High-Sequence Diversity and Rapid Virus Turnover Contribute to Higher Rates of Coreceptor Switching in Treatment-Experienced Subjects with HIV-1 Viremia

Abstract

Coreceptor switching from CCR5 to CXCR4 is common during chronic HIV-1 infection, but is even more common in individuals who have failed antiretroviral therapy (ART). Prior studies have suggested rapid mutation and/or recombination of HIV-1 envelope (env) genes during coreceptor switching. We compared the functional and genotypic changes in env of viruses from viremic subjects who had failed ART just before and after coreceptor switching and compared those to viruses from matched subjects without coreceptor switching. Analysis of multiple unique functional env clones from each subject revealed extensive diversity at both sample time points and rapid diversification of sequences during the 4-month interval in viruses from both 9 subjects with coreceptor switching and 15 control subjects. Only two subjects had envs with evidence of recombination. Three findings distinguished env clones from subjects with coreceptor switching from controls: (1) lower entry efficiency via CCR5; (2) longer V1/V2 regions; and (3), lower nadir CD4 T cell counts during prior years of infection. Most of these subjects harbored virus with lower replicative capacity associated with protease (PR) and/or reverse transcriptase inhibitor resistance mutations, and the extensive diversification tended to lead either to improved entry efficiency via CCR5 or the gain of entry function via CXCR4. These results suggest that R5X4 or X4 variants emerge from a diverse, low-fitness landscape shaped by chronic infection, multiple ART resistance mutations, the availability of target cells, and reduced entry efficiency via CCR5.

HIV tropism switch in archived DNA of HIV-HCV subjects successfully treated with direct-acting antivirals for HCV infection

“…We hypothesize that reshaping of naive and central memory CD4+ T cells harboring X4 species could be involved; CXCR4-using HIV strains predominate in these cells and there is a negative correlation between HCV RNA level and CD4 central memory frequency in HIV-HCV patients, who had a lower number of naive CD4+ cells with respect to HIV mono-infected subjects 26 – 28 . However, we cannot exclude the involvement of mechanism other than HCV cure, as heterozygosis for the CCR5D32 29 , 30 .…”

Korean Red Ginseng slows coreceptor switch in HIV-1 infected patients

“…X4 viruses have been shown to evolve from pre-existing R5 viral populations, with coreceptor switching being associated with high replication rates, but not selective pressure [ 3 ]. This coreceptor switching is more frequent in patients who have failed antiretroviral therapy (ART) [ 4 ], with immune activation correlating with X4 tropism [ 5 ]. A simulation study of a stochastic model showed that coreceptor switching occurs from 6 to more than 27 years after infection [ 6 ].…”