Two HIV-1 subtype C subclusters have been identified in Ethiopia (C and C′) with little knowledge regarding their biological or clinical differences. We longitudinally monitored HIV-1 viral loads and CD4+ T cell counts for 130 subtype C-infected individuals from Ethiopia over 5 years. The genetic subclusters C and C′ were determined and comparisons were made between the groups. None of the study individuals received antiretroviral therapy. Subcluster C′ was found to be the more prevalent (72.3%) genotype circulating. Individuals infected with subcluster C′ harbored higher viral loads in comparison to subcluster C-infected individuals when the CD4+ T cell counts were high (500–900 cells/mm3), whereas at low CD4+ T cell counts (0–150 cells/mm3) individuals infected with subcluster C viruses showed higher viral loads. We identified a greater number of deaths among individuals infected with subcluster C viruses in comparison to C′. Our results indicate that infection with subcluster C viruses leads to a more rapid onset of disease, despite the initial lower HIV-1 RNA plasma loads. Additionally, the higher viral loads seen for HIV-1 subcluster C′ infections at higher CD4+ T cell counts can help explain the higher prevalence of this subtype in Ethiopia.
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