Limited Immunogenicity of HIV CD8+ T-Cell Epitopes in Acute Clade C Virus Infection

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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).

Section: Resultssupporting

confidence: 92%

Section: Discussionsupporting

confidence: 90%

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

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“…3). In line with this result, other authors described a direct correlation between the magnitude of the anti-Nef CD8 ϩ T-cell response and viral load in a cohort of HIV subtype C acutely infected subjects (49). Overall, these results argue in favor of that an earlier and higher contribution of Gag-specific cells to the hierarchy of the total anti-HIV response at very early time points postinfection contributes to a slower disease progression.…”

Section: Discussionsupporting

confidence: 71%

“…8). As mentioned before, these molecules are produced by CD8 ϩ T cells upon stimulation, and the percentage of cells expressing IL-2 and MIP-1␤ either alone or in combination with other functions were previously associated with virus control (4,11,14,43,49). IL-2 is an important molecule for T-cell homeostasis and immune system activation (63).…”

Section: Cells Out Of the Total Cd107mentioning

confidence: 91%

Early Gag Immunodominance of the HIV-Specific T-Cell Response during Acute/Early Infection Is Associated with Higher CD8 ⁺ T-Cell Antiviral Activity and Correlates with Preservation of the CD4 ⁺ T-Cell Compartment

Turk

Ghiglione

Falivene

et al. 2013

The important role of the CD8؉ T-cell response on HIV control is well established. Moreover, the acute phase of infection represents a proper scenario to delineate the antiviral cellular functions that best correlate with control. Here, multiple functional aspects (specificity, ex vivo viral inhibitory activity [VIA] and polyfunctionality) of the HIV-specific CD8 ؉ T-cell subset arising early after infection, and their association with disease progression markers, were examined. Blood samples from 44 subjects recruited within 6 months from infection (primary HIV infection [PHI] group), 16 chronically infected subjects, 11 elite controllers (EC), and 10 healthy donors were obtained. Results indicated that, although Nef dominated the anti-HIV response during acute/early infection, a higher proportion of early anti-Gag T cells correlated with delayed progression. Polyfunctional HIV-specific CD8 ؉ T cells were detected at early time points but did not associate with virus control. Conversely, higher CD4 ؉ T-cell set points were observed in PHI subjects with higher HIV-specific CD8 ؉ T-cell VIA at baseline. Importantly, VIA levels correlated with the magnitude of the anti-Gag cellular response. The advantage of Gag-specific cells may result from their enhanced ability to mediate lysis of infected cells (evidenced by a higher capacity to degranulate and to mediate VIA) and to simultaneously produce IFN-␥. Finally, Gag immunodominance was associated with elevated plasma levels of interleukin 2 (IL-2) and macrophage inflammatory protein 1␤ (MIP-1␤). All together, this study underscores the importance of CD8 ؉ T-cell specificity in the improved control of disease progression, which was related to the capacity of Gag-specific cells to mediate both lytic and nonlytic antiviral mechanisms at early time points postinfection. Human immunodeficiency virus (HIV) still represents a major public health concern. Although the instauration of highly active antiretroviral treatment (HAART) had a tremendous impact on the epidemic dynamics, the development of an effective prophylactic vaccine is still a main objective in the HIV-related research field. As HIV is highly diverse among different isolates, evolves continuously under selective pressure, infects immune cells, and encodes proteins with the capacity to modulate immune cell functions, it imposes definite challenges that should be overcome in the race of getting a successful vaccine. However, the description of (i) infected subjects able to control HIV replication over long periods of time to very low levels without therapy (known as long-term nonprogressors [LTNP] and elite controllers [EC]); (ii) uninfected subjects who, despite being highly exposed to the virus, remain seronegative (exposed seronegatives [ESN]); and (iii) the results from the Thai vaccine trial RV-144, which showed 30% efficacy (1), suggests that the objective is reachable. In this line, much of the research work conducted over the past few years was aimed to define the immune correlates of protection, i.e....

“…Our analysis focused on memory responses to three HIV proteins: Gag, Nef, and Env. We chose these three HIV proteins for the following reasons: (i) T cell responses directed to the HIV Gag protein have consistently been associated with lower-level viremia (17,(32)(33)(34)(35); (ii) Nef responses are immunodominant early during acute HIV infection and may be involved in the initial control of viremia, and therefore, their persistence may be relevant to long-term viral control (36)(37)(38)(39); and (iii) responses targeting the Env region have been shown to be important for both T cell and B cell immune responses (40)(41)(42), and the breadth of Env-specific responses has been positively associated with viral load (17,43). Thus, elucidating the role of long-lived responses to these HIV proteins may be relevant for vaccines.…”

Section: Resultsmentioning

confidence: 99%

The Breadth of Expandable Memory CD8 ⁺ T Cells Inversely Correlates with Residual Viral Loads in HIV Elite Controllers

Ndhlovu

Stampouloglou

Cesa

et al. 2015

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Previous studies have shown that elite controllers with minimal effector T cell responses harbor a low-frequency, readily expandable, highly functional, and broadly directed memory population. Here, we interrogated the in vivo relevance of this cell population by investigating whether the breadth of expandable memory responses is associated with the magnitude of residual viremia in individuals achieving durable suppression of HIV infection. HIV-specific memory CD8؉ T cells were expanded by using autologous epitopic and variant peptides. Viral load was measured by an ultrasensitive single-copy PCR assay. Following expansion, controllers showed a greater increase in the overall breadth of Gag responses than did untreated progressors (P ‫؍‬ 0.01) as well as treated progressors (P ‫؍‬ 0.0003). Nef-and Env-specific memory cells expanded poorly for all groups, and their expanded breadths were indistinguishable among groups (P ‫؍‬ 0.9 for Nef as determined by a Kruskal-Wallis test; P ‫؍‬ 0.6 for Env as determined by a Kruskal-Wallis test). More importantly, we show that the breadth of expandable, previously undetectable Gag-specific responses was inversely correlated with residual viral load (r ‫؍‬ ؊0.6; P ‫؍‬ 0.009). Together, these data reveal a direct link between the abundance of Gag-specific expandable memory responses and prolonged maintenance of low-level viremia. Our studies highlight a CD8 ؉ T cell feature that would be desirable in a vaccine-induced T cell response. IMPORTANCEMany studies have shown that the rare ability of some individuals to control HIV infection in the absence of antiretroviral therapy appears to be heavily dependent upon special HIV-specific killer T lymphocytes that are able to inhibit viral replication. The identification of key features of these immune cells has the potential to inform rational HIV vaccine design. This study shows that a special subset of killer lymphocytes, known as central memory CD8 ؉ T lymphocytes, is at least partially involved in the durable control of HIV replication. HIV controllers maintain a large proportion of Gag-specific expandable memory CD8 ؉ T cells involved in ongoing viral suppression. These data suggest that induction of this cell subset by future HIV vaccines may be important for narrowing possible routes of rapid escape from vaccine-induced CD8 ؉ T cell responses. M ost human immunodeficiency virus (HIV)-infected individuals have continuous viral replication and, if left untreated, eventually progress to AIDS (1-4). Only a very small group of infected individuals, referred to as elite controllers (EC)or elite suppressors, achieves spontaneous control of viral replication for prolonged periods in the absence of treatment (5-8). This remarkable control of viral replication among elite controllers is believed to be mediated largely by major histocompatibility complex (MHC) class I-restricted CD8 ϩ T cell responses (9-13). These individuals therefore present a unique model for understanding the in vivo mechanisms of T cell-mediated immune contr...