Elite Controllers with Low to Absent Effector CD8
            <sup>+</sup>
            T Cell Responses Maintain Highly Functional, Broadly Directed Central Memory Responses

Section: A) C)mentioning

confidence: 99%

Comparative Analysis of the Capacity of Elite Suppressor CD4 ⁺ and CD8 ⁺ T Cells To Inhibit HIV-1 Replication in Monocyte-Derived Macrophages

Walker-Sperling

Buckheit

Blankson

2014

“…An ex vivo viral inhibition assay was carried out to determine the ability of CD8 ϩ T cells to suppress virus replication by measuring the amount of HIV p24 antigen as previously described (36,37). Log inhibition values were calculated by subtracting log 10 p24 values of the infected CD4 ϩ T cells cocultured with CD8 ϩ T cells from log 10 p24 values of the infected CD4 ϩ T cells without CD8 ϩ T cells at day 7.…”

Section: Methodsmentioning

confidence: 99%

“…Intracellular cytokine staining was performed as described previously (35,36). The cells were then acquired on a flow cytometer (LSR II; BD Biosciences).…”

Section: Methodsmentioning

confidence: 99%

CD8 ⁺ T Cell Breadth and Ex Vivo Virus Inhibition Capacity Distinguish between Viremic Controllers with and without Protective HLA Class I Alleles

Koofhethile

Ndhlovu

Thobakgale-Tshabalala

et al. 2016

Self Cite

The mechanisms of viral control and loss of viral control in chronically infected individuals with or without protective HLA class I alleles are not fully understood. We therefore characterized longitudinally the immunological and virological features that may explain divergence in disease outcome in 70 HIV-1 C-clade-infected antiretroviral therapy (ART)-naive South African adults, 35 of whom possessed protective HLA class I alleles. We demonstrate that, over 5 years of longitudinal study, 35% of individuals with protective HLA class I alleles lost viral control compared to none of the individuals without protective HLA class I alleles (P ‫؍‬ 0.06). Sustained HIV-1 control in patients with protective HLA class I alleles was characteristically related to the breadth of HIV-1 CD8 ؉ T cell responses against Gag and enhanced ability of CD8 ؉ T cells to suppress viral replication ex vivo. In some cases, loss of virological control was associated with reduction in the total breadth of CD8 ؉ T cell responses in the absence of differences in HIV-1-specific CD8 ؉ T cell polyfunctionality or proliferation. In contrast, viremic controllers without protective HLA class I alleles possessed reduced breadth of HIV-1-specific CD8 ؉ T cell responses characterized by reduced ability to suppress viral replication ex vivo. These data suggest that the control of HIV-1 in individuals with protective HLA class I alleles may be driven by broad CD8 ؉ T cell responses with potent viral inhibitory capacity while control among individuals without protective HLA class I alleles may be more durable and mediated by CD8 ؉ T cell-independent mechanisms. H IV remains a global problem, and sub-Saharan Africa continues to bear the brunt of the epidemic, accounting for 67% of the infected people worldwide (1). Understanding the mechanisms of natural viral control in HIV infection is crucial for the identification of correlates of immune protection and for the design of an effective HIV vaccine. Previous studies have linked HIV control to a number of immunological factors, particularly HIVspecific CD8 ϩ cytotoxic T lymphocytes (CTLs), which have been demonstrated to play an important role (2-5). However, virusspecific CD8 ϩ T cell immune responses are not equally effective in HIV control, as the majority of infected individuals progress to disease despite the presence of these cells. HIV is able to evade immune responses by developing mutations that mediate escape from CTL recognition (6-12). In addition, the expression of certain HLA class I molecules by HIV-infected patients, such as HLA-B*27, HLA-B*57, HLA-B*58:01, HLA-B*81:01, and HLA-A*74: 01, is associated with better clinical disease outcomes in some population settings (3,(13)(14)(15)(16)(17)(18). HLA class I proteins present viral peptides on the surface of antigen-presenting cells to CTLs, and a major mechanism by which these protective alleles slow HIV disease progression is believed to be through CTL activity (18).

“…In WR, it is possible that highly reactive HIV-specific memory CD8 ϩ T cells expand and acquire effector functions in response to relapses in viral replication, thereby controlling the virus when necessary. In fact, a recent report showed that CD8 ϩ T cells from WR HIC can gain the capacity to suppress HIV replication after a short period of in vitro stimulation with HIV peptides (18). However, cells from antiretroviraltreated patients have also been shown to acquire similar properties following peptide stimulation (19) but cannot prevent viral rebound following treatment interruption.…”

mentioning

confidence: 99%

Long-Term Control of Simian Immunodeficiency Virus (SIV) in Cynomolgus Macaques Not Associated with Efficient SIV-Specific CD8⁺T-Cell Responses

Bruel

Hamimi

Dereuddre‐Bosquet

et al. 2015

The spontaneous control of human and simian immunodeficiency viruses (HIV/SIV) is typically associated with specific major histocompatibility complex (MHC) class I alleles and efficient CD8؉ T-cell responses, but many controllers maintain viral control despite a nonprotective MHC background and weak CD8 ؉ T-cell responses. Therefore, the contribution of this response to maintaining long-term viral control remains unclear. cells are not unique contributors to the long-term maintenance of low viremia in this SIV controller model and that other mechanisms, such as weak viral reservoirs or control of activation, may be important players in control. IMPORTANCE Spontaneous control of HIV-1 to undetectable levels is associated with efficient anti-HIV CD8؉ T-cell responses. However, in some cases, this response fades over time, although viral control is maintained, and many HIV controllers (weak responders) have very low frequencies of HIV-specific CD8 ؉ T cells. In these cases, the importance of CD8 T cells in the maintenance of HIV-1 control is questionable. We developed a nonhuman primate model of durable SIV control with an immune profile resembling that of weak responders. Transient depletion of CD8 ؉ cells induced a rise in the viral load. However, viremia was correlated with CD4 ؉ T-cell activation subsequent to CD8 ؉ cell depletion. Regain of viral control to predepletion levels was not associated with restoration of the anti-SIV capacities of CD8 ؉ T cells. Our results suggest that CD8 ؉ T cells may not be involved in maintenance of viral control in weak responders and highlight the fact that additional mechanisms should not be underestimated.