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Role of PD-1 co-inhibitory pathway in HIV infection and potential therapeutic options.

Velu V, Shetty RD, Larsson M, Shankar EM - Retrovirology (2015)

Bottom Line: However, during chronic HIV infection, virus-specific CD8+ T cells undergo functional exhaustion, lose effector functions and fail to control viral infection.HIV-specific CD8 T cells expressing high levels of co-inhibitory molecule programmed death-1 (PD-1) during the chronic infection and are characterized by lower proliferation, cytokine production, and cytotoxic abilities.In recent years, studies in mice and non-human primate models of HIV infection demonstrated the functional exhaustion of virus-specific T and B cells could be reversed by blockade of interaction between PD-1 and its cognate ligands (PD-L1 and PD-L2).

View Article: PubMed Central - PubMed

ABSTRACT
Virus-specific CD8+ T cells play an important role in controlling viral infections including human immunodeficiency virus (HIV) infection. However, during chronic HIV infection, virus-specific CD8+ T cells undergo functional exhaustion, lose effector functions and fail to control viral infection. HIV-specific CD8 T cells expressing high levels of co-inhibitory molecule programmed death-1 (PD-1) during the chronic infection and are characterized by lower proliferation, cytokine production, and cytotoxic abilities. Although, antiretroviral therapy has resulted in dramatic decline in HIV replication, there is no effective treatment currently available to eradicate viral reservoirs or restore virus-specific T or B-cell functions that may complement ART in order to eliminate the virus. In recent years, studies in mice and non-human primate models of HIV infection demonstrated the functional exhaustion of virus-specific T and B cells could be reversed by blockade of interaction between PD-1 and its cognate ligands (PD-L1 and PD-L2). In this review, we discuss recent advances in our understanding of PD-1 pathway in HIV/SIV infection and discuss the beneficial effects of PD-1 blockade during chronic HIV/SIV infection and its potential role as immunotherapy for HIV/AIDS.

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PD-1 blockade enhances both T and B cell responses during chronic HIV/SIV infection. PD-1 blockade mediated functional restoration of exhausted virus-specific CD8+ T cells gain their qualities to clear viral antigens and control chronic viral infection. Blockade of PD-1 in virus specific CD4+ T cells restore functions associated with CD8+ T cell help and B-cell activation. Impaired B cells restore functions and produce virus-specific antibody following in vivo PD-1 blockade.
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Fig2: PD-1 blockade enhances both T and B cell responses during chronic HIV/SIV infection. PD-1 blockade mediated functional restoration of exhausted virus-specific CD8+ T cells gain their qualities to clear viral antigens and control chronic viral infection. Blockade of PD-1 in virus specific CD4+ T cells restore functions associated with CD8+ T cell help and B-cell activation. Impaired B cells restore functions and produce virus-specific antibody following in vivo PD-1 blockade.

Mentions: Blockade of the PD-1 pathway with a PDL-1 blocking antibody increased HIV-specific CD4+ T-cell proliferation and similar effects were also seen in SIV infected macaques CD4+ T cells [53]. The CD4+ T-cell proliferative responses that follow blockade of the PD-1 pathway likely vary between individuals, with striking effects in some individuals that correlates well with consequent CTL responses [21,60]. Importantly, the blockade of PD-1 pathway with anti-PD-L1 antibody in in vitro cultures of CD4+ T cells activated with HIV antigens enhanced the secretion of several T helper cell lineage-specific cytokines (Figure 2), known to mediate numerous functions in vivo [58]. Potential role of PD-1 pathway in B-cell responses has been identified, as the PD-1 expression that is induced on newly activated CD4+ T cells is maintained and further increased in CD4+ T cells that interact with cognate B cells called T follicular helper cells (Tfh) [61-63]. Tfh cells express CXCR5 and migrate to the germinal center (GC) where they select high affinity B cells by providing help via IL-21 and CD40L, which help them to survive and differentiate into memory and plasma cells. Recent findings in HIV and SIV models suggest that PD-1+++ CD4+ T cells in the lymph node are similar to Tfh cells that interact with cognate B cells in the germinal centers of HIV infected humans and SIV-infected macaques [64-67]. These cells express very high levels of follicular markers (CXCR5, BCl-6, ICOS) including PD-1, which may interact with the ligands expressed on B cells in the germinal centers and required for effective B-cell responses [64,68-70]. HIV/SIV infection induces multiple changes in Tfh cell numbers and function, ultimately affecting the development of HIV/SIV-specific antibodies [71-74]. In addition, it has been reported that GC and memory B cells express PD-1 ligands PD-L1 and PD-L2 respectively Table 1 [73]. More importantly, PD-1 engagement suppresses follicular T-regs, which appear to express high levels of PD-1, and a subset of Foxp3+ cells that limit GC reactions [61]. Future studies are needed to delineate the regulation of Tfh cells, i.e. role of PD-1, which could inform vaccination strategies with the goal of eliciting broadly neutralizing antibody responses and to address the impact of PD-1 blockade on CD4+ T cells beyond antiviral treatment, which may further shape the quality of CD8+ and B-cell responses.Figure 2


Role of PD-1 co-inhibitory pathway in HIV infection and potential therapeutic options.

Velu V, Shetty RD, Larsson M, Shankar EM - Retrovirology (2015)

PD-1 blockade enhances both T and B cell responses during chronic HIV/SIV infection. PD-1 blockade mediated functional restoration of exhausted virus-specific CD8+ T cells gain their qualities to clear viral antigens and control chronic viral infection. Blockade of PD-1 in virus specific CD4+ T cells restore functions associated with CD8+ T cell help and B-cell activation. Impaired B cells restore functions and produce virus-specific antibody following in vivo PD-1 blockade.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4340294&req=5

Fig2: PD-1 blockade enhances both T and B cell responses during chronic HIV/SIV infection. PD-1 blockade mediated functional restoration of exhausted virus-specific CD8+ T cells gain their qualities to clear viral antigens and control chronic viral infection. Blockade of PD-1 in virus specific CD4+ T cells restore functions associated with CD8+ T cell help and B-cell activation. Impaired B cells restore functions and produce virus-specific antibody following in vivo PD-1 blockade.
Mentions: Blockade of the PD-1 pathway with a PDL-1 blocking antibody increased HIV-specific CD4+ T-cell proliferation and similar effects were also seen in SIV infected macaques CD4+ T cells [53]. The CD4+ T-cell proliferative responses that follow blockade of the PD-1 pathway likely vary between individuals, with striking effects in some individuals that correlates well with consequent CTL responses [21,60]. Importantly, the blockade of PD-1 pathway with anti-PD-L1 antibody in in vitro cultures of CD4+ T cells activated with HIV antigens enhanced the secretion of several T helper cell lineage-specific cytokines (Figure 2), known to mediate numerous functions in vivo [58]. Potential role of PD-1 pathway in B-cell responses has been identified, as the PD-1 expression that is induced on newly activated CD4+ T cells is maintained and further increased in CD4+ T cells that interact with cognate B cells called T follicular helper cells (Tfh) [61-63]. Tfh cells express CXCR5 and migrate to the germinal center (GC) where they select high affinity B cells by providing help via IL-21 and CD40L, which help them to survive and differentiate into memory and plasma cells. Recent findings in HIV and SIV models suggest that PD-1+++ CD4+ T cells in the lymph node are similar to Tfh cells that interact with cognate B cells in the germinal centers of HIV infected humans and SIV-infected macaques [64-67]. These cells express very high levels of follicular markers (CXCR5, BCl-6, ICOS) including PD-1, which may interact with the ligands expressed on B cells in the germinal centers and required for effective B-cell responses [64,68-70]. HIV/SIV infection induces multiple changes in Tfh cell numbers and function, ultimately affecting the development of HIV/SIV-specific antibodies [71-74]. In addition, it has been reported that GC and memory B cells express PD-1 ligands PD-L1 and PD-L2 respectively Table 1 [73]. More importantly, PD-1 engagement suppresses follicular T-regs, which appear to express high levels of PD-1, and a subset of Foxp3+ cells that limit GC reactions [61]. Future studies are needed to delineate the regulation of Tfh cells, i.e. role of PD-1, which could inform vaccination strategies with the goal of eliciting broadly neutralizing antibody responses and to address the impact of PD-1 blockade on CD4+ T cells beyond antiviral treatment, which may further shape the quality of CD8+ and B-cell responses.Figure 2

Bottom Line: However, during chronic HIV infection, virus-specific CD8+ T cells undergo functional exhaustion, lose effector functions and fail to control viral infection.HIV-specific CD8 T cells expressing high levels of co-inhibitory molecule programmed death-1 (PD-1) during the chronic infection and are characterized by lower proliferation, cytokine production, and cytotoxic abilities.In recent years, studies in mice and non-human primate models of HIV infection demonstrated the functional exhaustion of virus-specific T and B cells could be reversed by blockade of interaction between PD-1 and its cognate ligands (PD-L1 and PD-L2).

View Article: PubMed Central - PubMed

ABSTRACT
Virus-specific CD8+ T cells play an important role in controlling viral infections including human immunodeficiency virus (HIV) infection. However, during chronic HIV infection, virus-specific CD8+ T cells undergo functional exhaustion, lose effector functions and fail to control viral infection. HIV-specific CD8 T cells expressing high levels of co-inhibitory molecule programmed death-1 (PD-1) during the chronic infection and are characterized by lower proliferation, cytokine production, and cytotoxic abilities. Although, antiretroviral therapy has resulted in dramatic decline in HIV replication, there is no effective treatment currently available to eradicate viral reservoirs or restore virus-specific T or B-cell functions that may complement ART in order to eliminate the virus. In recent years, studies in mice and non-human primate models of HIV infection demonstrated the functional exhaustion of virus-specific T and B cells could be reversed by blockade of interaction between PD-1 and its cognate ligands (PD-L1 and PD-L2). In this review, we discuss recent advances in our understanding of PD-1 pathway in HIV/SIV infection and discuss the beneficial effects of PD-1 blockade during chronic HIV/SIV infection and its potential role as immunotherapy for HIV/AIDS.

Show MeSH
Related in: MedlinePlus