Moreover, to trace back the epidemiological history of this virus, env gene sequences were obtained from 62 patients infected in Portugal between 1993 and 1998. Finally, to gain some insight into the selective forces promoting CXCR4 usage by isolates belonging to this CRF, we have used genetic methods to determine the tropism of a significant number of recent MK-4827 1038915-60-4 Portuguese isolates and phylogenetic methods to investigate positive selection in the V3 region. Our results indicate that CRF14_BG originated in Portugal in the beginning of the HIV-1 epidemics. From here, it probably spread to Galiza, Spain, in late 1990 s and to other countries in Europe in early 2000. Our results confirm that the CXCR4 tropism is a general and stable feature of CRF14_BG and suggest that this phenotype might be a consequence of successful escape from neutralizing antibody response. The early presence of CRF14_BG in these transmission groups implies that it was rapidly converted into a highly successful epidemic strain. CRF14_BG was found in Galiza, Spain, in 2002 among HIV-1 infected IVDU patients of Spanish and Portuguese origin. Between 1999 and 2007 CRF14_BG-like strains were found abundantly in Portugal, Spain and other European countries. In Portugal, in 2003, CRF14_BG prevailed over all other recombinants. Since then, however, CRF14_BG prevalence decreased significantly in Portugal and Spain and, to our knowledge, it has not been reported elsewhere in the world. One reason for this decrease in prevalence of CRF14_BG might be related with its high tendency for recombination with other subtypes or recombinant forms. This is suggested by the multiple CRF14_BG-like subgenomic fragments that have been described in the recent literature and by the existence of at least three other BG intersubtype CRFs. Alternatively, CRF14_BG prevalence may have decreased due to its unusually high pathogenicity. We show here that most CRF14_BG isolates circulating in Portugal form a single cluster and use the CXCR4 co-receptor. The majority of CRF14_BG isolates from Spain also use CXCR4, even those obtained from patients at early stages of infection. In subtype B infected subjects, baseline infection with a CXCR4-using virus is strongly associated with a greater decrease in CD4+ T cell count over time and a greater risk of disease progression. Consistent with this, a rapid decrease in CD4+ T cell counts has been observed in all patients infected with CRF14_BG isolates. Moreover, we have shown recently that CRF14_BG infected patients can progress very quickly to AIDS and death. Taken together, these results provide strong argument to suggest that, like HIV-1 subtype D, CRF14_BG may be highly pathogenic. We show that positive selection acts differently in the V3 loop of CRF14_BG isolates compared to B isolates. In fact, between 0–1 amino acids are under selective pressure in CRF14_BG V3 loop whereas in subtype B these are 4–5. Of particular interest in this context was the finding that amino acid 11 in the V3 loop, which is a main determinant of co-receptor usage, was not under selective pressure in the CRF14_BG cluster of viruses.