Rapid HIV disease progression following superinfection in an HLA-B*27:05/B*57:01-positive transmission recipient.

BACKGROUND: The factors determining differential HIV disease outcome among individuals expressing protective HLA alleles such as HLA-B*27:05 and HLA-B*57:01 remain unknown. We here analyse two HIV-infected subjects expressing both HLA-B*27:05 and HLA-B*57:01. One subject maintained low-to-undetectable viral loads for more than a decade of follow up. The other progressed to AIDS in < 3 years. RESULTS: The rapid progressor was the recipient within a known transmission pair, enabling virus sequences to be tracked from transmission. Progression was associated with a 12% Gag sequence change and 26% Nef sequence change at the amino acid level within 2 years. Although next generation sequencing from early timepoints indicated that multiple CD8+ cytotoxic T lymphocyte (CTL) escape mutants were being selected prior to superinfection, < 4% of the amino acid changes arising from superinfection could be ascribed to CTL escape. Analysis of an HLA-B*27:05/B*57:01 non-progressor, in contrast, demonstrated minimal virus sequence diversification (1.1% Gag amino acid sequence change over 10 years), and dominant HIV-specific CTL responses previously shown to be effective in control of viraemia were maintained. Clonal sequencing demonstrated that escape variants were generated within the non-progressor, but in many cases were not selected. In the rapid progressor, progression occurred despite substantial reductions in viral replicative capacity (VRC), and non-progression in the elite controller despite relatively high VRC. CONCLUSIONS: These data are consistent with previous studies demonstrating rapid progression in association with superinfection and that rapid disease progression can occur despite the relatively the low VRC that is typically observed in the setting of multiple CTL escape mutants

Sex Differences in Antiretroviral Therapy Initiation in Pediatric HIV Infection

The incidence and severity of infections in childhood is typically greater in males. The basis for these observed sex differences is not well understood, and potentially may facilitate novel approaches to reducing disease from a range of conditions. We here investigated sex differences in HIV-infected children in relation to antiretroviral therapy (ART) initiation and post-treatment outcome. In a South African cohort of 2,101 HIV-infected children, we observed that absolute CD4+ count and CD4% were significantly higher in ART-naïve female, compared to age-matched male, HIV-infected children. Absolute CD4 count and CD4% were also significantly higher in HIV-uninfected female versus male neonates. We next showed that significantly more male than female children were initiated on ART (47% female); and children not meeting criteria to start ART by >5yrs were more frequently female (59%; p<0.001). Among ART-treated children, immune reconstitution of CD4 T-cells was more rapid and more complete in female children, even after adjustment for pre-ART absolute CD4 count or CD4% (p=0.011, p=0.030, respectively). However, while ART was initiated as a result of meeting CD4 criteria less often in females (45%), ART initiation as a result of clinical disease in children whose CD4 counts were above treatment thresholds occurred more often in females (57%, p<0.001). The main sex difference in morbidity observed in children initiating ART above CD4 thresholds, above that of TB disease, was as a result of wasting and stunting observed in females with above-threshold CD4 counts (p=0.002). These findings suggest the possibility that optimal treatment of HIV-infected children might incorporate differential CD4 treatment thresholds for ART initiation according to sex

Rapid HIV disease progression following superinfection in an HLA-B*27:05/B*57:01-positive transmission recipient.

BACKGROUND: The factors determining differential HIV disease outcome among individuals expressing protective HLA alleles such as HLA-B*27:05 and HLA-B*57:01 remain unknown. We here analyse two HIV-infected subjects expressing both HLA-B*27:05 and HLA-B*57:01. One subject maintained low-to-undetectable viral loads for more than a decade of follow up. The other progressed to AIDS in < 3 years. RESULTS: The rapid progressor was the recipient within a known transmission pair, enabling virus sequences to be tracked from transmission. Progression was associated with a 12% Gag sequence change and 26% Nef sequence change at the amino acid level within 2 years. Although next generation sequencing from early timepoints indicated that multiple CD8+ cytotoxic T lymphocyte (CTL) escape mutants were being selected prior to superinfection, < 4% of the amino acid changes arising from superinfection could be ascribed to CTL escape. Analysis of an HLA-B*27:05/B*57:01 non-progressor, in contrast, demonstrated minimal virus sequence diversification (1.1% Gag amino acid sequence change over 10 years), and dominant HIV-specific CTL responses previously shown to be effective in control of viraemia were maintained. Clonal sequencing demonstrated that escape variants were generated within the non-progressor, but in many cases were not selected. In the rapid progressor, progression occurred despite substantial reductions in viral replicative capacity (VRC), and non-progression in the elite controller despite relatively high VRC. CONCLUSIONS: These data are consistent with previous studies demonstrating rapid progression in association with superinfection and that rapid disease progression can occur despite the relatively the low VRC that is typically observed in the setting of multiple CTL escape mutants

Sex differences in CD4+ T cell count, CD4% and viral load, amongst 2,101 ART-naïve South African children.

<p>A. Absolute CD4 counts changes with age. B. CD4% changes with age. C. Viral load changes with age. In each panel, the solid lines are Loess-smoothed regression lines for female children and the dotted lines are Loess-smoothed regression lines for male children. A multivariable linear regression model, with both sex and age as covariates, shows significantly lower absolute CD4 counts in males (p = 0.005); significantly lower CD4% in males (p = 3.7x10^-7); and no significant difference in viral load between the sexes.</p

Indications for ART Initiation in 222 children whose CD4 counts were above CD4 treatment thresholds.

<p>^a Not within the guidelines for ART initiation in children</p><p>Indications for ART Initiation in 222 children whose CD4 counts were above CD4 treatment thresholds.</p

Study cohorts of HIV-infected South African children analyzed.

<p>Study cohorts of HIV-infected South African children analyzed.</p

Multivariate analysis of sex differences in CD4+ T cell recovery after initiating ART.

<p>^a HR: Hazard ratio</p><p>^b 95% confidential interval range</p><p>^c aHR: adjusted hazard ratio</p><p>Multivariate analysis of sex differences in CD4+ T cell recovery after initiating ART.</p

Absolute CD4 count, CD4% and viral load in HIV-infected children and HIV-uninfected neonates.

<p>^<b>a</b> Mann Whitney test</p><p><u>HIV-Infected Children, n = 2,101</u>.</p