Human immunodeficiency virus type 1 subtype C: Molecular characterization and development of an animal model

Human immunodeficiency virus type 1 (HIV-1) subtype C accounts for more than 50% of all infections in the HIV/AIDS pandemic. HIV-1 subtype C is the predominant subtype in the rapidly growing epidemics of southern Africa and South East Asia. Several epidemiological studies suggest that HIV-1 subtype C may be more rapidly expanding and has greater pathogenic potential than other subtypes. Viral genetic determinants that may explain these epidemiological observations are poorly understood. We previously found evidence for subtype-specific genetic differences between subtypes B, C, and E in the long terminal repeats (LTRs). We now show that HIV-1 subtype C may have an increased responsiveness to the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-α). We carried out phylogenetic and other sequence analyses of full-length genetic clones of HIV-1 subtype C from Botswana and observed a higher level of diversity across the entire genome when compared with subtype C genomes from India or subtype B sequences. We have also generated and biologically characterized several non-infectious full-length HIV-1 subtype C clones. Analysis of four of the clones suggested defective envelope glycoprotein processing. Complementation of two of these clones with a functional envelope clone rendered them infectious. We have constructed MJ4, the first infectious molecular clone of HIV-1 subtype C from Africa. In order to establish an animal model for disease pathogenesis and immune responses to this subtype, we have constructed a simian-human immunodeficiency virus chimera (SHIV_MJ4) that bears genomic fragments of HIV-1 subtype C env, tat, and rev. In vitro and in vivo data demonstrate that SHIV_MJ4 is infectious in rhesus macaques. The SHIV_MJ4/rhesus model may facilitate studies of disease pathogenesis, immune responses, and vaccine evaluation for HIV-1 subtype C.; We have developed important reagents that may facilitate studies of determinants of pathogenicity for HIV-1 subtype C and may be useful for the development and evaluation of potential vaccines and therapeutic agents against HIV-1 subtype C.