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The loss of HIV-specific CD8+ T cell cytolytic function is a primary factor underlying progressive HIV infection, but whether HIV-specific CD8+ T cells initially possess cytolytic effector capacity, and when and why this may be lost during infection, is unclear. Here, we assessed CD8+ T cell functional evolution from primary to chronic HIV infection. We observed a profound expansion of perforin+ CD8+ T cells immediately following HIV infection that quickly waned after acute viremia resolution. Selective expression of the effector-associated transcription factors T-bet and eomesodermin in cytokine-producing HIV-specific CD8+ T cells differentiated HIV-specific from bulk memory CD8+ T cell effector expansion. As infection progressed expression of perforin was maintained in HIV-specific CD8+ T cells with high levels of T-bet, but not necessarily in the population of T-betLo HIV-specific CD8+ T cells that expand as infection progresses. Together, these data demonstrate that while HIV-specific CD8+ T cells in acute HIV infection initially possess cytolytic potential, progressive transcriptional dysregulation leads to the reduced CD8+ T cell perforin expression characteristic of chronic HIV infection. [ABSTRACT FROM AUTHOR]

During chronic human immunodeficiency virus (HIV) infection, virus-specific CD8(+) T cells become functionally exhausted. Unlike most chronically infected individuals, elite controllers of HIV retain CD8(+) T-cell polyfunctionality and cytolytic capacity. It remains unclear whether elite controllers manifest T-cell exhaustion similar to subjects with chronic progression of HIV infection. Here we assessed coexpression of PD-1, Lag-3, CD160, and 2B4 as a measure of T-cell exhaustion in a cohort of elite controllers and in chronic progressors. We found that elite controllers have a high proportion of potentially exhausted (PD1(+)CD160(+)2B4(+)) HIV-specific CD8(+) T cells that is comparable to the proportion in chronic progressors. However, elite controllers also harbor a population of HIV-specific CD160(+)2B4(+) CD8(+) T cells that correlates with cytolytic capacity, as measured by perforin expression, a population not commonly present in chronic progressors. We therefore propose that coexpression of CD160 and 2B4 delineates a population of cytolytic CD8(+) T cells important for the control of HIV. [ABSTRACT FROM AUTHOR]

CD8+ T cell exhaustion represents a major hallmark of chronic HIV infection. Two key transcription factors governing CD8+ T cell differentiation, T-bet and Eomesodermin (Eomes), have previously been shown in mice to differentially regulate T cell exhaustion in part through direct modulation of PD-1. Here, we examined the relationship between these transcription factors and the expression of several inhibitory receptors (PD-1, CD160, and 2B4), functional characteristics and memory differentiation of CD8+ T cells in chronic and treated HIV infection. The expression of PD-1, CD160, and 2B4 on total CD8+ T cells was elevated in chronically infected individuals and highly associated with a T-betdimEomeshi expressional profile. Interestingly, both resting and activated HIV-specific CD8+ T cells in chronic infection were almost exclusively T-betdimEomeshi cells, while CMV-specific CD8+ T cells displayed a balanced expression pattern of T-bet and Eomes. The T-betdimEomeshi virus-specific CD8+ T cells did not show features of terminal differentiation, but rather a transitional memory phenotype with poor polyfunctional (effector) characteristics. The transitional and exhausted phenotype of HIV-specific CD8+ T cells was longitudinally related to persistent Eomes expression after antiretroviral therapy (ART) initiation. Strikingly, these characteristics remained stable up to 10 years after ART initiation. This study supports the concept that poor human viral-specific CD8+ T cell functionality is due to an inverse expression balance between T-bet and Eomes, which is not reversed despite long-term viral control through ART. These results aid to explain the inability of HIV-specific CD8+ T cells to control the viral replication post-ART cessation. [ABSTRACT FROM AUTHOR]

A detailed understanding of the immune response to human immunodeficiency virus ( HIV) infection is needed to inform prevention and therapeutic strategies that aim to contain the acquired immunodeficiency syndrome ( AIDS) pandemic. The cellular immune response plays a critical role in controlling viral replication during HIV infection and will likely need to be a part of any vaccine approach. The qualitative feature of the cellular response most closely associated with immunological control of HIV infection is CD8+ T-cell cytotoxic potential, which is responsible for mediating the elimination of infected CD4+ T cells. Understanding the underlying mechanisms involved in regulating the elicitation and maintenance of this kind of effector response can provide guidance for vaccine design. In this review, we discuss the evidence for CD8+ T cells as correlates of protection, the means by which their antiviral capacity is evaluated, and transcription factors responsible for their function, or dysfunction, during HIV infection. [ABSTRACT FROM AUTHOR]

Cytotoxic T lymphocytes (CTL) and highly active antiretroviral therapy (HAART) are known to exert strong evolutionary pressures on the virus population during human immunodeficiency virus (HIV) infection. However, it is not known whether CTL responses continue to substantially affect viral evolution during treatment. To study the effect of immunologic pressure on viral sequences during HAART, we identified 10 targeted HIV-specific CD8+-T-cell epitopes in five treatment-naive patients, sequenced each epitope in plasma-derived viruses, and then identified evidence of immunologic pressure at these epitopes by comparing the frequency of viral variants in plasma to the frequency of the CD8+-T-cell response for each variant identified. For one of the five patients, evidence of viral evolution was found during therapy. The sequence of the CTL-targeted epitope changed from an apparent escape variant prior to the initiation of therapy, to the sequence that is best recognized by the CTL response after the initiation of therapy, and then finally to a new escape variant during continued therapy. These data show that CTL-mediated pressure can continue to affect viral evolution after the initiation of HAART, even when treatment drives the viral load below detectable levels, and suggest that antiretroviral therapy may preferentially inhibit those virus variants that escape the CTL response. [ABSTRACT FROM AUTHOR]

Investigates the infection of human immunodeficiency virus (HIV)-specific CD4+ T cells by HIV. Stages of HIV disease; Effects of cell division and interferon-γ secretion on HIV infection of CD4+ T cells; Steps in T-cell stimulation and sorting.

Abstract: Numerous studies have characterized the cytokine modulation observed in human immunodeficiency virus (HIV) infected individuals, from initial infection through chronic disease. Progressive and non-progressive HIV infection models show the cytokine milieu differs in terms of production and responsiveness in these two groups, suggesting an understanding of the role cytokines play during infection is necessary for directing the immune response toward viral control. This review will cover cytokine induction and dysfunction during HIV pathogenesis, with a focus on the interplay between cytokines and transcription factors, T cell activation, and exhaustion. We highlight cytokines that have either vaccine adjuvant or therapeutic potential and discuss the need to identify key factors required for prevention of progression, clearance of infection, or protection from acquisition. [Copyright &y& Elsevier]

• While blood CD8+ T cells control HIV using cytolytic functions, lymphoid tissue CD8+ T cells do so via non-cytolytic functions • HIV-specific CD8+ T cells in lymphoid and mucosal tissues are largely tissue-resident memory cells • The frequency of follicular CD8+ T cells negatively correlates with HIV viral load • Expression of inhibitory receptors by CD8+ T cells in lymphoid tissues do not necessarily indicate exhaustion • Lessons from autoimmune diseases suggest that a cure strategy inducing cytotoxic CD8+ T cells might cause undesired pathology CD8+ T cells are crucial for immunity against viral infections, including HIV. Several characteristics of CD8+ T cells, such as polyfunctionality and cytotoxicity, have been correlated with effective control of HIV. However, most of these correlates have been established in the peripheral blood. Meanwhile, HIV primarily replicates in lymphoid tissues. Therefore, it is unclear which aspects of CD8+ T cell biology are shared and which are different between blood and lymphoid tissues in the context of HIV infection. In this review, we will recapitulate the latest advancements of our knowledge on lymphoid tissue CD8+ T cells during HIV infection and discuss the insights these advancements might provide for the development of a HIV cure. [ABSTRACT FROM AUTHOR]

Attrition within the CD4+ T cell compartment, high viremia, and a cytokine storm characterize the early days after HIV infection. When the first emerging HIV-specific CD8+ T cell responses gain control over viral replication it is incomplete, and clearance of HIV infection is not achieved even in the rare cases of individuals who spontaneously control viral replication to nearly immeasurably low levels. Thus, despite their partial ability to control viremia, HIV-specific CD8+ T cell responses are insufficient to clear HIV infection. Studying individuals in the first few days of acute HIV infection, we detected the emergence of a unique population of CD38+ CD27- CD8+ T cells characterized by the low expression of the CD8 receptor (CD8dim). Interestingly, while high frequencies of HIV-specific CD8+ T cell responses occur within the CD38+ CD27- CD8dim T cell population, the minority populations of CD8bright T cells are significantly more effective in inhibiting HIV replication. Furthermore, the frequency of CD8dim T cells directly correlates with viral load and clinical predictors of more rapid disease progression. We found that a canonical burst of proliferative cytokines coincides with the emergence of CD8dim T cells, and the size of this population inversely correlates with the acute loss of CD4+ T cells. These data indicate, for the first time, that early CD4+ T cell loss coincides with the expansion of a functionally impaired HIV-specific CD8dim T cell population less efficient in controlling HIV viremia. [ABSTRACT FROM AUTHOR]

A clear understanding of the antiviral effects of CD8+ T cells in the context of chronic human immunodeficiency virus (HIV) infection is critical for the development of prophylactic vaccines and therapeutics designed to support T-cell-mediated immunity. However, defining the potential correlates of effective CD8+ T-cell immunity has proven difficult; notably, comprehensive analyses have demonstrated that the size and shape of the CD8+ T-cell response are not necessarily indicative of efficacy determined by measures of plasma viral load. Here, we conducted a detailed quantitative and qualitative analysis of CD8+ T-cell responses to autologous virus in a cohort of six HIV-infected individuals with a history of structured interruption of antiretroviral therapy (ART) (SIT). The magnitude and breadth of the HIV-specific response did not, by themselves, explain the changes observed in plasma virus levels after the cessation of ART. Furthermore, mutational escape from targeted epitopes could not account for the differential virological outcomes in this cohort. However, the functionality of HIV-specific CD8+ T-cell populations upon antigen encounter, determined by the simultaneous and independent measurement of five CD8+ T-cell functions (degranulation and gamma interferon, macrophage inflammatory protein 1β, tumor necrosis factor alpha, and interleukin-2 levels) reflected the emergent level of plasma virus, with multiple functions being elicited in those individuals with lower levels of viremia after SIT. These data show that the quality of the HIV-specific CD8+ T-cell response, rather than the quantity, is associated with the dynamics of viral replication in the absence of ART and suggest that the effects of SIT can be assessed by measuring the functional profile of HIV-specific CD8+ T cells. [ABSTRACT FROM AUTHOR]