High-dimensional immunomonitoring models of HIV-1–specific CD8 T-cell responses accurately identify subjects achieving spontaneous viral control

Ndhlovu, Zaza M.; Chibnik, Lori B.; Proudfoot, Jacqueline; Vine, Seanna; McMullen, Ashley; Cesa, Kevin; Porichis, Filippos; Jones, R. Brad; Alvino, Donna Marie L.; Hart, Meghan G.; Stampouloglou, Eleni; Piechocka-Trocha, Alicja; Kadie, Carl; Pereyra, Florencia; Heckerman, David; Jager, Philip L. De; Walker, Bruce D.; Kaufmann, Daniel E.

doi:10.1182/blood-2012-06-436295

Cited by 62 publications

(58 citation statements)

References 54 publications

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“…However, these suggestions are inconsistent with the fact that beneficial effects of Gag-specific responses are not universal among elite controllers, and indeed, most progressors also mount detectable responses against Gag (71,72). This discrepancy can partly be explained by our recent data showing that only a subset of Gag responses, particularly those restricted by protective alleles, exhibits superior antiviral function (10).…”

Section: Discussioncontrasting

confidence: 49%

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

Ndhlovu

Stampouloglou

Cesa

et al. 2015

J Virol

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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...

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Section: Discussioncontrasting

confidence: 49%

“…1F and I) for all groups. Together, these data demonstrate that the majority of the HIV-specific expandable memory pool (10,(44)(45)(46)(47). We therefore compared the virus inhibition capacities of memory CD8 ϩ T cells directed against the three HIV proteins.…”

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

J Virol

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“…Part of the evidence came from cohort studies where some alleles were overrepresented in EC and long-term nonprogressors (7,8), while other studies provided insights into functional performance of the "protective alleles" regarding specificity, proliferation, polyfunctionality, antigen presentation, immune pressure, among other factors (8,(54)(55)(56)(57)(58)(59)(60)(61). However, it has also been demonstrated that these protective alleles perform qualitatively different in controllers compared to progressors (60), indicating that a combination of T-cell function and phenotypes should coexist in order to achieve virus control. Conversely, some individuals reach EC status in the absence of protective alleles (as it can be observed in our cohort), indicating that they are not a requirement for virus control.…”

Section: Cells Out Of the Total Cd107mentioning

confidence: 99%

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

J Virol

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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....

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“…The LASSO method has been used to identify key variables from large, complex data sets contributing to particular outcomes such as protective HIV vaccine Ab profiles (44) and spontaneous control of HIV disease (45). Here, we used LASSO to resolve predictors of serological responses to TIV in HIV + and HC individuals.…”

Section: Figure 4 Coexpression Of Immune Activation Markers On Cd4 +mentioning

confidence: 99%

Reevaluation of immune activation in the era of cART and an aging HIV-infected population

Armas¹,

Pallikkuth²,

George³

et al. 2017

JCI Insight

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High-dimensional immunomonitoring models of HIV-1–specific CD8 T-cell responses accurately identify subjects achieving spontaneous viral control

Abstract: • Immune monitoring models integrating multiple functions of HIV-1-specific CD8 T cells distinguish controllers from subjects with progressive HIV-1 infection.• This strategy may have important applications in predictive model development and immune monitoring of HIV-1 vaccine trials.

Cited by 62 publications

References 54 publications

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

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

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

Reevaluation of immune activation in the era of cART and an aging HIV-infected population

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High-dimensional immunomonitoring models of HIV-1–specific CD8 T-cell responses accurately identify subjects achieving spontaneous viral control

Abstract: • Immune monitoring models integrating multiple functions of HIV-1-specific CD8 T cells distinguish controllers from subjects with progressive HIV-1 infection.• This strategy may have important applications in predictive model development and immune monitoring of HIV-1 vaccine trials.

Cited by 62 publications

References 54 publications

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

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

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

Reevaluation of immune activation in the era of cART and an aging HIV-infected population

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Product

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

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

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