RESUMO
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.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Linfócitos T Citotóxicos/imunologia , Viremia/imunologia , Adulto , Terapia Antirretroviral de Alta Atividade , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/virologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/virologia , HIV-1/efeitos dos fármacos , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Estudos Longitudinais , Carga Viral , Viremia/tratamento farmacológico , Replicação ViralRESUMO
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.
Assuntos
HIV-1/genética , Polimorfismo Genético , Seleção Genética , Produtos do Gene gag do Vírus da Imunodeficiência Humana/genética , Adolescente , Adulto , Sequência de Bases , Feminino , Frequência do Gene , Infecções por HIV/virologia , Antígenos HLA/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologiaRESUMO
OBJECTIVE: We characterized protein-specific CD8 T-cell immunodominance patterns during the first year of HIV-1 infection, and their impact on viral evolution and immune control. METHODS: We analyzed CD8 T-cell responses to the full HIV-1 proteome during the first year of infection in 18 antiretroviral-naïve individuals with acute HIV-1 subtype C infection, all identified prior to seroconversion. Ex-vivo and cultured interferon-γ ELISPOT assays were performed and viruses from plasma were sequenced within defined CTL Gag epitopes. RESULTS: Nef-specific CD8 T-cell responses were dominant during the first 4 weeks after infection and made up 40% of the total responses at this time; yet, by 1 year, responses against this region had declined and Gag responses made up to 47% of all T-cell responses measured. An inverse correlation between the breadth of Gag-specific responses and viral load set point was evident at 26 weeks after infection (Pâ=â0.0081, râ=â-0.60) and beyond. An inverse correlation between the number of persistent responses targeting Gag and viral set point was also identified (Pâ=â0.01, râ=â-0.58). Gag-specific responses detectable by the cultured ELISPOT assay correlated negatively with viral load set point (Pâ=â0.0013, râ=â-0.91). Sequence evolution in targeted and nontargeted Gag epitopes in this cohort was infrequent. CONCLUSIONS: These data underscore the importance of HIV-specific CD8 T-cell responses, particularly to the Gag protein, in the maintenance of low viral load levels during primary infection, and show that these responses are initially poorly elicited by natural infection. These data have implications for vaccine design strategies.
Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , HIV-1/imunologia , Epitopos Imunodominantes/imunologia , Produtos do Gene gag do Vírus da Imunodeficiência Humana/imunologia , Adulto , ELISPOT , Feminino , Humanos , Interferon gama/química , Masculino , Análise de Sequência de RNA , Carga ViralRESUMO
BACKGROUND: Pregnant women living with HIV (WLH) face daily challenges maintaining their own and their babies' health and mental health. Standard Prevention of Maternal to Child Transmission (PMTCT) programs are not designed to address these challenges. METHODS/DESIGN: As part of a cluster randomized controlled trial, WLH are invited to attend four antenatal and four postnatal small group sessions led by a peer WLH (a Peer Mentor). The WLH and their babies are assessed during pregnancy and at one week, six months, and twelve months post-birth. Mobile phones are used to collect routine information, complete questionnaires and remain in contact with participants over time. Pregnant WLH (N = 1200) are randomly assigned by clinic (N = 8 clinics) to an intervention program, called Masihambisane (n = 4 clinics, n = 600 WLH) or a standard care PMTCT control condition (n = 4 clinics; n = 600 WLH). DISCUSSION: Data collection with cellular phones are innovative and effective in low-resource settings. Standard PMTCT programs are not designed to address the daily challenges faced by WLH; Peer Mentors may be useful in supporting WLH to cope with these challenges. TRIAL REGISTRATION: ClinicalTrials.gov registration # NCT00972699.