HIV-1 subtype C: ecological fitness for efficient spread?

HIV-1 subtype C accounts for nearly half of global HIV infections and dominates in southern Africa, India, and parts of Asia. The global distribution and burden of subtype C may reflect founder effects, population size and structure, migration, transmission networks, epidemic history, and access to prevention and treatment, as well as efficient transmission fitness. The epidemiological success of clade C viruses seems at odds with conventional measurements of viral fitness. Several studies have reported that subtype C isolates exhibit reduced replication capacity compared to other clades of HIV-1 in activated peripheral blood mononuclear cells and blood-derived macrophages. These observations indicate that standard laboratory assays may not adequately capture the determinants of viral success in human populations. Here, we discuss the evidence that HIV-1 fitness may be ecological and dependent on the various changing cellular, anatomical, immunological, and epidemiological environments encountered during transmission and infection. Several characteristics of HIV-1 subtype C, including persistent CCR5 usage, CpG content, LTR promoter architecture, Tat function, and ongoing changes in regulatory and budding motifs, may influence transmission, replication, persistence, disease progression, and viral loads across distinct environments. Rather than representing a uniformly more or less fit lineage, subtype C may provide a model for understanding how ongoing adaptation to changing host environments may shape viral fitness and pandemic spread.