Shabashini Reddy

CD8+ T-cell responses to different HIV proteins have discordant associations with viral load

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.

Control of Human Immunodeficiency Virus Type 1 Is Associated with HLA-B*13 and Targeting of Multiple Gag-Specific CD8+ T-Cell Epitopes

ABSTRACT To better understand relationships between CD8+ T-cell specificity and the immune control of human immunodeficiency virus type 1 (HIV-1), we analyzed the role of HLA-B*13, an allele associated with low viremia, in a cohort of 578 C clade-infected individuals in Durban, South Africa. Six novel B*13-restricted cytotoxic T lymphocyte epitopes were defined from analyses of 37 B*13-positive subjects, including three Gag epitopes. These B*13-restricted epitopes contribute to a broad Gag-specific CD8+ response that is associated with the control of viremia. These data are consistent with data from studies of other HLA-class I alleles associated with HIV control that have shown that the targeting of multiple Gag epitopes is associated with relative suppression of viremia.

Possession of HLA Class II DRB1*1303 Associates with Reduced Viral Loads in Chronic HIV-1 Clade C and B Infection

BACKGROUND The HLA class II molecules play a central role in the generation of human immunodeficiency virus (HIV)-specific CD4(+) T-helper cells, which are critical for the induction of cytotoxic CD8(+) T cell responses. However, little is known about the impact of HLA class II alleles on HIV disease progression. METHODS In this study we investigated the effect of HLA class II alleles on HIV disease outcome and HIV-specific T cell responses in a cohort of 426 antiretroviral therapy-naive, HIV-1 clade C-infected, predominantly female black South Africans. RESULTS The HLA class II allele DRB1*1303 was independently associated with lower plasma viral loads in this population (P = .02), an association that was confirmed in a second cohort of 1436 untreated, HIV-1 clade B-infected, male European Americans, suggesting that DRB1*1303-mediated protection is independent of ethnicity, sex, and viral clade. Interestingly, DRB1*1303 carriage was not associated with an increased frequency of interferon (IFN) γ-positive HIV-specific CD4(+) T cell responses. CONCLUSIONS These data demonstrate the independent effect of an HLA class II allele, DRB1*1303, on HIV disease progression, in the absence of increased IFN-γ-positive HIV-specific CD4(+) T cell frequencies, suggesting that the protective activity of DRB1*1303 may be mediated via an alternative mechanism.

Lack of Duffy antigen receptor for chemokines: no influence on HIV disease progression in an African treatment-naive population.

Dear Editors: He et al recently reported an association between a single-nucleotide polymorphism (SNP, rs2814778, -46T→C) in the erythroid specific promoter region of the Duffy antigen receptor for chemokine (DARC) and HIV-1 acquisition and disease progression in African Americans (He et al., 2008). The authors described a higher frequency of the null homozygous genotype (-46C/C) in HIV-infected (70%) versus non-infected individuals (60%). Based on these findings they argued that the null allele confers susceptibility to infection with HIV-1 and suggested that up to 11% of the HIV-1 burden in sub-Saharan Africa could be attributed to homozygosity for the null allele. Oddly, however, these authors reported that the null genotype associated with better outcomes amongst those who became infected, including longer survival and more particularly decelerated loss of CD4+ T-lymphocytes. Another report showed an association between the -46C/C genotype and significantly reduced total white blood cells (WBC) in African Americans explaining ∼20% of population variation in WBC (Nalls et al., 2008). The -46C/C genotype is nearly fixed in those sub-Saharan African populations where Plasmodium vivax is endemic, apparently because it confers resistance against P. vivax malaria, but -46C is virtually absent in individuals of European descent (Tournamille et al., 1995; Hamblin and Di Rienzo, 2000). In those regions of sub-Saharan Africa that are not endemic for P. vivax, the -46C allele is not fixed, however, and the wildtype (-46T) allele is frequently observed (Rosenberg et al., 2007). Considering the potential importance of DARC on HIV-1 disease progression in Africans, we studied the effect of the DARC -46 genotype on outcomes to HIV infection in a cohort of untreated black South Africans. This region of Africa is not endemic for P. vivax and lies outside of the area of 96% mean fixation for -46C; thus, the null allele of DARC is not fixed in our study population and the allele frequency of -46T (the wildtype allele) is about 20%. We assessed the effects of the null (C/C), heterozygous (T/C), and wildtype (T/T) genotypes on rates of CD4 decline and mean HIV-1 viral loads in a group of 381 untreated black South Africans. Since the -46C/C genotype has previously been associated significantly with reduced total WBC (Nalls et al., 2008), we also determined WBC in our cohort in order to verify that our cohort is sufficiently powered to detect an effect of the -46 genotype, where -46C/C is expected to associate with low WBC as previously demonstrated.

Screening for acute HIV infection in South Africa: finding acute and chronic disease.

The yield of screening for acute HIV infection among general medical patients in resource‐scarce settings remains unclear. Our objective was to evaluate the strategy of using pooled HIV plasma RNA to diagnose acute HIV infection in patients with negative or discordant rapid HIV antibody tests in Durban, South Africa.

Impact of Select Immunologic and Virologic Biomarkers on CD4 Cell Count Decrease in Patients with Chronic HIV-1 Subtype C Infection: Results from Sinikithemba Cohort, Durban, South Africa

BACKGROUND The extent to which immunologic and clinical biomarkers influence human immunodeficiency virus type 1 (HIV-1) infection outcomes remains incompletely characterized, particularly for non-B subtypes. On the basis of data supporting in vitro HIV-1 protein-specific CD8 T lymphocyte responses as correlates of immune control in cross-sectional studies, we assessed the relationship of these responses, along with established HIV-1 biomarkers, with rates of CD4 cell count decrease in individuals infected with HIV-1 subtype C. METHODS Bivariate and multivariate mixed-effects models were used to assess the relationship of baseline CD4 cell count, plasma viral load, human leukocyte antigen (HLA) class I alleles, and HIV-1 protein-specific CD8 T cell responses with the rate of CD4 cell count decrease in a longitudinal population-based cohort of 300 therapy-naive, chronically infected adults with baseline CD4 cell counts >200 cells/mm(3) and plasma viral loads >500 copies/mL over a median of 25 months of follow-up. RESULTS In bivariate analyses, baseline CD4 cell count, plasma viral load, and possession of a protective HLA allele correlated significantly with the rate of CD4 cell count decrease. No relationship was observed between HIV-1 protein-specific CD8 T cell responses and CD4 cell count decrease. Results from multivariate models incorporating baseline CD4 cell counts (201-350 vs >350 cells/mm(3)), plasma viral load (< or =100,000 vs >100,000 copies/mL), and HLA (protective vs not protective) yielded the ability to discriminate CD4 cell count decreases over a 10-fold range. The fastest decrease was observed among individuals with CD4 cell counts >350 cells/mm(3) and plasma viral loads >100,000 copies/mL with no protective HLA alleles (-59 cells/mm(3) per year), whereas the slowest decrease was observed among individuals with CD4 cell counts 201-350 cells/mm(3), plasma viral loads < or =100,000 copies/mL, and a protective HLA allele (-6 cells/mm(3) per year). CONCLUSIONS The combination of plasma viral load and HLA class I type, but not in vitro HIV-1 protein-specific CD8 T cell responses, differentiates rates of CD4 cell count decrease in patients with chronic subtype-C infection better than either marker alone.Background The extent to which immunologic and clinical biomarkers influence HIV outcomes remains incompletely characterized, particularly for non-B subtypes. Based on data supporting in vitro HIV protein-specific CD8 T-lymphocyte responses as correlates of immune control in cross-sectional studies, we assessed the relationship of these responses, along with established HIV biomarkers, with rates of CD4 decline in subtype-C infection.

Preservation HIV-1-specific IFNγ+ CD4+ T-cell responses in breakthrough infections after exposure to tenofovir gel in the CAPRISA 004 microbicide trial.

Abstract:The Centre for the AIDS Program of Research in South Africa 004 trial demonstrated reduction of sexual HIV-1 acquisition in women using a vaginal microbicide containing tenofovir. A better understanding of the consequences of antiretroviral-containing microbicides for immune responses in individuals with intercurrent HIV-1 infection is needed for future trials combining the use of microbicides with HIV-1 vaccines. Investigation of immune responses in women who acquired HIV-1 although using tenofovir gel showed significantly higher (P = 0.01) Gag-specific IFN&ggr;+ CD4+ T-cell responses. The use of tenofovir-containing gel around the time of infection can modulate HIV-1 immunity, and these immunological changes need to be considered in future trials combining vaccines and microbicides.

Immunodominant HIV-1-specific HLA-B- and HLA-C-restricted CD8+ T cells do not differ in polyfunctionality

HIV-1 specific HLA-B-restricted CD8+ T cell responses differ from HLA-C-restricted responses in antiviral effectiveness. To investigate possible reasons for these differences, we characterized the frequency and polyfunctionality of immmunodominant HLA-B*57/B5801- and HLA-Cw*07-restricted CD8+ T cells occurring concurrently in nine study subjects assessing IFN-γ, TNF-α, IL-2, MIP-1β, and CD107a by flow cytometry and analyzed sequence variation in targeted epitopes. HLA-B*57/5801 and HLA-Cw*07 restricted CD8+ T cells did not differ significantly in polyfunctionality (p = 0.84). Possession of three or more functions correlated positively with CD4+ T cell counts (r = 0.85; p = 0.006) and monofunctional CD8+ T cells inversely correlated with CD4 cell counts (r = −0.79; p = 0.05). There were no differences in polyfunctionality of CD8+ T cells specific to wildtype versus mutated epitopes. These results suggest that loss of polyfunctionality and increase in monofunctional HIV-1-specific CD8+ T cells are associated with disease progression independent of restricting HLA allele. Furthermore, sequence variation does not appear to significantly impact CD8+ T cell polyfunctionality in chronic HIV-1 infection.

Use of abacavir in 30 HIV-infected children from Durban, South Africa: report from a pilot study.

This letter to the editor reports on the use of Abacavir from a pilot study conducted between February 2004 to August 2006 at King Edward VIII Hospital in Durban South Africa. The study included thirty antiretroviral therapy (ART) naive children aged between 2 and 12 years with vertically transmitted HIV-1 infection to assess the use of structured treatment interruptions.

Impact of select immunologic and virologic biomarkers on CD4 cell count decrease in patients with chronic HIV-1 subtype C infection

BACKGROUND The extent to which immunologic and clinical biomarkers influence human immunodeficiency virus type 1 (HIV-1) infection outcomes remains incompletely characterized, particularly for non-B subtypes. On the basis of data supporting in vitro HIV-1 protein-specific CD8 T lymphocyte responses as correlates of immune control in cross-sectional studies, we assessed the relationship of these responses, along with established HIV-1 biomarkers, with rates of CD4 cell count decrease in individuals infected with HIV-1 subtype C. METHODS Bivariate and multivariate mixed-effects models were used to assess the relationship of baseline CD4 cell count, plasma viral load, human leukocyte antigen (HLA) class I alleles, and HIV-1 protein-specific CD8 T cell responses with the rate of CD4 cell count decrease in a longitudinal population-based cohort of 300 therapy-naive, chronically infected adults with baseline CD4 cell counts >200 cells/mm(3) and plasma viral loads >500 copies/mL over a median of 25 months of follow-up. RESULTS In bivariate analyses, baseline CD4 cell count, plasma viral load, and possession of a protective HLA allele correlated significantly with the rate of CD4 cell count decrease. No relationship was observed between HIV-1 protein-specific CD8 T cell responses and CD4 cell count decrease. Results from multivariate models incorporating baseline CD4 cell counts (201-350 vs >350 cells/mm(3)), plasma viral load (< or =100,000 vs >100,000 copies/mL), and HLA (protective vs not protective) yielded the ability to discriminate CD4 cell count decreases over a 10-fold range. The fastest decrease was observed among individuals with CD4 cell counts >350 cells/mm(3) and plasma viral loads >100,000 copies/mL with no protective HLA alleles (-59 cells/mm(3) per year), whereas the slowest decrease was observed among individuals with CD4 cell counts 201-350 cells/mm(3), plasma viral loads < or =100,000 copies/mL, and a protective HLA allele (-6 cells/mm(3) per year). CONCLUSIONS The combination of plasma viral load and HLA class I type, but not in vitro HIV-1 protein-specific CD8 T cell responses, differentiates rates of CD4 cell count decrease in patients with chronic subtype-C infection better than either marker alone.Background The extent to which immunologic and clinical biomarkers influence HIV outcomes remains incompletely characterized, particularly for non-B subtypes. Based on data supporting in vitro HIV protein-specific CD8 T-lymphocyte responses as correlates of immune control in cross-sectional studies, we assessed the relationship of these responses, along with established HIV biomarkers, with rates of CD4 decline in subtype-C infection.