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Objective: To evaluate the association between treatment of HIV-tuberculosis (TB) coinfection and primary virologic failure among children initiating antiretroviral therapy in South Africa., Design: We performed a retrospective cohort study of 1029 children initiating antiretroviral therapy at two medical centers in KwaZulu Natal, South Africa, a region of very high TB incidence., Methods: Data were extracted from electronic medical records and charts and the impact of TB cotreatment on viral suppression at 6 and 12 months was assessed using logistic regression., Results: The overall rate of virologic suppression (<400 HIV RNA copies/ml) was 85% at 6 months and 87% at 12 months. Children who received concurrent treatment for TB had a significantly lower rate of virologic suppression at 6 months (79 vs. 88%; P = 0.003). Those who received nonnucleoside reverse transcriptase inhibitor-based HAART had similar rates of viral suppression regardless of whether they received concurrent TB therapy. In contrast, children who received protease inhibitor-based HAART had significantly lower viral suppression rates at both 6 and 12 months if treated concurrently for TB (P = 0.02 and 0.03). Multivariate logistic regression revealed that age at initiation, protease inhibitor therapy, and TB coinfection were each independently associated with primary virologic failure., Conclusion: Concurrent treatment for TB is associated with lower rates of viral suppression among children receiving protease inhibitor-based HAART, but not among those receiving nonnucleoside reverse transcriptase inhibitor-based HAART. Guidelines for the care of young HIV-TB coinfected infants should be continually evaluated, as protease inhibitor-based antiviral therapy may not provide optimal viral suppression in this population.

Objective: We sought to identify immunologic and virologic correlates of spontaneous viral control among long-term survivors of perinatal HIV infection expressing the protective human leukocyte antigen (HLA)-B57 allele., Design: The frequency, epitope specificity, and functional attributes of HIV-specific T cells and sequence variation within B57-restricted epitopes were compared between 'spontaneous controllers' who maintained normal CD4 percentages and viral loads less than 3000 copies/ml without antiretroviral therapy, and 'treated progressors' who had initiated HAART., Methods: Recognition of HIV optimal epitopes was assessed by interferon gamma (IFNgamma) enzyme-linked immunosorbent spot. Functional characterization of CD8 cells targeting B57 epitopes was performed by staining for cytokine production (intracellular IFNgamma, interleukin-2, tumor necrosis factor alpha) and degranulation. Sequencing of autologous RNA was performed to determine the prevalence of viral escape mutations within B57-restricted epitopes and associated compensatory mutations., Results: HLA-B57 remained immunodominant during chronic infection in both controllers and progressors, but controllers recognized fewer epitopes and targeted epitopes within Gag and reverse transcriptase only, whereas progressors demonstrated a broader response targeting additional proteins. No individual epitope was targeted more frequently by spontaneous controllers. CD8 cytokine production patterns were heterogeneous among individuals and even among different epitopes in the same individual and did not correlate with spontaneous viral control. Extensive sequence variation within B57 epitopes was observed in both groups, but only progressors displayed additional capsid mutations that are known to offset the viral fitness cost of B57-driven immune escape., Conclusion: Among HLA-B57-positive long-term survivors, spontaneous control of viremia is not associated with a qualitatively or quantitatively superior T-cell response, but with uncompensated fitness-attenuating mutations in the viral capsid.

Background: Antigen-specific CD8 T cells following infection or immunization are typically assessed by measuring interferon-gamma production after stimulation with overlapping peptides spanning the region of interest. The effect of epitope location within such peptides is not known but may influence recognition., Objective: To examine if peptides containing the appropriate C-terminal anchor amino acid residue would provide more sensitive detection of T cell responses. The impact was examined of epitope location within overlapping peptides on recognition of epitope-specific CD8 T cell responses., Methods: C-terminal amino acid residues were analyzed in well-defined optimal epitopes for HIV, Epstein-Barr virus, cytomegalovirus and influenza and in peptide-binding motifs. Recognition of known epitopes within longer synthesized peptides by peripheral blood mononuclear cells or CD8 T cell lines was tested using interferon-gamma Elispot at various peptide concentrations., Results: Only 9 of 20 amino acids served as the C-terminal anchor position in 96% of described optimal epitopes and in 95% of peptide-binding motifs. A CD8 T cell response to an epitope within a longer peptide is best detected when the epitope is situated at the C-terminal end of the longer peptide, both when using peptides designed to include the optimal epitope at every possible position and when comparing responses towards optimal epitopes and corresponding overlapping peptides in a larger group of subjects., Conclusion: When using overlapping peptides to screen for CD8 T cell responses, more sensitive detection will be achieved using known C-terminal anchor amino acid residues at the C-terminus.

Background: HLA-B57, as well as cytotoxic T-lymphocyte (CTL) responses restricted by this allele, have been strongly associated with long-term non-progressive chronic HIV-1 infection. However, their impact on viral replication during acute HIV-1 infection is not known., Methods: Clinical and immunological parameters during acute and early HIV-1 infection in individuals expressing HLA-B57 were assessed. HIV-1-specific T-cell responses were determined by peptide-specific interferon-gamma production measured using Elispot assay and flow-based intracellular cytokine quantification., Results: Individuals expressing HLA-B57 presented significantly less frequently with symptomatic acute HIV-1 infection (4/116, 3.4%) than expected from the frequency of chronically infected individuals expressing this allele (43/446, 9.6%; P < 0.05). During acute infection, virus-specific CD8 T-cell responses were dominated by HLA-B57-restricted responses, with significantly broader (P < 0.02) and stronger (P < 0.03) responses restricted by HLA-B57 than restricted by all other co-expressed HLA class I alleles combined. Six out of nine individuals expressing HLA-B57 controlled HIV-1 viremia in the absence of therapy at levels < 5000 copies/ml (median, 515 copies/ml) during up to 29 months following acute infection., Conclusion: These data demonstrate that host genetic factors can influence the clinical manifestations of acute HIV-1 infection and provide a functional link between HLA-B57 and viral immune control.

Objectives: HIV-1 p15 Gag and its protease cleavage products, NCp7 and p6, are believed to play a major role in viral infectivity and assembly during the early and late stages of the retroviral life cycle. However, the extent to which p15 Gag is targeted by the host immune system in natural infection as well as precise cytotoxic T lymphocyte (CTL) epitopes within this protein remains to be defined., Methods: In this study, 57 HIV-1 infected individuals and 10 HIV-1 negative controls were screened for CD8 and CD4 T-cell responses using overlapping peptides spanning the entire p15 Gag protein as well as the p17 Gag and p24 Gag proteins. Peptide-specific interferon-gamma production was measured by Elispot assay and flow-based intracellular cytokine quantification, and cytotoxic activity was confirmed after isolation of peptide-specific CD8 T-cell lines., Results: CD8 T lymphocytes specific to p15 Gag were found in 46% (26/57) of HIV-1 infected individuals studied and contributed on average 17% (range, 0-100%) to the total Gag-specific T-cell responses. Responses were clustered within three immunodominant regions of p15 Gag, mapping to important functional sites. These studies also include the description of the first three optimally defined CTL epitopes within p15 Gag., Conclusions: These results indicate that p15 Gag is frequently recognized by HIV-1-specific CD8 T cells in HIV-1 infection and will be important in the comprehensive assessments of CTL responses in infected persons, as well as the design and testing of future HIV-1 vaccines and immunotherapeutic interventions.