective against SIV infection (47). Furthermore, in some contexts, CD8 dim T cells substituted for CD4 + T cells and provided B cell help, leading to antibody production (48,49).…”

Section: Consistent With Our Findings Are Reports That Cd8mentioning

confidence: 99%

High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells

Falanga¹,

Frascoli²,

Kaymaz³

et al. 2017

JCI Insight

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Cellular and humoral constituents of the immune system differ significantly between children and adults, yet very little is known about the impact of early-life pathogen exposure on this immunologic transition. We examined CD4+ and CD8+ T cell subsets defined by CCR7 and CD45RA expression in two longitudinal pediatric cohorts experiencing divergent levels of pathogen burden. Using multiparameter flow cytometry, along with serological, cytokine, and transcriptomic data, we show that cumulative pathogen burden promotes the development of atypical CD8dim T cells with an innate-like profile (Granzyme Bhi, IFNγlow, TNFαlow, PLFZhi, ID2hi, IKZF2hi) in contrast to age-matched children residing in a low pathogen-exposure area who display a more conventional CD8bright profile (IFNγ+, TNFα+, CCL4+). Furthermore, these unconventional T cells had stunted proliferation, distinct transcriptional programs, and impaired T cell receptor signaling and were enriched in hallmark TNFα, NF-κB, and IL-6 gene signaling pathways, reminiscent of NK cells and type-1 innate lymphoid cells. Our findings suggest that these unconventional CD8dim T cells arise in a very particular immunological context and may provide a deeper understanding of the heterogeneity in human immune responses

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“…Adult AGMs have low CD4 ϩ T cell counts (4,5) and a large population of CD8␣ dim T cells that express CD8␣␣ homodimers and are distinct from the classical CD8 T cells that express the ␣ and ␤ chain of CD8 (4,6,7). These CD8␣␣ T cells arise postthymically through CD4 downregulation by CD4 ϩ T cells (4).…”

mentioning

confidence: 99%

“…These CD8␣␣ T cells arise postthymically through CD4 downregulation by CD4 ϩ T cells (4). The resulting CD8␣␣ T cells retain many characteristics of CD4 ϩ T cells, including major histocompatibility complex (MHC) class II restriction and expression of FoxP3, CD40 ligand, IL-17, and/or IL-2 (4).…”

mentioning

confidence: 99%

Homeostatic Cytokines Induce CD4 Downregulation in African Green Monkeys Independently of Antigen Exposure To Generate Simian Immunodeficiency Virus-Resistant CD8αα T Cells

Perkins

Briant

Calantone

et al. 2014

J Virol

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African green monkeys (AGMs; genus Chlorocebus) are a natural host of simian immunodeficiency virus (SIV AGM ). As they do not develop simian AIDS, there is great interest in understanding how this species has evolved to avoid immunodeficiency. Adult African green monkeys naturally have low numbers of CD4 T cells and a large population of major histocompatibility complex class II-restricted CD8␣ dim T cells that are generated through CD4 downregulation in CD4 ؉ T cells. Mechanisms that drive this process of CD4 downregulation are unknown. Here, we show that juvenile AGMs accelerate CD4-to-CD8␣␣ conversion upon SIV infection and avoid progression to AIDS. The CD4 downregulation induced by SIV infection is not limited to SIV-specific T cells, and vaccination of an adult AGM who had a negligible number of CD4 T cells demonstrated that CD4 downregulation can occur without antigenic exposure. Finally, we show that the T cell homeostatic cytokines interleukin-2 (IL-2), IL-7, and IL-15 can induce CD4 downregulation in vitro. These data identify a mechanism that allows AGMs to generate a large, diverse population of T cells that perform CD4 T cell functions but are resistant to SIV infection. A better understanding of this mechanism may allow the development of treatments to induce protective CD4 downregulation in humans. IMPORTANCE Many African primate species are naturally infected with SIV. African green monkeys, one natural host species, avoid simian AIDS by creating a population of T cells that lack CD4, the human immunodeficiency virus/SIV receptor; therefore, they are resistant to infection. However, these T cells maintain properties of CD4؉ T cells even after receptor downregulation and preserve immune function. Here, we show that juvenile AGMs, who have not undergone extensive CD4 downregulation, accelerate this process upon SIV infection. Furthermore, we show that in vivo, CD4 downregulation does not occur exclusively in antigen-experienced T cells. Finally, we show that the cytokines IL-2, IL-7, and IL-15, which induce homeostatic T cell proliferation, lead to CD4 downregulation in vitro; therefore, they can provide signals that lead to antigen-independent CD4 downregulation. These results suggest that if a similar process of CD4 downregulation could be induced in humans, it could provide a cure for AIDS.

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CD4 downregulation by memory CD4+ T cells in vivo renders African green monkeys resistant to progressive SIVagm infection

Cited by 129 publications

References 54 publications

210 Low Post-Seroconversion CD4 Count and Rapid Decrease of CD4 Density Identify HIV+ Fast Progressors

210 Low Post-Seroconversion CD4 Count and Rapid Decrease of CD4 Density Identify HIV+ Fast Progressors

High pathogen burden in childhood promotes the development of unconventional innate-like CD8+ T cells

Homeostatic Cytokines Induce CD4 Downregulation in African Green Monkeys Independently of Antigen Exposure To Generate Simian Immunodeficiency Virus-Resistant CD8αα T Cells

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