PATHOGENESIS Differences in HIV Type 1 RNA Plasma Load Profile of Closely Related Cocirculating Ethiopian Subtype C Strains: C and C 0 Workenesh Ayele, 1 Yared Mekonnen, 1 Tsehaynesh Messele, 1 Yohannes Mengistu, 2 Aster Tsegaye, 1 Margreet Bakker, 3 Ben Berkhout, 3 Wendelien Dorigo-Zetsma, 4 Dawit Wolday, 1 Jaap Goudsmit, 5 Roel Coutinho, 6 Michel de Baar, 7 William A. Paxton, 3 and Georgios Pollakis 3 Abstract Two HIV-1 subtype C subclusters have been identified in Ethiopia (C and C 0 ) with little knowledge regarding their biological or clinical differences. We longitudinally monitored HIV-1 viral loads and CD4 þ T cell counts for 130 subtype C-infected individuals from Ethiopia over 5 years. The genetic subclusters C and C 0 were deter- mined and comparisons were made between the groups. None of the study individuals received antiretroviral therapy. Subcluster C 0 was found to be the more prevalent (72.3%) genotype circulating. Individuals infected with subcluster C 0 harbored higher viral loads in comparison to subcluster C-infected individuals when the CD4 þ T cell counts were high (500–900 cells/mm 3 ), whereas at low CD4 þ T cell counts (0–150 cells/mm 3 ) 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 0 . 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 0 infections at higher CD4 þ T cell counts can help explain the higher prevalence of this subtype in Ethiopia. Introduction I nfection with HIV-1 leads to a large variation in disease course and rates of clinical progression. Many different HIV-1 subtypes circulate worldwide (including A, B, C, D, and F) as well as their circulating recombinant forms (CRFs). 1 Sub- type C HIV-1 is a paradox since it has been shown to be spreading rapidly in southern Africa, Ethiopia, and India and currently accounts for over 50% of HIV-1 cases worldwide. 2 Meanwhile, extensive research has shown a lack of replication fitness when comparing this subtype to others. 3,4 Understanding differences between the variant subtypes with regard to rates of disease progression may have implications for the treatment of HIV-1-infected individuals in different regions of the world. The markers most associated with disease progression have been viral setpoint (following the period of acute infection), CD4 cell counts, and rates of CD4 cell decline, with higher viral loads and steeper slopes being associated with faster progression. 5,6 The activation state of the immune system was also shown to be associated with disease progression, 7 which is pertinent for regions of the world in which coinfection with an array of different pathogens is common. When comparing infection with the variant subtypes some differences have been observed in the disease course, for example, infection with subtype A viruses provides for slower progression in comparison to other subtypes, 8 infection with CRF-01_AE has been associated with higher viral loads among injecting drug users (IDUs) in comparison to subtype B-infected IDUs in The Netherlands, 9 and infection with subtype B viruses in The Netherlands was associated with faster rates of CD4 þ T cell decline than rates found in individuals infected with subtype C viruses in Ethiopia. 10 There is cumulating evidence that 1 Ethiopian Health and Nutrition Research Institute (EHNRI), Addis Ababa, Ethiopia. 2 Department of Microbiology, Immunology and Parasitology, Faculty of Medicine, Addis Ababa University, Addis Ababa, Ethiopia. 3 Laboratory of Experimental Virology (LEV), Department of Medical Microbiology–Center for Infection and Immunity Amsterdam (CINIMA), Academic Medical Center of the University of Amsterdam, Amsterdam, The Netherlands. 4 Regional Microbiological and Serological Laboratory, Hospital Hilversum, Hilversum, The Netherlands. 5 Crucell Holland B.V., Leiden, The Netherlands. 6 Rijksinstituut voor Volksgezondheid en Milieu (RIVM), 3721 MA Bilthoven, The Netherlands. 7 Primagen, Amsterdam, The Netherlands. AIDS RESEARCH AND HUMAN RETROVIRUSES Volume 26, Number 7, 2010 ª Mary Ann Liebert, Inc. DOI: 10.1089/aid.2009.0152 805