Magnitude and Kinetics of CD8+ T Cell Activation during Hyperacute HIV Infection Impact Viral Set Point

Ndhlovu, Zaza M.; Kamya, Philomena; Mewalal, Nikoshia; Kløverpris, Henrik N.; Nkosi, Thandeka; Pretorius, Karyn; Laher, Faatima.; Ogunshola, Funsho; Chopera, Denis; Shekhar, Karthik; Ghebremichael, Musie; Ismail, Nasreen; Moodley, Amber; Malik, Amna; Leslie, Alasdair; Goulder, Philip; Buus, Søren; Chakraborty, Arup K.; Dong, Krista; Ndung’u, Thumbi; Walker, Bruce D.

doi:10.1016/j.immuni.2015.08.012

Cited by 241 publications

(287 citation statements)

References 52 publications

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“…Studies also showed a direct relationship between higher frequency and function of HIV-specific CD8 T cells and enhanced viral control (4)(5)(6). In particular, early induction of HIV-specific CD8 T cells resulted in a concomitant decline in plasma viremia (7,8), suggesting that antiviral CD8 T-cell responses elicited early after HIV/SIV infection can significantly modulate viral control outcome. Consistent with this, contemporary vaccine strategies designed to elicit high frequencies of antiviral CD8 T cells have contained pathogenic SHIV (9, 10) and SIV challenges (11,12) in macaques.…”

mentioning

confidence: 99%

Dynamics of SIV-specific CXCR5+ CD8 T cells during chronic SIV infection

Mylvaganam

Ríos

Abdelaal

et al. 2017

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

113

137

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A significant challenge to HIV eradication is the elimination of viral reservoirs in germinal center (GC) T follicular helper (Tfh) cells. However, GCs are considered to be immune privileged for antiviral CD8 T cells. Here, we show a population of simian immunodeficiency virus (SIV)-specific CD8 T cells express CXCR5 (C-X-C chemokine receptor type 5, a chemokine receptor required for homing to GCs) and expand in lymph nodes (LNs) following pathogenic SIV infection in a cohort of vaccinated macaques. This expansion was greater in animals that exhibited superior control of SIV. The CXCR5+ SIV-specific CD8 T cells demonstrated enhanced polyfunctionality, restricted expansion of antigen-pulsed Tfh cells in vitro,and possessed a unique gene expression pattern related to Tfh and Th2 cells. The increase in CXCR5+ CD8 T cells was associated with the presence of higher frequencies of SIV-specific CD8 T cells in the GC. Following TCR-driven stimulation in vitro, CXCR5+ but not CXCR5– CD8 T cells generated both CXCR5+ as well as CXCR5– cells. However, the addition of TGF-β to CXCR5– CD8 T cells induced a population of CXCR5+ CD8 T cells, suggesting that this cytokine may be important in modulating these CXCR5+ CD8 T cells in vivo. Thus, CXCR5+ CD8 T cells represent a unique subset of antiviral CD8 T cells that expand in LNs during chronic SIV infection and may play a significant role in the control of pathogenic SIV infection.

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mentioning

confidence: 99%

Dynamics of SIV-specific CXCR5+ CD8 T cells during chronic SIV infection

Mylvaganam

Ríos

Abdelaal

et al. 2017

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

113

137

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“…Plasma viral load kinetics in acute and early chronic phases of infection (Fig. 5) were nearly indistinguishable from human infection by HIV-1 (72,73). All CD4 T-cell subsets, not just CD4 naïve cells, underwent gradual decline; GALT was selectively depleted of CD4 T cells early in infection and did not recover; and R5 tropism of SHIVs did not change to X4 tropism, even in animals that died of accelerated AIDS within the first 3 mo of infection (Fig.…”

Section: Discussionmentioning

confidence: 86%

“…In each case, we were successful in constructing SHIVs that replicated well in RMs with plasma viral load kinetics (Fig. 5) remarkably similar to acute and early chronic HIV-1 infection in humans (72,73). In other recent studies, we created a seventh SHIV, this one from a T/F HIV-1 subtype C virus Ce1176 (74), that is part of a widely used 12-member global neutralization panel developed by Montefiori, Seaman, and coworkers (71).…”

Section: Discussionmentioning

confidence: 91%

Envelope residue 375 substitutions in simian–human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques

Wang

Kong

et al. 2016

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

186

343

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Most simian–human immunodeficiency viruses (SHIVs) bearing envelope (Env) glycoproteins from primary HIV-1 strains fail to infect rhesus macaques (RMs). We hypothesized that inefficient Env binding to rhesus CD4 (rhCD4) limits virus entry and replication and could be enhanced by substituting naturally occurring simian immunodeficiency virus Env residues at position 375, which resides at a critical location in the CD4-binding pocket and is under strong positive evolutionary pressure across the broad spectrum of primate lentiviruses. SHIVs containing primary or transmitted/founder HIV-1 subtype A, B, C, or D Envs with genotypic variants at residue 375 were constructed and analyzed in vitro and in vivo. Bulky hydrophobic or basic amino acids substituted for serine-375 enhanced Env affinity for rhCD4, virus entry into cells bearing rhCD4, and virus replication in primary rhCD4 T cells without appreciably affecting antigenicity or antibody-mediated neutralization sensitivity. Twenty-four RMs inoculated with subtype A, B, C, or D SHIVs all became productively infected with different Env375 variants—S, M, Y, H, W, or F—that were differentially selected in different Env backbones. Notably, SHIVs replicated persistently at titers comparable to HIV-1 in humans and elicited autologous neutralizing antibody responses typical of HIV-1. Seven animals succumbed to AIDS. These findings identify Env–rhCD4 binding as a critical determinant for productive SHIV infection in RMs and validate a novel and generalizable strategy for constructing SHIVs with Env glycoproteins of interest, including those that in humans elicit broadly neutralizing antibodies or bind particular Ig germ-line B-cell receptors.

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“…These two studies suggest that timely ART initiation may pave the way for a better viral control after ART cessation but the mechanism of viral control in post-treatment controller still needs to be identified (67). Early in infection, HIV-specific CD8 T cells can contribute to control viremia (68–71) but become rapidly dysfunctional after peak viremia due to sustained hyperactivation and change in their metabolism (72). Therefore, initiating ART in the earliest stage of acute infection before peak viremia is reached might be necessary to achieve HIV remission due to initiating ART early in infection.…”

Section: Strategies To Boost Hiv-specific Cd8 T Cell Responses In Artmentioning

confidence: 99%

Kill

Trautmann

2016

Current Opinion in HIV and AIDS

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Purpose of review Increasing evidences suggest that purging the latent HIV reservoir in virally-suppressed individuals will require both the induction of viral replication from its latent state and the elimination of these reactivated HIV infected cells (“Shock and Kill” strategy). Boosting potent HIV-specific CD8 T cells is a promising way to achieve an HIV cure. Recent findings Recent studies provided the rationale for developing immune interventions to increase the numbers, function and location of HIV-specific CD8 T cells to purge HIV reservoirs. Multiple approaches are being evaluated including very early suppression of HIV replication in acute infection, adoptive cell transfer, therapeutic vaccination or use of immunomodulatory molecules. New assays to measure the killing and antiviral function of induced HIV-specific CD8 T cells have been developed to assess the efficacy of these new approaches. The strategies combining HIV reactivation and immunobased therapies to boost HIV-specific CD8 T cells can be tested in in vivo and in silico models to accelerate the design of new clinical trials. Summary New immunobased strategies are explored to boost HIV-specific CD8 T cells able to purge the HIV-infected cells with the ultimate goal of achieving spontaneous control of viral replication without antiretroviral treatment.

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Magnitude and Kinetics of CD8+ T Cell Activation during Hyperacute HIV Infection Impact Viral Set Point

Cited by 241 publications

References 52 publications

Dynamics of SIV-specific CXCR5+ CD8 T cells during chronic SIV infection

Dynamics of SIV-specific CXCR5+ CD8 T cells during chronic SIV infection

Envelope residue 375 substitutions in simian–human immunodeficiency viruses enhance CD4 binding and replication in rhesus macaques

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