Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection.
ABSTRACT Major histocompatibility complex (MHC) genes (HLA in humans) regulate the immune response to foreign antigens. Molecular and serologic techniques were used to identify products of HLA class I, class II and transporter (TAP) genes (also part of the MHC) in homosexual seroconverters to human immunodeficiency virus type 1 (HIV-1). Comprehensive statistical analysis produced an HLA profile that predicted time from HIV-1 infection to the onset of AIDS. The profile was developed in a cohort of 139 men and evaluated in a second unrelated cohort of 102 men. In the evaluation cohort, the profile discriminated a sixfold difference between groups with the shortest and longest times to AIDS (P = 0.001). These findings support current theory about control of antigen processing by HLA genes and have implications for immunopathogenesis of HIV-1 and other infections.
SourceAvailable from: María Eugenia Socías[Show abstract] [Hide abstract]
ABSTRACT: Variants in HIV-coreceptor C-C chemokine receptor type 5 (CCR5) and Human leukocyte antigen (HLA) genes are the most important host genetic factors associated with HIV infection and disease progression. Our aim was to analyze the association of these genetic factors in the presence of clinical symptoms during Primary HIV Infection (PHI) and disease progression within the first year. Seventy subjects diagnosed during PHI were studied (55 symptomatic and 15 asymptomatic). Viral load (VL) and CD4 T-cell count were evaluated. HIV progression was defined by presence of B or C events and/or CD4 T-cell counts <350 cell/mm3. CCR5 haplotypes were characterized by polymerase chain reaction and SDM-PCR-RFLP. HLA-I characterization was performed by Sequencing. Symptoms during PHI were significantly associated with lower frequency of CCR5-CF1 (1.8% vs. 26.7%, p = 0.006). Rapid progression was significantly associated with higher frequency of CCR5-CF2 (16.7% vs. 0%, p = 0.024) and HLA-A*11 (16.7% vs. 1.2%, p = 0.003) and lower frequency of HLA-C*3 (2.8% vs. 17.5%, p = 0.035). Higher baseline VL was significantly associated with presence of HLA-A*11, HLA-A*24, and absence of HLA-A*31 and HLA-B*57. Higher 6-month VL was significantly associated with presence of CCR5-HHE, HLA-A*24, HLA-B*53, and absence of HLA-A*31 and CCR5-CF1. Lower baseline CD4 T-cell count was significantly associated with presence of HLA-A*24/*33, HLA-B*53, CCR5-CF2 and absence of HLA-A*01/*23 and CCR5-HHA. Lower 6-month CD4 T-cell count was associated with presence of HLA-A*24 and HLA-B*53, and absence of HLA-A*01 and HLA-B*07/*39. Moreover, lower 12-month CD4 T-cell count was significantly associated with presence of HLA-A*33, HLA-B*14, HLA-C*08, CCR5-CF2, and absence of HLA-B*07 and HLA-C*07. Several host factors were significantly associated with disease progression in PHI subjects. Most results agree with previous studies performed in other groups. However, some genetic factor associations are being described for the first time, highlighting the importance of genetic studies at a local level.PLoS ONE 11/2014; 9(11):e113146. DOI:10.1371/journal.pone.0113146 · 3.53 Impact Factor
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ABSTRACT: We quantified the collective impact of source partner HIV-1 RNA levels, human leukocyte antigen (HLA) alleles, and innate responses through toll-like receptor (TLR) alleles on HIV-1 set-point. Data came from HIV-1 seroconverters in African HIV-1 serodiscordant couple cohorts. Linear regression was used to determine associations with set-point and R(2) to estimate variation explained by covariates. The strongest predictors of set-point were HLA alleles (B*53:01, B*14:01, and B*27:03) and plasma HIV-1 levels of the transmitting partner, which explained 13% and 10% of variation in set-point, respectively. HLA-A concordance between partners and TLR polymorphisms (TLR2-rs3804100, TLR7-rs179012) were also associated with set-point, explaining 6% and 5% of variation, respectively. Overall, these factors and genital factors of the transmitter (i.e. male circumcision, bacterial vaginosis and use of acyclovir) explained 46% of variation in set-point. We found that both innate and adaptive immune responses, together with plasma HIV-1 levels of the transmitting partner, explain almost half of the variation in viral load set-point. After HIV-1 infection, uncontrolled virus replication leads to a rapid increase in HIV-1 concentrations. Once host immune responses develop, however, HIV-1 levels reach a peak and subsequently decline until they reach a stable level that may persist for years. This stable HIV-1 set-point represents an equilibrium between the virus and host responses, and is predictive of later disease progression and transmission potential. Understanding how host and virus factors interact to determine HIV-1 set-point may elucidate novel mechanisms or biological pathways for treating HIV-1 infection. We identified host and virus factors that predict HIV-1 set-point in people who recently acquired HIV-1, finding that both innate and adaptive immune responses, along with factors that likely influence HIV-1 virulence and inoculum, explain ∼46% of the variation in HIV-1 set-point. Copyright © 2014, American Society for Microbiology. All Rights Reserved.Journal of Virology 12/2014; DOI:10.1128/JVI.01573-14 · 4.65 Impact Factor
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ABSTRACT: Whole-genome sequencing of Mauritian cynomolgus macaques reveals novel candidate loci for controlling simian immunodeficiency virus replication.Genome Biology 11/2014; 15(11):507. DOI:10.1186/s13059-014-0507-y · 10.47 Impact Factor