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Selection of T-cell vaccine antigens for chronic persistent viral infections has been largely empirical. To define the relationship, at the population level, between the specificity of the cellular immune response and viral control for a relevant human pathogen, we performed a comprehensive analysis of the 160 dominant CD8[sup.+] T-cell responses in 578 untreated HIV-infected individuals from KwaZulu-Natal, South Africa. Of the HIV proteins targeted, only Gag-specific responses were associated with lowering viremia. Env-specific and Accessory/Regulatory protein-specific responses were associated with higher viremia. Increasing breadth of Gag-specific responses was associated with decreasing viremia and increasing Env breadth with increasing viremia. Association of the specific CD8[sup.+] T-cell response with low viremia was independent of HLA type and unrelated to epitope sequence conservation. These population-based data, suggesting the existence of both effective immune responses and responses lacking demonstrable biological impact in chronic HIV infection, are of relevance to HIV vaccine design and evaluation., Author(s): Photini Kiepiela [1]; Kholiswa Ngumbela [1]; Christina Thobakgale [1]; Dhanwanthie Ramduth [1]; Isobella Honeyborne [2]; Eshia Moodley [1]; Shabashini Reddy [1]; Chantal de Pierres [1]; Zenele Mncube [1]; Nompumelelo [...]

HIV-1 viremia has been shown to induce several phenotypic and functional abnormalities in natural killer (NK) cells. To assess immune defects associated with HIV viremia, we examined NK cell function, differentiation status, and phenotypic alterations based on expression of inhibitory and activating receptors on NK cells in HIV-1 subtype C chronically infected participants from Durban, South Africa. NK cell phenotypic profiles were characterized by assessing sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7), NKG2A, and NKG2C markers on frozen peripheral blood mononuclear cells from viremic, antiretroviral therapy (ART)-naive HIV-1 chronically infected participants ( n = 23), HIV-1 chronically infected participants who had been on combination antiretroviral therapy (cART) for at least 12 months ( n = 23) compared with healthy donors ( n = 23). NK cell differentiation was assessed by measurement of killer immunoglobulin receptor (KIR) and NKG2A expression; CD57 and CD107a measurements were carried out in HIV viremic and healthy donors. All phenotypic and functional assessments were analyzed by using multicolor flow cytometry. HIV-1-infected participants displayed greater frequencies of the CD56−CD16+ (CD56negative) NK cell subset compared with healthy donors ( p < .0001). Downregulation of Siglec-7 and NKG2A and upregulation of NKG2C were more pronounced in the CD56negative NK cell subset of viremic participants. The CD56negative subset demonstrated a differentiated (KIR+NKG2A−) phenotype with reduced CD57 expression and lower degranulation capacity in HIV-1-infected participants compared with healthy donors. HIV-1 infection induces the expansion of the CD56negative NK cell subset marked by altered receptor expression profiles that are indicative of impaired function and may explain the overall NK cell dysfunction observed in chronic HIV-1 infection. [ABSTRACT FROM AUTHOR]

Selection of T-cell vaccine antigens for chronic persistent viral infections has been largely empirical. To define the relationship, at the population level, between the specificity of the cellular immune response and viral control for a relevant human pathogen, we performed a comprehensive analysis of the 160 dominant CD8+ T-cell responses in 578 untreated HIV-infected individuals from KwaZulu-Natal, South Africa. Of the HIV proteins targeted, only Gag-specific responses were associated with lowering viremia. Env-specific and Accessory/Regulatory protein–specific responses were associated with higher viremia. Increasing breadth of Gag-specific responses was associated with decreasing viremia and increasing Env breadth with increasing viremia. Association of the specific CD8+ T-cell response with low viremia was independent of HLA type and unrelated to epitope sequence conservation. These population-based data, suggesting the existence of both effective immune responses and responses lacking demonstrable biological impact in chronic HIV infection, are of relevance to HIV vaccine design and evaluation. [ABSTRACT FROM AUTHOR]

Background. Human immunodeficiency virus type 1 (HIV-1)–specific CD8+ responses contribute to the decline in acute peak viremia following infection. However, data on the relative immunogenicity of CD8+ T-cell epitopes during and after acute viremia are lacking.Methods. We characterized CD8+ T-cell responses in 20 acutely infected, antiretroviral-naive individuals with HIV-1 subtype C infection using the interferon-γ enzyme-linked immunosorbent spot assay. Eleven of these had not fully seroconverted at the time of analysis. Viruses from plasma were sequenced within defined cytotoxic T-lymphocyte (CTL) cell epitopes for selected subjects.Results. At approximately 28 days after estimated initial infection, CD8+ T-cell responses were directed against an average of 3 of the 410 peptides tested (range, 0–6); 2 individuals had no detectable responses at this time. At 18 weeks, the average number of peptides targeted had increased to 5 (range 0–11). Of the 56 optimal Gag CTL epitopes sequenced, 31 were wild-type in the infecting viruses, but only 11 of 31 elicited measurable CD8+ T-cell responses.Conclusions. These data demonstrate that the majority of CD8+ responses are not elicited during acute HIV infection despite the presence of the cognate epitope in the infecting strain. There is a need to define factors that influence lack of induction of effective immune responses and the parameters that dictate immunodominance in acute infection. [ABSTRACT FROM PUBLISHER]

An abstract of the article "Phenotypic and Functional Characteristics of Siglec-7, NKG2A and NKG2C Expressing NK Cells in Chronic HIV-1 Clade C Infection" by Michael Z. Zulu and colleagues is presented.

An abstract of the article "Limited Immunogenicity of HIV CD8+ T-Cell Epitopes in Acute Clade C Virus Infection," by Mopo Radebe and colleagues is presented.

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. [ABSTRACT FROM AUTHOR]

HIV-1 viremia has been shown to induce several phenotypic and functional abnormalities in natural killer (NK) cells. To assess immune defects associated with HIV viremia, we examined NK cell function, differentiation status, and phenotypic alterations based on expression of inhibitory and activating receptors on NK cells in HIV-1 subtype C chronically infected participants from Durban, South Africa. NK cell phenotypic profiles were characterized by assessing sialic acid-binding immunoglobulin-like lectin-7 (Siglec-7), NKG2A, and NKG2C markers on frozen peripheral blood mononuclear cells from viremic, antiretroviral therapy (ART)-naive HIV-1 chronically infected participants (n = 23), HIV-1 chronically infected participants who had been on combination antiretroviral therapy (cART) for at least 12 months (n = 23) compared with healthy donors (n = 23). NK cell differentiation was assessed by measurement of killer immunoglobulin receptor (KIR) and NKG2A expression; CD57 and CD107a measurements were carried out in HIV viremic and healthy donors. All phenotypic and functional assessments were analyzed by using multicolor flow cytometry. HIV-1-infected participants displayed greater frequencies of the CD56 - CD16 + (CD56negative) NK cell subset compared with healthy donors (p < .0001). Downregulation of Siglec-7 and NKG2A and upregulation of NKG2C were more pronounced in the CD56negative NK cell subset of viremic participants. The CD56negative subset demonstrated a differentiated (KIR + NKG2A - ) phenotype with reduced CD57 expression and lower degranulation capacity in HIV-1-infected participants compared with healthy donors. HIV-1 infection induces the expansion of the CD56negative NK cell subset marked by altered receptor expression profiles that are indicative of impaired function and may explain the overall NK cell dysfunction observed in chronic HIV-1 infection.

Unlabelled: 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., Importance: Host mechanisms of natural HIV-1 control are not fully understood. In a longitudinal study of antiretroviral therapy (ART)-naive individuals, we show that those with protective HLA class I alleles subsequently experienced virologic failure compared to those without protective alleles. Among individuals with protective HLA class I alleles, viremic control was associated with broad CD8(+) T cells that targeted the Gag protein, and CD8(+) T cells from these individuals exhibited superior virus inhibition capacity. In individuals without protective HLA class I alleles, HIV-1-specific CD8(+) T cell responses were narrow and poorly inhibited virus replication. These results suggest that broad, highly functional cytotoxic T cells (cytotoxic T lymphocytes [CTLs]) against the HIV-1 Gag protein are associated with control among those with protective HLA class I alleles and that loss of these responses eventually leads to viremia. A subset of individuals appears to have alternative, non-CTL mechanisms of viral control. These controllers may hold the key to an effective HIV vaccine., (Copyright © 2016, American Society for Microbiology. All Rights Reserved.)

Multiple HIV-1-specific cytokine and proliferative responses by CD4(+) T cells have not been studied in acutely infected infants. Using an intracellular cytokine staining assay, 34 untreated clade C HIV-1-infected infants (2-102 days old) were assessed for IFN-gamma, 28/34 for IL-2, and 26/34 for TNF-alpha responses to all HIV-1 proteins. Responses were detected in 29%, 36%, and 15% of infants, respectively. Twelve of the original 34 infants were then studied longitudinally for 14 months to determine the effect of viral load on IFN-gamma Gag-specific responses: seven infants were treated for 1 year, stopped treatment, and resumed when CD4% was < 20 and five infants were treated only when the CD4% was <20. Following treatment cessation, there was an immediate increase in viral load followed by an increase in the magnitude of CD4(+) Gag-specific responses. Despite this, the majority of infants (54%) had to restart treatment by 24 months of age, indicating that the immune responses were antigen driven but not associated with protection. Among untreated infants HIV-specific CD4(+) responses were detected sporadically indicating a dysfunctional immune response in the face of constant exposure to high levels of viremia.