During chronic HIV infection, immune cells become increasingly dysfunctional and exhausted. Little is known about how immune functions are restored after initiation of antiretroviral therapy (ART). In this study, we assessed cellular and metabolic activity and evaluated the effect of individual antiretrovirals on cellular subsets ex vivo in ART-treated and treatment-naive chronically HIV-infected individuals. We observed that cellular respiration was significantly decreased in most immune cells in chronic HIV infection. The respiration was correlated to immune activation and the inhibitory receptor programmed cell death 1 on CD8 ⁺ T cells. ART restored the metabolic phenotype, but the respiratory impairment persisted in CD4 ⁺ T cells. This was particularly the case for individuals receiving integrase strand transfer inhibitors. CD4 ⁺ T cells from these individuals showed a significant reduction in ex vivo proliferative capacity compared with individuals treated with protease inhibitors or nonnucleoside reverse transcriptase inhibitors. We noticed a significant decrease in respiration of cells treated with dolutegravir (DLG) or elvitegravir (EVG) and a switch from polyfunctional to TNF-α–dominated “stress” immune response. There was no effect on glycolysis, consistent with impaired mitochondrial function. We detected increased levels of mitochondrial ROS and mitochondrial mass. These findings indicate that EVG and DLG use is associated with slow proliferation and impaired respiration with underlying mitochondrial dysfunction, resulting in overall decreased cellular function in CD4 ⁺ T cells.

The COVID-19 crisis has elicited a global response by the scientific community that has led to a burst of publications on the pathophysiology of the virus. However, without coordinated efforts to organize this knowledge, it can remain hidden away from individual research groups. By extracting and formalizing this knowledge in a structured and computable form, as in the form of a knowledge graph, researchers can readily reason and analyze this information on a much larger scale. Here, we present the COVID-19 Knowledge Graph, an expansive cause-and-effect network constructed from scientific literature on the new coronavirus that aims to provide a comprehensive view of its pathophysiology. To make this resource available to the research community and facilitate its exploration and analysis, we also implemented a web application and released the KG in multiple standard formats. The COVID-19 Knowledge Graph is publicly available under CC-0 license at https://github.com/covid19kg and https://bikmi.covid19-knowledgespace.de. Supplementary data are available at Bioinformatics online.

CD4 ⁺ T cells play a pivotal role in the control of chronic viral infections. Recently, nontraditional CD4 ⁺ T cell functions beyond helper effects have been described, and a role for cytolytic CD4 ⁺ T cells in the control of HIV infection has been suggested. We define here the transcriptional, phenotypic, and functional profiles of HIV-specific cytolytic CD4 ⁺ T cells. Fluidigm BioMark and multiparameter flow cytometric analysis of HIV-specific cytolytic CD4 ⁺ T cells revealed a distinct transcriptional signature compared to Th1 CD4 ⁺ cells but shared similar features with HIV-specific cytolytic CD8 ⁺ T cells. Furthermore, HIV-specific cytolytic CD4 ⁺ T cells showed comparable killing activity relative to HIV-specific CD8 ⁺ T cells and worked cooperatively in the elimination of virally infected cells. Interestingly, we found that cytolytic CD4 ⁺ T cells emerge early during acute HIV infection and tightly follow acute viral load trajectory. This emergence was associated to the early viral set point, suggesting an involvement in early control, in spite of CD4 T cell susceptibility to HIV infection. Our data suggest cytolytic CD4 ⁺ T cells as an independent subset distinct from Th1 cells that show combined activity with CD8 ⁺ T cells in the long-term control of HIV infection. IMPORTANCE The ability of the immune system to control chronic HIV infection is of critical interest to both vaccine design and therapeutic approaches. Much research has focused on the effect of the ability of CD8 ⁺ T cells to control the virus, while CD4 ⁺ T cells have been overlooked as effectors in HIV control due to the fact that they are preferentially infected. We show here that a subset of HIV-specific CD4 ⁺ T cells cooperate in the cytolytic control of HIV replication. Moreover, these cells represent a distinct subset of CD4 ⁺ T cells showing significant transcriptional and phenotypic differences compared to HIV-specific Th1 cells but with similarities to CD8 ⁺ T cells. These findings are important for our understanding of HIV immunopathology.

Effector CD4 T cell responses have been shown to be critically involved in the containment and clearance of viral pathogens. However, their involvement in the pathogenesis of HIV infection is less clear, given their additional role as preferred viral targets. We previously demonstrated that the presence of HIV-specific CD4 T cell responses is somewhat associated with HIV control and that specific CD4 T cell functions, such as direct cytolytic activity, can contribute to control of HIV viremia. However, little is known about how the induction of HIV-specific CD4 T cell responses during acute HIV infection influences disease progression and whether responses induced during the early phase of infection are preferentially depleted. We therefore longitudinally assessed, in a cohort of 55 acutely HIV-infected individuals, HIV-specific CD4 T cell responses from acute to chronic infection. Interestingly, we found that the breadth, magnitude, and protein dominance of HIV-specific CD4 T cell responses remained remarkably stable over time. Moreover, we found that the epitopes targeted at a high frequency in acute HIV infection were recognized at the same frequency by HIV-specific CD4 T cells in chronic HIV infection. Interestingly the induction of Gag-specific CD4 T cell responses in acute HIV infection was significantly inversely correlated with viral set point in chronic HIV infection ( R = −0.5; P = 0.03), while the cumulative contribution of Env-specific CD4 T cell responses showed the reverse effect. Moreover, individuals with HIV-specific CD4 T cell responses dominantly targeting Gag over Env in acute HIV infection remained off antiretroviral therapy significantly longer ( P = 0.03; log rank). Thus, our data suggest that the induction of HIV-specific CD4 T cell responses during acute HIV infection is beneficial overall and does not fuel disease progression. IMPORTANCE CD4 T cells are critical for the clearance and control of viral infections. However, HIV preferentially infects HIV-specific CD4 T cells. Thus, their contribution to the control of HIV viremia is uncertain. Here, we study HIV-specific CD4 T cell responses from acute to chronic HIV infection and show that the generation of certain CD4 responses is associated with control rather than disease progression.

The maturation process of high-affinity antibodies is a result of intricate interactions between B cells and follicular helper T (Tfh) cells occurring in lymphoid germinal centers. HIV infection induces significant chronic immune activation, phenotypic skewing, and inflammation driven by years of continuous viral replication. High levels of viremia as well as immune activation and dysfunction have been demonstrated to have a perturbing impact on the B cell memory compartment and contribute to B cell exhaustion. Counterintuitively, the factors associated with perturbation of the B cell compartment seem to be favorable for the generation of highly affinity-matured Env-specific antibodies in a minority of HIV-infected individuals. Thus, the impact of HIV antigenemia on B cells and Tfh cell interactions warrants further exploration. We therefore studied immunophenotypes of HIV-specific B cells in individuals with differing levels of viral control using HIV Env gp120 probes and characterized the functionality of matched T cells in peripheral blood. While CXCR5 ⁺ CD4 ⁺ T cells were significantly diminished in HIV progressors, we found that a small subset of gp120-specific interleukin-21 (IL-21)-secreting CXCR5 ⁺ CD4 ⁺ T cells were significantly associated with gp120-specific B cell frequencies. In contrast, neither bulk CXCR5 ⁺ CD4 ⁺ T cells nor other HIV antigen specificities were associated with gp120-specific B cell levels. HIV-specific B cells derived from elite controllers displayed greater amounts of gp120-specific B cells in the resting memory subset, whereas HIV-specific B cells in progressors accumulated in tissue-like and activated memory subsets. Furthermore, CXCR5 ⁺ CD4 ⁺ T cells from elite controllers showed a stronger ex vivo capacity to induce B cell maturation and immunoglobulin class switching than cells from HIV progressors. IMPORTANCE Dissecting the factors that are involved in B cell maturation and antibody development is important for HIV vaccine design. In this study, we found that HIV Env-specific CXCR5 ⁺ CD4 ⁺ T cells that secrete interleukin-21 are strongly associated with B cell memory phenotypes and function. Moreover, we found that the immune responses of HIV controllers showed intrinsically better helper activity than those of HIV progressors.