e Mycoplasma genitalium causes persistent urogenital tract infection in humans. Antigenic variation of the protein encoded by the MG192 gene has been proposed as one of the mechanisms for persistence. The aims of this study were to determine MG192 sequence variation in patients with chronic M. genitalium infection and to analyze the sequence structural features of the MG192 gene and its encoded protein. Urogenital specimens were obtained from 13 patients who were followed for 10 days to 14 months. The variable region of the MG192 gene was PCR amplified, subcloned into plasmids, and sequenced. Sequence analysis of 220 plasmid clones yielded 97 unique MG192 variant sequences. MG192 sequence shift was identified between sequential specimens from all but one patient. Despite great variation of the MG192 gene among and within clinical specimens from different patients, MG192 sequences were more related within M. genitalium specimens from an individual patient than between patients. The MG192 variable region consisted of 11 discrete subvariable regions with different degrees of variability. Analysis of the two most variable regions (V4 and V6) in five sequential specimens from one patient showed that sequence changes increased over time and that most sequences were present at only one time point, suggesting immune selection. Topology analysis of the deduced MG192 protein predicted a surface-exposed membrane protein. Extensive variation of the MG192 sequence may not only change the antigenicity of the protein to allow immune evasion but also alter the mobility and adhesion ability of the organism to adapt to diverse host microenvironments, thus facilitating persistent infection.A s a sexually transmitted human pathogen, Mycoplasma genitalium causes nongonococcal urethritis (NGU) in men and is associated with genital tract inflammatory diseases in women, including endometritis, cervicitis, pelvic inflammatory disease, and tubal factor infertility (reviewed in reference 1). Additionally, there are increasing numbers of studies suggesting that M. genitalium increases the risk of HIV-1 acquisition and/or transmission (2-4). Like other pathogenic mycoplasmas, M. genitalium is capable of causing chronic infections, as has been documented in cultured human endocervical epithelial cells (5), in animal models (6, 7), in men with NGU (8, 9), and in women with cervicitis (10). The mechanisms for persistence remain poorly understood.The MgPa operon in the M. genitalium genome encodes three proteins, MG190 (mgpA), MG191 (mgpB or P140), and MG192 (mgpC or P110). The latter two are the known major adhesion proteins located on the surface of the terminal structure of M. genitalium, which plays a major role in the attachment of the organism to host epithelial cells (11,12). Both proteins are highly antigenic and capable of eliciting strong antibody responses in M. genitalium-infected patients and experimentally infected animals (6,(12)(13)(14), suggesting an important role in pathogenesis. According to the genome sequence of M. genital...