Table 1.
HLA alleles associated with significant protection from CD4+ T cell decline.
Fig 1.
Multiplicities of protective HLA alleles and their additive effects on CD4+ T cell decline and set point viral loads.
HLA-B*1401, B*57, B*5801, B*81, HLA-DQB1*02, and HLA-DRB1*15 were defined as CD4-protective in this cohort. (A) Kaplan-Meier survival curves, with an endpoint defined as CD4 counts < 300/μl, demonstrating the effect of carriage of increasing numbers of protective HLA alleles on CD4+ T cell decline. P-values represent significantly different decline trajectories between adjacent groups and were generated from a Cox proportional hazards model. (B) Mean set point viral loads between individuals carrying increasing numbers of protective HLA alleles.
Fig 2.
Protective HLA class I, but not HLA class II, alleles are associated with reduced levels of circulating lipopolysaccharide early after HIV infection.
Lipopolysaccharide (LPS) levels were measured in the plasma for 124 seroconvertors a median of 44 days after the estimated date of infection. (A and B) The levels of LPS in the plasma were compared between individuals carrying any of the defined protective HLA class I (panel A) or HLA class II alleles (panel B). Statistical comparisons were made using the Student’s t test (A and C) or an ANOVA (B) and reported p-values are one-tailed. (C) Comparison of viral load at the time of LPS measurement between individuals with or without protective HLA class I alleles. (D) A graphical depiction of a generalized linear model showing the relative associations between both plasma viral load and the presence of protective HLA class I alleles with LPS levels measured in the plasma. The distance between horizontal lines represent the difference in means between individuals with (light blue) and without (gray) protective HLA class I alleles whereas the direction of the lines represents regression between the two continuous variables: viral load (x-axis) and LPS in the plasma (y-axis).
Fig 3.
Associations between protective HLA-I alleles and markers of gut damage and microbial translocation at 6 months post HIV infection.
(A–C) Comparison of levels of lipopolysaccharide, soluble CD14, and intestinal fatty acid binding protein (I-FABP) measured at 6 months post HIV infection between those with and without protective HLA-I alleles for a subset of the cohort (n = 30). Statistical comparisons were made using the Student’s t test and reported p-values are one-tailed. (D) Changes in IL-10 levels as measured in the plasma from seroconversion (mean of 44 days post infection) to 6 months post infection between individuals with (light blue) and without (gray) protective HLA-I alleles. Statistical comparison was made using a multivariate analysis of variance (MANOVA). Bars represent the standard error of the mean.
Fig 4.
Circulating LPS levels measured during acute infection are associated with longitudinal CD4+ T cell decline.
A Kaplan-Meier survival analysis comparing CD4+ T cell decline between individuals with LPS levels above or below the median for the cohort (n = 124). Thirteen individuals with CD4-protective HLA class I alleles were contained in the >50% LPS group, and 21 in the <50% LPS group. Statistics were generated from the log-rank test.
Fig 5.
The levels of circulating LPS at seroconversion predict levels of cellular immune activation in the T cell compartment at 3 months post infection.
Cryopreserved PBMCs isolated 3 months (mean of 97 days) post infection were stained for markers of immune activation, exhaustion, and cellular turnover as well as for the delineation of memory subsets in CD4 and CD8 T cells for a subset of the cohort for whom cryopreserved PBMCs were available (n = 19). Five of these 19 individuals carried CD4-protective HLA class I alleles. (A–B) Direct associations between LPS levels and the percentage of PD-1+ cells in central memory (CD45RO+/CCR7+) and effector memory (CD45RO+/CCR7-) CD4+ T cells. (C–E) Direct associations between LPS levels and markers of activation (CD38+/HLA-DR+, CD38 MFI) and turnover (Ki67+) in CD8+ T cells. Correlation statistics were generated using linear regression. Solid lines indicate trend lines and dashed lines represent 95% confidence bands.
Fig 6.
Individuals with CD4-protective HLA class I alleles more efficiently target conserved regions of Gag.
(A) A graphical depiction of a generalized linear model showing the relative association between the presence of CD4-protective HLA class I alleles with IFNγ ELISpot responses to Gag PTE peptide pools from cryopreserved PBMCs collected a median of 45 days post infection. A correction factor for transmitted Gag sequence similarity to the PTE peptide pools was added as a covariate. The distance between horizontal lines represent the difference in means between individuals with (light blue, n = 6) and without (gray, n = 27) protective HLA class I alleles whereas the direction of the lines represents regression between the two continuous variables: Gag sequence similarity to peptide pools (x-axis) and IFNγ ELISpot responses reported as spot forming units per million PBMCs (y-axis). (B) Cryopreserved PBMCs collected at one-year post infection (median 339 days post infection) were interrogated with peptide pools containing 300 clade C consensus 10-mer PTE Gag peptides, with subsequent deconvolution to identify single peptide responses. The number of individual Gag peptide responses for individuals with (blue bar, n = 6) and without (gray bar, n = 12) CD4-protective HLA class I alleles are depicted. (C) A graphical depiction of a generalized linear model showing the relative association between the presence of CD4-protective HLA class I alleles with IFNγ ELISpot responses to Gag HIVconsv peptides [51] from cryopreserved PBMCs collected a median of 45 days post infection. A correction factor for transmitted Gag sequence similarity to the 3 Gag regions covered by the 31 HIVconsv Gag peptides was added as a covariate. The distance between horizontal lines represent the difference in means between individuals with (light blue, n = 6) and without (gray, n = 27) protective HLA class I alleles whereas the direction of the lines represents regression between the two continuous variables: Gag sequence similarity to HIVconsv Gag peptides (x-axis) and IFNγ ELISpot responses reported as spot forming units per million PBMCs (y-axis).