Cellular Immune Responses and Viral Diversity in Individuals Treated during Acute and Early HIV-1 Infection

Immune responses induced during the early stages of chronic viral infections are thought to influence disease outcome. Using HIV as a model, we examined virus-specific cytotoxic T lymphocytes (CTLs), T helper cells, and viral genetic diversity in relation to duration of infection and subsequent response to antiviral therapy. Individuals with acute HIV-1 infection treated before seroconversion had weaker CTL responses directed at fewer epitopes than persons who were treated after seroconversion. However, treatment-induced control of viremia was associated with the development of strong T helper cell responses in both groups. After 1 yr of antiviral treatment initiated in acute or early infection, all epitope-specific CTL responses persisted despite undetectable viral loads. The breadth and magnitude of CTL responses remained significantly less in treated acute infection than in treated chronic infection, but viral diversity was also significantly less with immediate therapy. We conclude that early treatment of acute HIV infection leads to a more narrowly directed CTL response, stronger T helper cell responses, and a less diverse virus population. Given the need for T helper cells to maintain effective CTL responses and the ability of virus diversification to accommodate immune escape, we hypothesize that early therapy of primary infection may be beneficial despite induction of less robust CTL responses. These data also provide rationale for therapeutic immunization aimed at broadening CTL responses in treated primary HIV infection

Evolution of HLA-B*5703 HIV-1 escape mutations in HLA-B*5703–positive individuals and their transmission recipients

HLA-B*57 is the class I allele most consistently associated with control of human immunodeficiency virus (HIV) replication, which may be linked to the specific HIV peptides that this allele presents to cytotoxic T lymphocytes (CTLs), and the resulting efficacy of these cellular immune responses. In two HIV C clade–infected populations in South Africa and Zambia, we sought to elucidate the role of HLA-B*5703 in HIV disease outcome. HLA-B*5703–restricted CTL responses select for escape mutations in three Gag p24 epitopes, in a predictable order. We show that the accumulation of these mutations sequentially reduces viral replicative capacity in vitro. Despite this, in vivo data demonstrate that there is ultimately an increase in viral load concomitant with evasion of all three HLA-B*5703–restricted CTL responses. In HLA-B*5703–mismatched recipients, the previously described early benefit of transmitted HLA-B*5703–associated escape mutations is abrogated by the increase in viral load coincident with reversion. Rapid disease progression is observed in HLA-matched recipients to whom mutated virus is transmitted. These data demonstrate that, although costly escape from CTL responses can progressively attenuate the virus, high viral loads develop in the absence of adequate, continued CTL responses. These data underline the need for a CTL vaccine against multiple conserved epitopes

Tracking the culprit: HIV-1 evolution and immune selection revealed by single-genome amplification

Early control of HIV-1 infection is determined by a balance between the host immune response and the ability of the virus to escape this response. Studies using single-genome amplification now reveal new details about the kinetics and specificity of the CD8+ T cell response and the evolution of the virus during early HIV infection

Non-Immunogenicity of Overlapping Gag Peptides Pulsed on Autologous Cells after Vaccination of HIV Infected Individuals

Background: HIV Gag-specific CD4+ and CD8+ T-cell responses are important for HIV immune control. Pulsing overlapping Gag peptides on autologous lymphocytes (OPAL) has proven immunogenic and effective in reducing viral loads in multiple pigtail macaque studies, warranting clinical evaluation. Methodology We performed a phase I, single centre, placebo-controlled, double-blinded and dose-escalating study to evaluate the safety and preliminary immunogenicity of a novel therapeutic vaccine approach ‘OPAL-HIV-Gag(c)’. This vaccine is comprised of 120 15mer peptides, overlapping by 11 amino acids, spanning the HIV Gag C clade sequence proteome, pulsed on white blood cells enriched from whole blood using a closed system, followed by intravenous reinfusion. Patients with undetectable HIV viral loads (<50 copies/ml plasma) on HAART received four administrations at week 0, 4, 8 and 12, and were followed up for 12 weeks post-treatment. Twenty-three people were enrolled in four groups: 12 mg (n = 6), 24 mg (n = 7), 48 mg (n = 2) or matching placebo (n = 8) with 18 immunologically evaluable. T-cell immunogenicity was assessed by IFNγ ELIspot and intracellular cytokine staining (ICS). Results: The OPAL-HIV-Gag(c) peptides were antigenic in vitro in 17/17 subjects. After vaccination with OPAL-HIV-Gag(c), 1/6 subjects at 12 mg and 1/6 subjects at 24 mg dose groups had a 2- and 3-fold increase in ELIspot magnitudes from baseline, respectively, of Gag-specific CD8+ T-cells at week 14, compared to 0/6 subjects in the placebo group. No Gag-specific CD4+ T-cell responses or overall change in Rev, Nef, Tat and CMV specific responses were detected. Marked, transient and self-limiting lymphopenia was observed immediately post-vaccination (4 hours) in OPAL-HIV-Gag(c) but not in placebo recipients, with median fall from 1.72 to 0.67 million lymphocytes/mL for active groups (P<0.001), compared to post-placebo from 1.70 to 1.56 lymphocytes/ml (P = 0.16). Conclusion/Significance Despite strong immunogenicity observed in several Macaca nemestrina studies using this approach, OPAL-HIV-Gag(c) was not significantly immunogenic in humans and improved methods of generating high-frequency Gag-specific T-cell responses are required. Name of Registry ClinicalTrials.gov, Registry number: NCT01123915, URL trial registry database: http://www.clinicaltrials.gov/ct2/results?term=OPAL-HIV-1001&Search=Searc

HLA-Driven Convergence of HIV-1 Viral Subtypes B and F Toward the Adaptation to Immune Responses in Human Populations

BACKGROUND: Cytotoxic T-Lymphocyte (CTL) response drives the evolution of HIV-1 at a host-level by selecting HLA-restricted escape mutations. Dissecting the dynamics of these escape mutations at a population-level would help to understand how HLA-mediated selection drives the evolution of HIV-1. METHODOLOGY/PRINCIPAL FINDINGS: We undertook a study of the dynamics of HIV-1 CTL-escape mutations by analyzing through statistical approaches and phylogenetic methods the viral gene gag sequenced in plasma samples collected between the years 1987 and 2006 from 302 drug-naive HIV-positive patients. By applying logistic regression models and after performing correction for multiple test, we identified 22 potential CTL-escape mutations (p-value<0.05; q-value<0.2); 10 of these associations were confirmed in samples biologically independent by a Bayesian Markov Chain Monte-Carlo method. Analyzing their prevalence back in time we found that escape mutations that are the consensus residue in samples collected after 2003 have actually significantly increased in time in one of either B or F subtype until becoming the most frequent residue, while dominating the other viral subtype. Their estimated prevalence in the viral subtype they did not dominate was lower than 30% for the majority of samples collected at the end of the 80's. In addition, when screening the entire viral region, we found that the 75% of positions significantly changing in time (p<0.05) were located within known CTL epitopes. CONCLUSIONS: Across HIV Gag protein, the rise of polymorphisms from independent origin during the last twenty years of epidemic in our setting was related to an association with an HLA allele. The fact that these mutations accumulated in one of either B or F subtypes have also dominated the other subtype shows how this selection might be causing a convergence of viral subtypes to variants which are more likely to evade the immune response of the population where they circulate

Chapter 15 - National and sub-national policies and institutions

This chapter assesses national and sub-national mitigation policies and their institutional settings. There has been a marked increase in national policies and legislation on climate change since the AR4 with a diversity of approaches and a multiplicity of objectives (see Section 15.2). However, Figure 1.9 of Chapter 1 suggests that these policies, taken together, have not yet achieved a substantial deviation in emissions from the past trend. Limiting concentrations to levels that would be consistent with a likely probability of maintaining temperature increases below 2 degrees C this century (scenarios generally in the range of 430-480 ppmv CO2eq) would require that emissions break from these trends and be decreased substantially. In contrast, concentrations exceed 1000 ppmv CO2eq by 2100 in many baseline scenarios (that is, scenarios without additional efforts to reduce emissions). The literature on mitigation scenarios provides a wide range of CO2 shadow price levels consistent with these goals, with estimates of less than US$50/tCO2 in 2020 in many studies and exceeding US$100/tCO2 in others, assuming a globally-efficient and immediate effort to reduce emissions. These shadow prices exhibit a strongly increasing trend thereafter. Policies and instruments are assessed in this light. Section 15.2 assesses the role of institutions and governance. Section 15.3 lays out the classification of policy instruments and packages, while 15.4 discusses the methodologies used to evaluate policies and institutions. The performance of various policy instruments and measures are individually assessed in Sections 15.5 and 15.6. The two main types of economic instruments are price instruments, that is, taxes and subsidies (including removal of subsidies on fossil fuels), and quantity instruments - emission-trading systems. These are assessed in Sections 15.5.2 and 15.5.3 respectively. An important feature of both these instruments is that they can be applied at a very broad, economy-wide scale. This is in contrast to the regulation and information policies and voluntary agreements which are usually sector- specific. These policies are assessed in Sections 15.5.4, 15.5.5, and 15.5.7. Government provision and planning is discussed in 15.5.6. The next section, 15.6, provides a focused discussion on technology policy including research and development and the deployment and diffusion of clean energy technologies. In addition to technology policy, longer-term effects of the policies assessed in Section 15.5 are addressed in Section 15.6. Both these sections, 15.5 and 15.6, bring together lessons from policies and policy packages used at the sectoral level from Chapters 7 (Energy), 8 (Transport), 9 (Buildings), 10 (Industry), 11 (Agriculture, Forestry and Land Use) and Chapter 12 (Human Settlements, Infrastructure, and Spatial Planning). The following sections further assess the interaction among policy instruments, as they are not usually used in isolation, and the impacts of particular instruments depend on the entire package of policies and the institutional context. Section 15.7 reviews interactions, both beneficial and harmful, that may not have been planned. The presence of such interactions is in part a consequence of the multi-jurisdictional nature of climate governance as well as the use of multiple policy instruments within a jurisdiction. Section 15.8 examines the deliberate linkage of policies across national and sub-national jurisdictions. Other key issues are further discussed in dedicated sections. They are: the role of stakeholders including non-governmental organizations (NGOs) (15.9), capacity building (15.10), links between adaptation and mitigation policies (15.11), and investment and finance (15.12). Gaps in knowledge are collected in 15.13