We previously reported finding the RNA of a particle-coding human endogenous retrovirus type K, HERV-K (HML-2), in the plasma of HIV-1 patients. We found that the HERV-K (HML-2) RNA was contained in HERV-K viral particles as observed by immunoelectron microscopy. Surprisingly, a novel HERV-K (HML-2) provirus was discovered, termed K111, which seems to be transcriptionally active exclusively during HIV infection. Using real time RT-PCR specific for the K111 env sequence, we corroborate the detection of K111 RNA in plasma of HIV patients and not in breast cancer or lymphoma patients. K111 RNA was also found in the supernatants of cultured cell lines and PBMCs infected with R5 and X4 HIV strains. A K111 counterpart was found to be present in Chimpanzees. The human K111 provirus was fully amplified and sequenced. K111 proviruses were detected in all human DNA samples tested (140 individuals and 10 cell lines) and may produce only the Np9 oncoprotein. K111 is polymorphic in humans, represented by a minimum of at least 6 copies in each individual. K111 soloLTRs can also be found in the centromeric region. All these variants are integrated into tandemly repetitive D22Z3 sequences, which have been found uniquely in the centromere of the chromosome 22. The existence of more than one centromeric full-length K111 in every single patient and a balanced number of synonymous and non-synonymous mutations in their RNA sequences indicates that K111 has been expanded, possibly by homologous recombination. The degree of variability in the different K111 forms is only appreciated in HIV infected patients, where these proviruses are transcriptionally active. Furthermore, the discovery of the first centromeric HERV-K (HML-2) described so far might have only been possible due to a unique effect of HIV on chromatin remodeling of the centromere of chromosome 22, exposing K111 to active transcription.