Patterns and features of HIV-1 specific CD8+ T-cell responses during acute HIV-1 infection and their association with viral control.

Ph. D University of KwaZulu-Natal, Durban 2015.Evidence suggests that CD8+ T-­‐cells play a major role in the control of HIV-­‐1 viremia and apply significant immune pressure on HIV-­‐1 replication. However, the presence of virus-­‐specific CD8+ T-­‐cells in individuals with varying levels of viral control suggests that CD8+ T-­‐cells may differ in their antiviral function or efficacy. The mechanisms underlying differences in the control of viremia, particularly the reasons why particular individuals experience more effective acute viremia resolution, which is a good correlate of the subsequent rate of disease progression, are still not well understood. In order to uncover some of the features of CD8+ T-­‐cell subsets responsible for the control of HIV replication, particularly during the critical early infection phase, we investigated the patterns and features of HIV-­‐1-­‐specific CD8+ T-­‐ cell responses during acute and primary HIV-­‐1 infection and their association with viral control. We also sought to determine the impact of acute phase immune activation on the acute HIV-­‐1-­‐specific CD8+ T-­‐cell response and on disease progression. We hypothesized that protein-­‐specific and epitope-­‐specific immunodominance patterns during the first 12 weeks of HIV-­‐1 infection are associated with subsequent disease progression. Our data show the presence of HIV-­‐1 specific CD8+ T-­‐cells with limited breadth during acute HIV-­‐1 infection and also demonstrate that the magnitude and breadth of interferon gamma (IFN-­‐γ) ELISPOT assay responses measured within 12 weeks post-­‐infection are unrelated to the course of disease in the first year of infection. During the first weeks of infection Nef protein was most frequently recognized by T-­‐ xv cells and was the target for the earliest response. Although initially subdominant, there was a broadening of the Gag-­‐specific T-­‐cell immune response such that these responses became immunodominant by one year post infection. The broadening and preservation of early Gag–specific T-­‐cell responses during the follow up period was associated with better control of viremia and lower viral load set point. Although many of the acute/early HIV-­‐1-­‐specific IFN-­‐γ enzyme linked immunospot assay (ELISPOT) CD8+ T-­‐cell responses targeting Gag and Pol persisted, the majority of acute and early T-­‐cell responses targeting Env, Nef and other regulatory proteins waxed and waned over time and could not be detected at the last time point evaluated. Some of the early T-­‐cell responses which where no longer detectable when using overnight ELISPOT assay were detectable when PBMCs were stimulated with corresponding peptides and cultured for 10 days before measuring IFN-­‐γ secretion via the ELISPOT assay. The presence of these cultured ELISPOT central memory type T-­‐cell responses targeting epitopes in Pol, Env, Nef, Regulatory and Accessory proteins were not significantly associated with viral set point. However, cultured ELISPOT Gag-­‐specific responses correlated with low plasma viremia, thus further providing evidence for the favourable role of Gag-­‐specific T-­‐cell responses in the control of viral replication. We also show that three cytokines IL-­‐10, IP-­‐10 and IL-­‐ 12 were associated with changes in viral load set point and/or CD4+ T-­‐cell dynamics during the first year of HIV-­‐1 infection. Interestingly, the activation of the PD-­‐1 inhibitory pathway in acute HIV-­‐1 infection was associated with a slower disease progression

Predicted effects of the introduction of long-acting injectable cabotegravir pre-exposure prophylaxis in sub-Saharan Africa: a modelling study.

BACKGROUND: Long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) is recommended by WHO as an additional option for HIV prevention in sub-Saharan Africa, but there is concern that its introduction could lead to an increase in integrase-inhibitor resistance undermining treatment programmes that rely on dolutegravir. We aimed to project the health benefits and risks of cabotegravir-PrEP introduction in settings in sub-Saharan Africa. METHODS: With HIV Synthesis, an individual-based HIV model, we simulated 1000 setting-scenarios reflecting both variability and uncertainty about HIV epidemics in sub-Saharan Africa and compared outcomes for each with and without cabotegravir-PrEP introduction. PrEP use is assumed to be risk-informed and to be used only in 3-month periods (the time step for the model) when having condomless sex. We consider three groups at risk of integrase-inhibitor resistance emergence: people who start cabotegravir-PrEP after (unknowingly) being infected with HIV, those who seroconvert while on PrEP, and those with HIV who have residual cabotegravir drugs concentrations during the early tail period after recently stopping PrEP. We projected the outcomes of policies of cabotegravir-PrEP introduction and of no introduction in 2022 across 50 years. In 50% of setting-scenarios we considered that more sensitive nucleic-acid-based HIV diagnostic testing (NAT), rather than regular antibody-based HIV rapid testing, might be used to reduce resistance risk. For cost-effectiveness analysis we assumed in our base case a cost of cabotegravir-PrEP drug to be similar to oral PrEP, resulting in a total annual cost of USD$144 per year ($114 per year and $264 per year considered in sensitivity analyses), a cost-effectiveness threshold of$500 per disability-adjusted life years averted, and a discount rate of 3% per year. FINDINGS: Reflecting our assumptions on the appeal of cabotegravir-PrEP, its introduction is predicted to lead to a substantial increase in PrEP use with approximately 2·6% of the adult population (and 46% of those with a current indication for PrEP) receiving PrEP compared with 1·5% (28%) without cabotegravir-PrEP introduction across 20 years. As a result, HIV incidence is expected to be lower by 29% (90% range across setting-scenarios 6-52%) across the same period compared with no introduction of cabotegravir-PrEP. In people initiating antiretroviral therapy, the proportion with integrase-inhibitor resistance after 20 years is projected to be 1·7% (0-6·4%) without cabotegravir-PrEP introduction but 13·1% (4·1-30·9%) with. Cabotegravir-PrEP introduction is predicted to lower the proportion of all people on antiretroviral therapy with viral loads less than 1000 copies per mL by 0·9% (-2·5% to 0·3%) at 20 years. For an adult population of 10 million an overall decrease in number of AIDS deaths of about 4540 per year (-13 000 to -300) across 50 years is predicted, with little discernible benefit with NAT when compared with standard antibody-based rapid testing. AIDS deaths are predicted to be averted with cabotegravir-PrEP introduction in 99% of setting-scenarios. Across the 50-year time horizon, overall HIV programme costs are predicted to be similar regardless of whether cabotegravir-PrEP is introduced (total mean discounted annual HIV programme costs per year across 50 years is $151·3 million vs$150·7 million), assuming the use of standard antibody testing. With antibody-based rapid HIV testing, the introduction of cabotegravir-PrEP is predicted to be cost-effective under an assumed threshold of $500 per disability-adjusted life year averted in 82$144 per year, in 52% at $264, and in 87$114. INTERPRETATION: Despite leading to increases in integrase-inhibitor drug resistance, cabotegravir-PrEP introduction is likely to reduce AIDS deaths in addition to HIV incidence. Long-acting cabotegravir-PrEP is predicted to be cost-effective if delivered at similar cost to oral PrEP with antibody-based rapid HIV testing. FUNDING: Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases of the National Institutes of Health

High Frequency of Transmitted HIV-1 Gag HLA Class I-Driven Immune Escape Variants but Minimal Immune Selection over the First Year of Clade C Infection

In chronic HIV infection, CD8+ T cell responses to Gag are associated with lower viral loads, but longitudinal studies of HLA-restricted CD8+ T cell-driven selection pressure in Gag from the time of acute infection are limited. In this study we examined Gag sequence evolution over the first year of infection in 22 patients identified prior to seroconversion. A total of 310 and 337 full-length Gag sequences from the earliest available samples (median = 14 days after infection [Fiebig stage I/II]) and at one-year post infection respectively were generated. Six of 22 (27%) individuals were infected with multiple variants. There was a trend towards early intra-patient viral sequence diversity correlating with viral load set point (p = 0.07, r = 0.39). At 14 days post infection, 59.7% of Gag CTL epitopes contained non-consensus polymorphisms and over half of these (35.3%) comprised of previously described CTL escape variants. Consensus and variant CTL epitope proportions were equally distributed irrespective of the selecting host HLA allele and most epitopes remained unchanged over 12 months post infection. These data suggest that intrapatient diversity during acute infection is an indicator of disease outcome. In this setting, there is a high rate of transmitted CTL escape variants and limited immune selection in Gag during the first year of infection. These data have relevance for vaccine strategies designed to elicit effective CD8+ T cell immune responses

Neighbour joining trees and Highlighter plots of longitudinal HIV-1 gag diversity from recently infected individuals.

<p>(A) Neighbour-joining phylogenetic tree of longitudinal (from 14 days to 1 year post infection) <i>gag</i> sequences from 22 recently infected HIV-1 participants and consensus subtype C reference sequence from the HIV database (<a href="http://www.hiv.lanl.gov" target="_blank">www.hiv.lanl.gov</a>). Gag sequences from the earliest time point are shown in red circles and in blue circles at 1 year post infection. (*) denotes samples sequenced later than 14 days post infection (AS3–0513, AS2–1037, AS2–0802, AS2–0945 and AS1–0876 were sequenced at 28, 34, 35, 46 and 101 days post-infection respectively). (B) Participant AS3_0513 with a highly homogeneous <i>gag</i> sequence population at screening (∼28 days post infection) displaying limited structure on a tree (left) and little or no nucleotide changes from the intrapatient consensus at 28 days post infection. (C) Participant AS3_0767 infected with four closely related <i>gag</i> populations based on the clustering of sequences. Heterogeneous, multiple variant <i>gag</i> sequences population at 14 days post infection visually represented by a phylogenetic tree (left) with extensive branching topology and Highlighter plots (right) with diverse pattern of nucleotide base mutations compared to consensus. Nucleotide polymorphisms are indicated by a colored tic mark (thymine in red, adenine in green, cytosine in blue and guanine in orange) and deletions are shown by gray tics in the Highlighter plots. (★) denotes the consensus sequence obtained from the earliest time point sequences.</p

Demographic and clinical characteristics of the study participants.

<p>*CD4+ cell counts were not performed at screening; the values given are for 2–4 weeks post screening</p><p>♦Viral loads were performed at screening</p><p>† CDC criteria followed for the interpretation of Western Blot results</p><p>Demographic and clinical characteristics of the study participants.</p

Percentage distribution of consensus and variant Gag sequence patterns in individuals over one year of HIV-1 infection.

<p>(A) Percentage of consensus, variant and known CTL variants within host specific epitopes from HLA class I alleles at one year post infection. Distribution of consensus, variant and percentage of variants as CTL variants within host-specific HLA restricted Gag epitopes in individuals possessing the selecting HLA-A (B), HLA-B (C) and HLA-C (D) allele and those individuals who do not possess the selecting HLA allele over one year of infection. (E) Overall distribution of adapted and non-adapted HLA-associated escape mutations within individuals that select and do not select for Gag polymorphisms by one year post infection. Distribution of adapted (F) and non-adapted (G) mutations expressing HLA-A, HLA-B and HLA-C alleles that select and do not select for Gag polymorphisms one year post infection.</p

Predicted effects of the introduction of long-acting injectable cabotegravir pre-exposure prophylaxis in sub-Saharan Africa: a modelling study

Background: Long-acting injectable cabotegravir pre-exposure prophylaxis (PrEP) is recommended by WHO as an additional option for HIV prevention in sub-Saharan Africa, but there is concern that its introduction could lead to an increase in integrase-inhibitor resistance undermining treatment programmes that rely on dolutegravir. We aimed to project the health benefits and risks of cabotegravir-PrEP introduction in settings in sub-Saharan Africa. Methods: With HIV Synthesis, an individual-based HIV model, we simulated 1000 setting-scenarios reflecting both variability and uncertainty about HIV epidemics in sub-Saharan Africa and compared outcomes for each with and without cabotegravir-PrEP introduction. PrEP use is assumed to be risk-informed and to be used only in 3-month periods (the time step for the model) when having condomless sex. We consider three groups at risk of integrase-inhibitor resistance emergence: people who start cabotegravir-PrEP after (unknowingly) being infected with HIV, those who seroconvert while on PrEP, and those with HIV who have residual cabotegravir drugs concentrations during the early tail period after recently stopping PrEP. We projected the outcomes of policies of cabotegravir-PrEP introduction and of no introduction in 2022 across 50 years. In 50% of setting-scenarios we considered that more sensitive nucleic-acid-based HIV diagnostic testing (NAT), rather than regular antibody-based HIV rapid testing, might be used to reduce resistance risk. For cost-effectiveness analysis we assumed in our base case a cost of cabotegravir-PrEP drug to be similar to oral PrEP, resulting in a total annual cost of USD$144 per year ($114 per year and $264 per year considered in sensitivity analyses), a cost-effectiveness threshold of$500 per disability-adjusted life years averted, and a discount rate of 3% per year. Findings: Reflecting our assumptions on the appeal of cabotegravir-PrEP, its introduction is predicted to lead to a substantial increase in PrEP use with approximately 2·6% of the adult population (and 46% of those with a current indication for PrEP) receiving PrEP compared with 1·5% (28%) without cabotegravir-PrEP introduction across 20 years. As a result, HIV incidence is expected to be lower by 29% (90% range across setting-scenarios 6–52%) across the same period compared with no introduction of cabotegravir-PrEP. In people initiating antiretroviral therapy, the proportion with integrase-inhibitor resistance after 20 years is projected to be 1·7% (0–6·4%) without cabotegravir-PrEP introduction but 13·1% (4·1–30·9%) with. Cabotegravir-PrEP introduction is predicted to lower the proportion of all people on antiretroviral therapy with viral loads less than 1000 copies per mL by 0·9% (–2·5% to 0·3%) at 20 years. For an adult population of 10 million an overall decrease in number of AIDS deaths of about 4540 per year (–13 000 to –300) across 50 years is predicted, with little discernible benefit with NAT when compared with standard antibody-based rapid testing. AIDS deaths are predicted to be averted with cabotegravir-PrEP introduction in 99% of setting-scenarios. Across the 50-year time horizon, overall HIV programme costs are predicted to be similar regardless of whether cabotegravir-PrEP is introduced (total mean discounted annual HIV programme costs per year across 50 years is $151·3 million vs$150·7 million), assuming the use of standard antibody testing. With antibody-based rapid HIV testing, the introduction of cabotegravir-PrEP is predicted to be cost-effective under an assumed threshold of $500 per disability-adjusted life year averted in 82$144 per year, in 52% at $264, and in 87$114. Interpretation: Despite leading to increases in integrase-inhibitor drug resistance, cabotegravir-PrEP introduction is likely to reduce AIDS deaths in addition to HIV incidence. Long-acting cabotegravir-PrEP is predicted to be cost-effective if delivered at similar cost to oral PrEP with antibody-based rapid HIV testing. Funding: Bill & Melinda Gates Foundation, National Institute of Allergy and Infectious Diseases of the National Institutes of Health