HIV Type 1 Disease Progression to AIDS and Death in a Rural Ugandan Cohort Is Primarily Dependent on Viral Load Despite Variable Subtype and T-Cell Immune Activation Levels

Abstract

Background: Untreated human immunodeficiency virus type 1 (HIV) infection is associated with persistent immune activation, which is an independent driver of disease progression in European and United States cohorts. In Uganda, HIV-1 subtypes A and D and recombinant AD viruses predominate and exhibit differential rates of disease progression.

Methods: HIV-1 seroconverters (n = 156) from rural Uganda were evaluated to assess the effects of T-cell activation, viral load, and viral subtype on disease progression during clinical follow-up.

Results: The frequency of activated T cells was increased in HIV-1-infected Ugandans, compared with community matched uninfected individuals, but did not differ significantly between viral subtypes. Higher HIV-1 load, subtype D, older age, and high T-cell activation levels were associated with faster disease progression to AIDS or death. In a multivariate Cox regression analysis, HIV-1 load was the strongest predictor of progression, with subtype also contributing. T-cell activation did not emerge an independent predictor of disease progression from this particular cohort.

Conclusions: These findings suggest that the independent contribution of T-cell activation on morbidity and mortality observed in European and North American cohorts may not be directly translated to the HIV epidemic in East Africa. In this setting, HIV-1 load appears to be the primary determinant of disease progression.

Keywords: AIDS; HIV-1; PD-1; immune activation; subtype D; viral load.

Figure 1.

Characterization of immune activation and relationship to human immunodeficiency virus type 1 (HIV-1) load. Phenotypic markers of immune activation were enumerated from cryopreserved peripheral blood mononuclear cells, using flow cytometry. Lymphocytes were identified on the basis of size and granularity scatter profiles. A, Pseudo-color histogram of CD3-PerCP expression in combination with CD4-FITC identified helper T cells on a representative HIV-infected donor. CD38-PE and HLA-DR-APC, associated with activated phenotypes, or CD38-PE and CD279-APC, corresponding to activated T cells with potentially impaired function, were calculated. B and C, Relationship to HIV-1 load was determined for CD38-PE and HLA-DR-APC (B) and CD38-PE and CD279-APC (C), where positive Spearman correlations were observed. D, Pseudo-color histogram of cytotoxic T cells identified from CD3-PerCP expression in combination with CD8-FITC from a representative HIV-1–infected donor. CD38 and HLA-DR or CD279 in combination were evaluated. E and F, CD38-PE and HLA-DR-APC (E) and CD38-PE and CD279-APC (F) showed a positive relationship to HIV-1 load using a spearman correlation.

Figure 2.

Kaplan–Meier estimates to AIDS or death by T-cell activation, human immunodeficiency virus type 1 (HIV-1) subtype, or viral load. Kaplan–Meier estimates are presented, comparing the time to AIDS, as defined by CD4 T-cell counts of <250 cells/µL of whole blood, or the time to death for T-cell activation, HIV-1 subtype, and viral load. A and B, Individuals were stratified into quartiles on the basis of the percentage of CD8 T cells coexpressing CD38 and HLA-DR from lowest frequency (first quartile; blue) to the highest frequency (fourth quartile; brown) for time to AIDS (A) or time to death (B). C and D, Kaplan–Meier estimates for HIV-1 subtype A (blue), recombinant/dual infections (red), and subtype D (green) are displayed for time to AIDS (C) or time to death (D). E and F, Individuals were stratified into quartiles on the basis of HIV-1 load from lowest frequency (first quartile; blue) to highest frequency (fourth quartile; brown) for time to AIDS (E) or time to death (F). All P values were calculated with the log-rank test.